@article {805, title = {Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches.}, journal = {Front Immunol}, volume = {14}, year = {2024}, month = {2023}, pages = {1282859}, abstract = {

INTRODUCTION: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing.

METHODS: Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors.

RESULTS: Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19.

DISCUSSION: The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies.

}, keywords = {Computer Simulation, COVID-19, drug repositioning, Humans, SARS-CoV-2, Systems biology}, issn = {1664-3224}, doi = {10.3389/fimmu.2023.1282859}, author = {Niarakis, Anna and Ostaszewski, Marek and Mazein, Alexander and Kuperstein, Inna and Kutmon, Martina and Gillespie, Marc E and Funahashi, Akira and Acencio, Marcio Luis and Hemedan, Ahmed and Aichem, Michael and Klein, Karsten and Czauderna, Tobias and Burtscher, Felicia and Yamada, Takahiro G and Hiki, Yusuke and Hiroi, Noriko F and Hu, Finterly and Pham, Nhung and Ehrhart, Friederike and Willighagen, Egon L and Valdeolivas, Alberto and Dugourd, Aur{\'e}lien and Messina, Francesco and Esteban-Medina, Marina and Pe{\~n}a-Chilet, Maria and Rian, Kinza and Soliman, Sylvain and Aghamiri, Sara Sadat and Puniya, Bhanwar Lal and Naldi, Aur{\'e}lien and Helikar, Tom{\'a}{\v s} and Singh, Vidisha and Fern{\'a}ndez, Marco Fari{\~n}as and Bermudez, Viviam and Tsirvouli, Eirini and Montagud, Arnau and No{\"e}l, Vincent and Ponce-de-Leon, Miguel and Maier, Dieter and Bauch, Angela and Gyori, Benjamin M and Bachman, John A and Luna, Augustin and Pi{\~n}ero, Janet and Furlong, Laura I and Balaur, Irina and Rougny, Adrien and Jarosz, Yohan and Overall, Rupert W and Phair, Robert and Perfetto, Livia and Matthews, Lisa and Rex, Devasahayam Arokia Balaya and Orlic-Milacic, Marija and Gomez, Luis Cristobal Monraz and De Meulder, Bertrand and Ravel, Jean Marie and Jassal, Bijay and Satagopam, Venkata and Wu, Guanming and Golebiewski, Martin and Gawron, Piotr and Calzone, Laurence and Beckmann, Jacques S and Evelo, Chris T and D{\textquoteright}Eustachio, Peter and Schreiber, Falk and Saez-Rodriguez, Julio and Dopazo, Joaquin and Kuiper, Martin and Valencia, Alfonso and Wolkenhauer, Olaf and Kitano, Hiroaki and Barillot, Emmanuel and Auffray, Charles and Balling, Rudi and Schneider, Reinhard} } @book {798, title = {Cell-Level Pathway Scoring Comparison with~a~Biologically Constrained Variational Autoencoder}, series = {Lecture Notes in Computer Science. Computational Methods in Systems Biology}, volume = {14137}, year = {2023}, pages = {62 - 77}, publisher = {Springer Nature Switzerland}, organization = {Springer Nature Switzerland}, address = {Cham}, isbn = {978-3-031-42696-4}, issn = {0302-9743}, doi = {10.1007/978-3-031-42697-110.1007/978-3-031-42697-1_5}, url = {https://link.springer.com/chapter/10.1007/978-3-031-42697-1_5}, author = {Gundogdu, Pelin and Pay{\'a}-Milans, Miriam and Alamo-Alvarez, Inmaculada and Nepomuceno-Chamorro, Isabel A. and Dopazo, Joaquin and Loucera, Carlos} } @article {770, title = {A Comprehensive Analysis of 21 Actionable Pharmacogenes in the Spanish Population: From Genetic Characterisation to Clinical Impact.}, journal = {Pharmaceutics}, volume = {15}, year = {2023}, month = {2023 Apr 19}, abstract = {

The implementation of pharmacogenetics (PGx) is a main milestones of precision medicine nowadays in order to achieve safer and more effective therapies. Nevertheless, the implementation of PGx diagnostics is extremely slow and unequal worldwide, in part due to a lack of ethnic PGx information. We analysed genetic data from 3006 Spanish individuals obtained by different high-throughput (HT) techniques. Allele frequencies were determined in our population for the main 21 actionable PGx genes associated with therapeutical changes. We found that 98\% of the Spanish population harbours at least one allele associated with a therapeutical change and, thus, there would be a need for a therapeutical change in a mean of 3.31 of the 64 associated drugs. We also identified 326 putative deleterious variants that were not previously related with PGx in 18 out of the 21 main PGx genes evaluated and a total of 7122 putative deleterious variants for the 1045 PGx genes described. Additionally, we performed a comparison of the main HT diagnostic techniques, revealing that after whole genome sequencing, genotyping with the PGx HT array is the most suitable solution for PGx diagnostics. Finally, all this information was integrated in the Collaborative Spanish Variant Server to be available to and updated by the scientific community.

}, issn = {1999-4923}, doi = {10.3390/pharmaceutics15041286}, author = {N{\'u}{\~n}ez-Torres, Roc{\'\i}o and Pita, Guillermo and Pe{\~n}a-Chilet, Maria and L{\'o}pez-L{\'o}pez, Daniel and Zamora, Jorge and Rold{\'a}n, Gema and Herr{\'a}ez, Bel{\'e}n and Alvarez, Nuria and Alonso, Mar{\'\i}a Rosario and Dopazo, Joaquin and Gonz{\'a}lez-Neira, Anna} } @article {769, title = {A crowdsourcing database for the copy-number variation of the Spanish population.}, journal = {Hum Genomics}, volume = {17}, year = {2023}, month = {2023 Mar 09}, pages = {20}, abstract = {

BACKGROUND: Despite being a very common type of genetic variation, the distribution of copy-number variations (CNVs) in the population is still poorly understood. The knowledge of the genetic variability, especially at the level of the local population, is a critical factor for distinguishing pathogenic from non-pathogenic variation in the discovery of new disease variants.

RESULTS: Here, we present the SPAnish Copy Number Alterations Collaborative Server (SPACNACS), which currently contains copy number variation profiles obtained from more than 400 genomes and exomes of unrelated Spanish individuals. By means of a collaborative crowdsourcing effort whole genome and whole exome sequencing data, produced by local genomic projects and for other purposes, is continuously collected. Once checked both, the Spanish ancestry and the lack of kinship with other individuals in the SPACNACS, the CNVs are inferred for these sequences and they are used to populate the database. A web interface allows querying the database with different filters that include ICD10 upper categories. This allows discarding samples from the disease under study and obtaining pseudo-control CNV profiles from the local population. We also show here additional studies on the local impact of CNVs in some phenotypes and on pharmacogenomic variants. SPACNACS can be accessed at: http://csvs.clinbioinfosspa.es/spacnacs/ .

CONCLUSION: SPACNACS facilitates disease gene discovery by providing detailed information of the local variability of the population and exemplifies how to reuse genomic data produced for other purposes to build a local reference database.

}, issn = {1479-7364}, doi = {10.1186/s40246-023-00466-8}, author = {L{\'o}pez-L{\'o}pez, Daniel and Rold{\'a}n, Gema and Fernandez-Rueda, Jose L and Bostelmann, Gerrit and Carmona, Rosario and Aquino, Virginia and Perez-Florido, Javier and Ortuno, Francisco and Pita, Guillermo and N{\'u}{\~n}ez-Torres, Roc{\'\i}o and Gonz{\'a}lez-Neira, Anna and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin} } @article {766, title = {Detection of High Level of Co-Infection and the Emergence of Novel SARS CoV-2 Delta-Omicron and Omicron-Omicron Recombinants in the Epidemiological Surveillance of Andalusia.}, journal = {Int J Mol Sci}, volume = {24}, year = {2023}, month = {2023 Jan 26}, abstract = {

Recombination is an evolutionary strategy to quickly acquire new viral properties inherited from the parental lineages. The systematic survey of the SARS-CoV-2 genome sequences of the Andalusian genomic surveillance strategy has allowed the detection of an unexpectedly high number of co-infections, which constitute the ideal scenario for the emergence of new recombinants. Whole genome sequence of SARS-CoV-2 has been carried out as part of the genomic surveillance programme. Sample sources included the main hospitals in the Andalusia region. In addition to the increase of co-infections and known recombinants, three novel SARS-CoV-2 delta-omicron and omicron-omicron recombinant variants with two break points have been detected. Our observations document an epidemiological scenario in which co-infection and recombination are detected more frequently. Finally, we describe a family case in which co-infection is followed by the detection of a recombinant made from the two co-infecting variants. This increased number of recombinants raises the risk of emergence of recombinant variants with increased transmissibility and pathogenicity.

}, issn = {1422-0067}, doi = {10.3390/ijms24032419}, author = {Perez-Florido, Javier and Casimiro-Soriguer, Carlos S and Ortuno, Francisco and Fernandez-Rueda, Jose L and Aguado, Andrea and Lara, Mar{\'\i}a and Riazzo, Cristina and Rodriguez-Iglesias, Manuel A and Camacho-Martinez, Pedro and Merino-Diaz, Laura and Pupo-Ledo, Inmaculada and de Salazar, Adolfo and Vi{\~n}uela, Laura and Fuentes, Ana and Chueca, Natalia and Garc{\'\i}a, Federico and Dopazo, Joaquin and Lepe, Jose A} } @article {800, title = {Evidence of the association between increased use of direct oral anticoagulants and a reduction in the rate of atrial fibrillation-related stroke and major bleeding at the population level (2012-2019).}, journal = {Med Clin (Barc)}, year = {2023}, month = {2023 Nov 20}, abstract = {

BACKGROUND: The introduction of direct-acting oral anticoagulants (DOACs) has shown to decrease atrial fibrillation (AF)-related stroke and bleeding rates in clinical studies, but there is no certain evidence about their effects at the population level. Our aim was to assess changes in AF-related stroke and major bleeding rates between 2012 and 2019 in Andalusia (Spain), and the association between DOACs use and events rates at the population level.

METHODS: All patients with an AF diagnosis from 2012 to 2019 were identified using the Andalusian Health Population Base, that provides clinical information on all Andalusian people. Annual ischemic and hemorrhagic stroke, major bleeding rates, and used antithrombotic treatments were determined. Marginal hazard ratios (HR) were calculated for each treatment.

RESULTS: A total of 95,085 patients with an AF diagnosis were identified. Mean age was 76.1{\textpm}10.2 years (49.7\% women). An increase in the use of DOACs was observed throughout the study period in both males and females (p<0.001). The annual rate of ischemic stroke decreased by one third, while that of hemorrhagic stroke and major bleeding decreased 2-3-fold from 2012 to 2019. Marginal HR was lower than 0.50 for DOACs compared to VKA for all ischemic or hemorrhagic events.

CONCLUSIONS: In this contemporary population-based study using clinical and administrative databases in Andalusia, a significant reduction in the incidence of AF-related ischemic and hemorrhagic stroke and major bleeding was observed between 2012 and 2019. The increased use of DOACs seems to be associated with this reduction.

}, issn = {1578-8989}, doi = {10.1016/j.medcli.2023.10.008}, author = {Loucera, Carlos and Carmona, Rosario and Bostelmann, Gerrit and Mu{\~n}oyerro-Mu{\~n}iz, Dolores and Villegas, Rom{\'a}n and Gonzalez-Manzanares, Rafael and Dopazo, Joaquin and Anguita, Manuel} } @article {772, title = {SigPrimedNet: A Signaling-Informed Neural Network for scRNA-seq Annotation of Known and Unknown Cell Types.}, journal = {Biology (Basel)}, volume = {12}, year = {2023}, month = {2023 Apr 10}, abstract = {

Single-cell RNA sequencing is increasing our understanding of the behavior of complex tissues or organs, by providing unprecedented details on the complex cell type landscape at the level of individual cells. Cell type definition and functional annotation are key steps to understanding the molecular processes behind the underlying cellular communication machinery. However, the exponential growth of scRNA-seq data has made the task of manually annotating cells unfeasible, due not only to an unparalleled resolution of the technology but to an ever-increasing heterogeneity of the data. Many supervised and unsupervised methods have been proposed to automatically annotate cells. Supervised approaches for cell-type annotation outperform unsupervised methods except when new (unknown) cell types are present. Here, we introduce SigPrimedNet an artificial neural network approach that leverages (i) efficient training by means of a sparsity-inducing signaling circuits-informed layer, (ii) feature representation learning through supervised training, and (iii) unknown cell-type identification by fitting an anomaly detection method on the learned representation. We show that SigPrimedNet can efficiently annotate known cell types while keeping a low false-positive rate for unseen cells across a set of publicly available datasets. In addition, the learned representation acts as a proxy for signaling circuit activity measurements, which provide useful estimations of the cell functionalities.

}, issn = {2079-7737}, doi = {10.3390/biology12040579}, author = {Gundogdu, Pelin and Alamo, Inmaculada and Nepomuceno-Chamorro, Isabel A and Dopazo, Joaquin and Loucera, Carlos} } @article {795, title = {Visualization of automatically combined disease maps and pathway diagrams for rare diseases.}, journal = {Front Bioinform}, volume = {3}, year = {2023}, month = {2023}, pages = {1101505}, abstract = {

Investigation of molecular mechanisms of human disorders, especially rare diseases, require exploration of various knowledge repositories for building precise hypotheses and complex data interpretation. Recently, increasingly more resources offer diagrammatic representation of such mechanisms, including disease-dedicated schematics in pathway databases and disease maps. However, collection of knowledge across them is challenging, especially for research projects with limited manpower. In this article we present an automated workflow for construction of maps of molecular mechanisms for rare diseases. The workflow requires a standardized definition of a disease using Orphanet or HPO identifiers to collect relevant genes and variants, and to assemble a functional, visual repository of related mechanisms, including data overlays. The diagrams composing the final map are unified to a common systems biology format from CellDesigner SBML, GPML and SBML+layout+render. The constructed resource contains disease-relevant genes and variants as data overlays for immediate visual exploration, including embedded genetic variant browser and protein structure viewer. We demonstrate the functionality of our workflow on two examples of rare diseases: Kawasaki disease and retinitis pigmentosa. Two maps are constructed based on their corresponding identifiers. Moreover, for the retinitis pigmentosa use-case, we include a list of differentially expressed genes to demonstrate how to tailor the workflow using omics datasets. In summary, our work allows for an ad-hoc construction of molecular diagrams combined from different sources, preserving their layout and graphical style, but integrating them into a single resource. This allows to reduce time consuming tasks of prototyping of a molecular disease map, enabling visual exploration, hypothesis building, data visualization and further refinement. The code of the workflow is open and accessible at https://gitlab.lcsb.uni.lu/minerva/automap/.

}, issn = {2673-7647}, doi = {10.3389/fbinf.2023.1101505}, author = {Gawron, Piotr and Hoksza, David and Pi{\~n}ero, Janet and Pe{\~n}a-Chilet, Maria and Esteban-Medina, Marina and Fernandez-Rueda, Jose Luis and Colonna, Vincenza and Smula, Ewa and Heirendt, Laurent and Ancien, Fran{\c c}ois and Grou{\`e}s, Valentin and Satagopam, Venkata P and Schneider, Reinhard and Dopazo, Joaquin and Furlong, Laura I and Ostaszewski, Marek} } @article {750, title = {CIBERER: Spanish National Network for Research on Rare Diseases: a highly productive collaborative initiative.}, journal = {Clin Genet}, year = {2022}, month = {2022 Jan 20}, abstract = {

CIBER (Center for Biomedical Network Research; Centro de Investigaci{\'o}n Biom{\'e}dica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on Rare Diseases currently consists of 75 research groups belonging to universities, research centers and hospitals of the entire country. CIBERER{\textquoteright}s mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical and cellular research of rare diseases. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this paper, we intend to review CIBERER{\textquoteright}s 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions towards the discovery of new therapies and novel genes associated to diseases, cooperation with patients{\textquoteright} associations and many other topics related to rare disease research. This article is protected by copyright. All rights reserved.

}, issn = {1399-0004}, doi = {10.1111/cge.14113}, author = {Luque, Juan and Mendes, Ingrid and G{\'o}mez, Beatriz and Morte, Beatriz and de Heredia, Miguel L{\'o}pez and Herreras, Enrique and Corrochano, Virginia and Bueren, Juan and Gallano, Pia and Artuch, Rafael and Fillat, Cristina and P{\'e}rez-Jurado, Luis A and Montoliu, Lluis and Carracedo, {\'A}ngel and Mill{\'a}n, Jos{\'e} M and Webb, Susan M and Palau, Francesc and Lapunzina, Pablo} } @article {763, title = {Endoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell-Matrix Interactions.}, journal = {Int J Mol Sci}, volume = {23}, year = {2022}, month = {2022 Aug 04}, abstract = {

Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell-matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease.

}, keywords = {Bone Neoplasms, Endoglin, Humans, Matrix Metalloproteinase 14, Proteomics, Receptors, Growth Factor, Sarcoma, Ewing, Signal Transduction}, issn = {1422-0067}, doi = {10.3390/ijms23158657}, author = {Puerto-Camacho, Pilar and Diaz-Martin, Juan and Olmedo-Pelayo, Joaqu{\'\i}n and Bolado-Carrancio, Alfonso and Salguero-Aranda, Carmen and Jord{\'a}n-P{\'e}rez, Carmen and Esteban-Medina, Marina and Alamo-Alvarez, Inmaculada and Delgado-Bellido, Daniel and Lobo-Selma, Laura and Dopazo, Joaquin and Sastre, Ana and Alonso, Javier and Gr{\"u}newald, Thomas G P and Bernabeu, Carmelo and Byron, Adam and Brunton, Valerie G and Amaral, Ana Teresa and de Alava, Enrique} } @article {754, title = {Incidence and Prevalence of Children{\textquoteright}s Diffuse Lung Disease in Spain.}, journal = {Arch Bronconeumol}, volume = {58}, year = {2022}, month = {2022 Jan}, pages = {22-29}, abstract = {

BACKGROUND: Children{\textquoteright}s diffuse lung disease, also known as children{\textquoteright}s Interstitial Lung Diseases (chILD), are a heterogeneous group of rare diseases with relevant morbidity and mortality, which diagnosis and classification are very complex. Epidemiological data are scarce. The aim of this study was to analyse incidence and prevalence of chILD in Spain.

METHODS: Multicentre observational prospective study in patients from 0 to 18 years of age with chILD to analyse its incidence and prevalence in Spain, based on data reported in 2018 and 2019.

RESULTS: A total of 381 cases with chILD were notified from 51 paediatric pulmonology units all over Spain, covering the 91.7\% of the paediatric population. The average incidence of chILD was 8.18 (CI 95\% 6.28-10.48) new cases/million of children per year. The average prevalence of chILD was 46.53 (CI 95\% 41.81-51.62) cases/million of children. The age group with the highest prevalence were children under 1 year of age. Different types of disorders were seen in children 2-18 years of age compared with children 0-2 years of age. Most frequent cases were: primary pulmonary interstitial glycogenosis in neonates (17/65), neuroendocrine cell hyperplasia of infancy in infants from 1 to 12 months (44/144), idiopathic pulmonary haemosiderosis in children from 1 to 5 years old (13/74), hypersensitivity pneumonitis in children from 5 to 10 years old (9/51), and scleroderma in older than 10 years old (8/47).

CONCLUSIONS: We found a higher incidence and prevalence of chILD than previously described probably due to greater understanding and increased clinician awareness of these rare diseases.

}, issn = {1579-2129}, doi = {10.1016/j.arbres.2021.06.001}, author = {Torrent-Vernetta, Alba and Gaboli, Mirella and Castillo-Corull{\'o}n, Silvia and Mond{\'e}jar-L{\'o}pez, Pedro and Sanz Santiago, Ver{\'o}nica and Costa-Colomer, Jordi and Osona, Borja and Torres-Borrego, Javier and de la Serna-Bl{\'a}zquez, Olga and Bell{\'o}n Alonso, Sara and Caro Aguilera, Pilar and Gimeno-D{\'\i}az de Atauri, {\'A}lvaro and Valenzuela Soria, Alfredo and Ayats, Roser and Martin de Vicente, Carlos and Velasco Gonz{\'a}lez, Valle and Moure Gonz{\'a}lez, Jos{\'e} Domingo and Canino Calder{\'\i}n, Elisa Mar{\'\i}a and Pastor-Vivero, Mar{\'\i}a Dolores and Villar {\'A}lvarez, Mar{\'\i}a {\'A}ngeles and Rovira-Amigo, Sandra and Iglesias Serrano, Ignacio and D{\'\i}ez Izquierdo, Ana and de Mir Messa, In{\'e}s and Gartner, Silvia and Navarro, Alexandra and Baz-Red{\'o}n, Noelia and Carmona, Rosario and Camats-Tarruella, N{\'u}ria and Fern{\'a}ndez-Cancio, M{\'o}nica and Rapp, Christina and Dopazo, Joaquin and Griese, Matthias and Moreno-Gald{\'o}, Antonio} } @article {749, title = {Integrating pathway knowledge with deep neural networks to reduce the dimensionality in single-cell RNA-seq data.}, journal = {BioData Min}, volume = {15}, year = {2022}, month = {2022 Jan 03}, pages = {1}, abstract = {

BACKGROUND: Single-cell RNA sequencing (scRNA-seq) data provide valuable insights into cellular heterogeneity which is significantly improving the current knowledge on biology and human disease. One of the main applications of scRNA-seq data analysis is the identification of new cell types and cell states. Deep neural networks (DNNs) are among the best methods to address this problem. However, this performance comes with the trade-off for a lack of interpretability in the results. In this work we propose an intelligible pathway-driven neural network to correctly solve cell-type related problems at single-cell resolution while providing a biologically meaningful representation of the data.

RESULTS: In this study, we explored the deep neural networks constrained by several types of prior biological information, e.g. signaling pathway information, as a way to reduce the dimensionality of the scRNA-seq data. We have tested the proposed biologically-based architectures on thousands of cells of human and mouse origin across a collection of public datasets in order to check the performance of the model. Specifically, we tested the architecture across different validation scenarios that try to mimic how unknown cell types are clustered by the DNN and how it correctly annotates cell types by querying a database in a retrieval problem. Moreover, our approach demonstrated to be comparable to other less interpretable DNN approaches constrained by using protein-protein interactions gene regulation data. Finally, we show how the latent structure learned by the network could be used to visualize and to interpret the composition of human single cell datasets.

CONCLUSIONS: Here we demonstrate how the integration of pathways, which convey fundamental information on functional relationships between genes, with DNNs, that provide an excellent classification framework, results in an excellent alternative to learn a biologically meaningful representation of scRNA-seq data. In addition, the introduction of prior biological knowledge in the DNN reduces the size of the network architecture. Comparative results demonstrate a superior performance of this approach with respect to other similar approaches. As an additional advantage, the use of pathways within the DNN structure enables easy interpretability of the results by connecting features to cell functionalities by means of the pathway nodes, as demonstrated with an example with human melanoma tumor cells.

}, issn = {1756-0381}, doi = {10.1186/s13040-021-00285-4}, author = {Gundogdu, Pelin and Loucera, Carlos and Alamo-Alvarez, Inmaculada and Dopazo, Joaquin and Nepomuceno, Isabel} } @article {760, title = {Novel genes and sex differences in COVID-19 severity.}, journal = {Hum Mol Genet}, year = {2022}, month = {2022 Jun 16}, abstract = {

Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p =~1.3x10-22 and p =~8.1x10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p =~4.4x10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p =~2.7x10-8) and ARHGAP33 (p =~1.3x10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or >= 60~years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddac132}, author = {Cruz, Raquel and Almeida, Silvia Diz-de and Heredia, Miguel L{\'o}pez and Quintela, In{\'e}s and Ceballos, Francisco C and Pita, Guillermo and Lorenzo-Salazar, Jos{\'e} M and Gonz{\'a}lez-Montelongo, Rafaela and Gago-Dom{\'\i}nguez, Manuela and Porras, Marta Sevilla and Casta{\~n}o, Jair Antonio Tenorio and Nevado, Juli{\'a}n and Aguado, Jose Mar{\'\i}a and Aguilar, Carlos and Aguilera-Albesa, Sergio and Almadana, Virginia and Almoguera, Berta and Alvarez, Nuria and Andreu-Bernabeu, {\'A}lvaro and Arana-Arri, Eunate and Arango, Celso and Arranz, Mar{\'\i}a J and Artiga, Maria-Jesus and Baptista-Rosas, Ra{\'u}l C and Barreda-S{\'a}nchez, Mar{\'\i}a and Belhassen-Garcia, Moncef and Bezerra, Joao F and Bezerra, Marcos A C and Boix-Palop, Luc{\'\i}a and Bri{\'o}n, Maria and Brugada, Ram{\'o}n and Bustos, Matilde and Calder{\'o}n, Enrique J and Carbonell, Cristina and Castano, Luis and Castelao, Jose E and Conde-Vicente, Rosa and Cordero-Lorenzana, M Lourdes and Cortes-Sanchez, Jose L and Corton, Marta and Darnaude, M Teresa and De Martino-Rodr{\'\i}guez, Alba and Campo-P{\'e}rez, Victor and Bustamante, Aranzazu Diaz and Dom{\'\i}nguez-Garrido, Elena and Luchessi, Andr{\'e} D and Eir{\'o}s, Roc{\'\i}o and Sanabria, Gladys Mercedes Estigarribia and Fari{\~n}as, Mar{\'\i}a Carmen and Fern{\'a}ndez-Robelo, Ux{\'\i}a and Fern{\'a}ndez-Rodr{\'\i}guez, Amanda and Fern{\'a}ndez-Villa, Tania and Gil-Fournier, Bel{\'e}n and G{\'o}mez-Arrue, Javier and {\'A}lvarez, Beatriz Gonz{\'a}lez and Quir{\'o}s, Fernan Gonzalez Bernaldo and Gonz{\'a}lez-Pe{\~n}as, Javier and Guti{\'e}rrez-Bautista, Juan F and Herrero, Mar{\'\i}a Jos{\'e} and Herrero-Gonzalez, Antonio and Jimenez-Sousa, Mar{\'\i}a A and Lattig, Mar{\'\i}a Claudia and Borja, Anabel Liger and Lopez-Rodriguez, Rosario and Mancebo, Esther and Mart{\'\i}n-L{\'o}pez, Caridad and Mart{\'\i}n, Vicente and Martinez-Nieto, Oscar and Martinez-Lopez, Iciar and Martinez-Resendez, Michel F and Martinez-Perez, {\'A}ngel and Mazzeu, Juliana A and Mac{\'\i}as, Eleuterio Merayo and Minguez, Pablo and Cuerda, Victor Moreno and Silbiger, Vivian N and Oliveira, Silviene F and Ortega-Paino, Eva and Parellada, Mara and Paz-Artal, Estela and Santos, Ney P C and P{\'e}rez-Matute, Patricia and Perez, Patricia and P{\'e}rez-Tom{\'a}s, M Elena and Perucho, Teresa and Pinsach-Abuin, Mel Lina and Pompa-Mera, Ericka N and Porras-Hurtado, Gloria L and Pujol, Aurora and Le{\'o}n, Soraya Ramiro and Resino, Salvador and Fernandes, Marianne R and Rodr{\'\i}guez-Ruiz, Emilio and Rodriguez-Artalejo, Fernando and Rodriguez-Garcia, Jos{\'e} A and Ruiz-Cabello, Francisco and Ruiz-Hornillos, Javier and Ryan, Pablo and Soria, Jos{\'e} Manuel and Souto, Juan Carlos and Tamayo, Eduardo and Tamayo-Velasco, Alvaro and Taracido-Fernandez, Juan Carlos and Teper, Alejandro and Torres-Tobar, Lilian and Urioste, Miguel and Valencia-Ramos, Juan and Y{\'a}{\~n}ez, Zuleima and Zarate, Ruth and Nakanishi, Tomoko and Pigazzini, Sara and Degenhardt, Frauke and Butler-Laporte, Guillaume and Maya-Miles, Douglas and Bujanda, Luis and Bouysran, Youssef and Palom, Adriana and Ellinghaus, David and Mart{\'\i}nez-Bueno, Manuel and Rolker, Selina and Amitrano, Sara and Roade, Luisa and Fava, Francesca and Spinner, Christoph D and Prati, Daniele and Bernardo, David and Garc{\'\i}a, Federico and Darcis, Gilles and Fern{\'a}ndez-Cadenas, Israel and Holter, Jan Cato and Banales, Jesus M and Frithiof, Robert and Duga, Stefano and Asselta, Rosanna and Pereira, Alexandre C and Romero-G{\'o}mez, Manuel and Nafr{\'\i}a-Jim{\'e}nez, Beatriz and Hov, Johannes R and Migeotte, Isabelle and Renieri, Alessandra and Planas, Anna M and Ludwig, Kerstin U and Buti, Maria and Rahmouni, Souad and Alarc{\'o}n-Riquelme, Marta E and Schulte, Eva C and Franke, Andre and Karlsen, Tom H and Valenti, Luca and Zeberg, Hugo and Richards, Brent and Ganna, Andrea and Boada, Merc{\`e} and Rojas, Itziar and Ruiz, Agust{\'\i}n and S{\'a}nchez, Pascual and Real, Luis Miguel and Guill{\'e}n-Navarro, Encarna and Ayuso, Carmen and Gonz{\'a}lez-Neira, Anna and Riancho, Jos{\'e} A and Rojas-Martinez, Augusto and Flores, Carlos and Lapunzina, Pablo and Carracedo, {\'A}ngel} } @article {759, title = {Protein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus.}, journal = {Sci Rep}, volume = {12}, year = {2022}, month = {2022 Jul 02}, pages = {11219}, abstract = {

Systemic lupus erythematosus (SLE) is the prototype of an autoimmune disease. Belimumab, a monoclonal antibody targets BAFF, is the only biologic approved for SLE and active lupus nephritis. BAFF is a cytokine with a key-regulatory role in the B cell homeostasis, which acts by binding to three receptors: BAFF-R, TACI and BCMA. TACI and BCMA also bind APRIL. Many studies reported elevated soluble BAFF and APRIL levels in the sera of SLE patients, but other questions about the role of this system in the disease remain open. The study aimed to investigate the utility of the cytokine levels in serum and urine as biomarkers, the role of non-functional isoforms, and the association of gene variants with the disease. This case-control study includes a cohort (women, 18-60~years old) of 100 patients (48\% with nephritis) and 100 healthy controls. We used ELISA assays to measure the cytokine concentrations in serum (sBAFF and sAPRIL) and urine (uBAFF and uAPRIL); TaqMan Gene Expression Assays to quantify the relative mRNA expression of ΔBAFF, βAPRIL, and εAPRIL, and next-generation sequencing to genotype the cytokine (TNFSF13 and TNFSF13B) and receptor (TNFRSF13B, TNFRSF17 and TNFRSF13C) genes. The statistical tests used were: Kruskal-Wallis (qualitative variables), the Spearman Rho coefficient (correlations), the Chi-square and SKAT (association of common and rare genetic variants, respectively). As expected, sBAFF and sAPRIL levels were higher in patients than in controls (p <= 0.001) but found differences between patient subgroups. sBAFF and sAPRIL significantly correlated only in patients with nephritis (r = 0.67, p <= 0.001) and βAPRIL levels were lower in patients with nephritis (p = 0.04), and ΔBAFF levels were lower in patients with dsDNA antibodies (p = 0.04). Rare variants of TNFSF13 and TNFRSF13B and TNFSF13 p.Gly67Arg and TNFRSF13B p.Val220Ala were associated with SLE. Our study supports differences among SLE patient subgroups with diverse clinical features in the BAFF/APRIL pathway. In addition, it suggests the involvement of genetic variants in the susceptibility to the disease.

}, issn = {2045-2322}, doi = {10.1038/s41598-022-15549-0}, author = {Ortiz-Aljaro, Pilar and Montes-Cano, Marco Antonio and Garc{\'\i}a-Lozano, Jos{\'e}-Ra{\'u}l and Aquino, Virginia and Carmona, Rosario and Perez-Florido, Javier and Garc{\'\i}a-Hern{\'a}ndez, Francisco Jos{\'e} and Dopazo, Joaquin and Gonz{\'a}lez-Escribano, Mar{\'\i}a Francisca} } @article {726, title = {A comprehensive database for integrated analysis of omics data in autoimmune diseases.}, journal = {BMC Bioinformatics}, volume = {22}, year = {2021}, month = {2021 Jun 24}, pages = {343}, abstract = {

BACKGROUND: Autoimmune diseases are heterogeneous pathologies with difficult diagnosis and few therapeutic options. In the last decade, several omics studies have provided significant insights into the molecular mechanisms of these diseases. Nevertheless, data from different cohorts and pathologies are stored independently in public repositories and a unified resource is imperative to assist researchers in this field.

RESULTS: Here, we present Autoimmune Diseases Explorer ( https://adex.genyo.es ), a database that integrates 82 curated transcriptomics and methylation studies covering 5609 samples for some of the most common autoimmune diseases. The database provides, in an easy-to-use environment, advanced data analysis and statistical methods for exploring omics datasets, including meta-analysis, differential expression or pathway analysis.

CONCLUSIONS: This is the first omics database focused on autoimmune diseases. This resource incorporates homogeneously processed data to facilitate integrative analyses among studies.

}, keywords = {Autoimmune Diseases, Computational Biology, Databases, Factual, Humans}, issn = {1471-2105}, doi = {10.1186/s12859-021-04268-4}, author = {Martorell-Marug{\'a}n, Jordi and L{\'o}pez-Dom{\'\i}nguez, Ra{\'u}l and Garc{\'\i}a-Moreno, Adri{\'a}n and Toro-Dom{\'\i}nguez, Daniel and Villatoro-Garc{\'\i}a, Juan Antonio and Barturen, Guillermo and Mart{\'\i}n-G{\'o}mez, Adoraci{\'o}n and Troule, Kevin and G{\'o}mez-L{\'o}pez, Gonzalo and Al-Shahrour, F{\'a}tima and Gonz{\'a}lez-Rumayor, V{\'\i}ctor and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin and Saez-Rodriguez, Julio and Alarc{\'o}n-Riquelme, Marta E and Carmona-S{\'a}ez, Pedro} } @article {736, title = {COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms.}, journal = {Mol Syst Biol}, volume = {17}, year = {2021}, month = {2021 10}, pages = {e10387}, abstract = {

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.

}, keywords = {Antiviral Agents, Computational Biology, Computer Graphics, COVID-19, Cytokines, Data Mining, Databases, Factual, Gene Expression Regulation, Host Microbial Interactions, Humans, Immunity, Cellular, Immunity, Humoral, Immunity, Innate, Lymphocytes, Metabolic Networks and Pathways, Myeloid Cells, Protein Interaction Mapping, SARS-CoV-2, Signal Transduction, Software, Transcription Factors, Viral Proteins}, issn = {1744-4292}, doi = {10.15252/msb.202110387}, author = {Ostaszewski, Marek and Niarakis, Anna and Mazein, Alexander and Kuperstein, Inna and Phair, Robert and Orta-Resendiz, Aurelio and Singh, Vidisha and Aghamiri, Sara Sadat and Acencio, Marcio Luis and Glaab, Enrico and Ruepp, Andreas and Fobo, Gisela and Montrone, Corinna and Brauner, Barbara and Frishman, Goar and Monraz G{\'o}mez, Luis Crist{\'o}bal and Somers, Julia and Hoch, Matti and Kumar Gupta, Shailendra and Scheel, Julia and Borlinghaus, Hanna and Czauderna, Tobias and Schreiber, Falk and Montagud, Arnau and Ponce de Leon, Miguel and Funahashi, Akira and Hiki, Yusuke and Hiroi, Noriko and Yamada, Takahiro G and Dr{\"a}ger, Andreas and Renz, Alina and Naveez, Muhammad and Bocskei, Zsolt and Messina, Francesco and B{\"o}rnigen, Daniela and Fergusson, Liam and Conti, Marta and Rameil, Marius and Nakonecnij, Vanessa and Vanhoefer, Jakob and Schmiester, Leonard and Wang, Muying and Ackerman, Emily E and Shoemaker, Jason E and Zucker, Jeremy and Oxford, Kristie and Teuton, Jeremy and Kocakaya, Ebru and Summak, G{\"o}k{\c c}e Ya{\u g}mur and Hanspers, Kristina and Kutmon, Martina and Coort, Susan and Eijssen, Lars and Ehrhart, Friederike and Rex, Devasahayam Arokia Balaya and Slenter, Denise and Martens, Marvin and Pham, Nhung and Haw, Robin and Jassal, Bijay and Matthews, Lisa and Orlic-Milacic, Marija and Senff Ribeiro, Andrea and Rothfels, Karen and Shamovsky, Veronica and Stephan, Ralf and Sevilla, Cristoffer and Varusai, Thawfeek and Ravel, Jean-Marie and Fraser, Rupsha and Ortseifen, Vera and Marchesi, Silvia and Gawron, Piotr and Smula, Ewa and Heirendt, Laurent and Satagopam, Venkata and Wu, Guanming and Riutta, Anders and Golebiewski, Martin and Owen, Stuart and Goble, Carole and Hu, Xiaoming and Overall, Rupert W and Maier, Dieter and Bauch, Angela and Gyori, Benjamin M and Bachman, John A and Vega, Carlos and Grou{\`e}s, Valentin and Vazquez, Miguel and Porras, Pablo and Licata, Luana and Iannuccelli, Marta and Sacco, Francesca and Nesterova, Anastasia and Yuryev, Anton and de Waard, Anita and Turei, Denes and Luna, Augustin and Babur, Ozgun and Soliman, Sylvain and Valdeolivas, Alberto and Esteban-Medina, Marina and Pe{\~n}a-Chilet, Maria and Rian, Kinza and Helikar, Tom{\'a}{\v s} and Puniya, Bhanwar Lal and Modos, Dezso and Treveil, Agatha and Olbei, Marton and De Meulder, Bertrand and Ballereau, Stephane and Dugourd, Aur{\'e}lien and Naldi, Aur{\'e}lien and No{\"e}l, Vincent and Calzone, Laurence and Sander, Chris and Demir, Emek and Korcsmaros, Tamas and Freeman, Tom C and Aug{\'e}, Franck and Beckmann, Jacques S and Hasenauer, Jan and Wolkenhauer, Olaf and Wilighagen, Egon L and Pico, Alexander R and Evelo, Chris T and Gillespie, Marc E and Stein, Lincoln D and Hermjakob, Henning and D{\textquoteright}Eustachio, Peter and Saez-Rodriguez, Julio and Dopazo, Joaquin and Valencia, Alfonso and Kitano, Hiroaki and Barillot, Emmanuel and Auffray, Charles and Balling, Rudi and Schneider, Reinhard} } @article {701, title = {CSVS, a crowdsourcing database of the Spanish population genetic variability.}, journal = {Nucleic Acids Res}, volume = {49}, year = {2021}, month = {2021 01 08}, pages = {D1130-D1137}, abstract = {

The knowledge of the genetic variability of the local population is of utmost importance in personalized medicine and has been revealed as a critical factor for the discovery of new disease variants. Here, we present the Collaborative Spanish Variability Server (CSVS), which currently contains more than 2000 genomes and exomes of unrelated Spanish individuals. This database has been generated in a collaborative crowdsourcing effort collecting sequencing data produced by local genomic projects and for other purposes. Sequences have been grouped by ICD10 upper categories. A web interface allows querying the database removing one or more ICD10 categories. In this way, aggregated counts of allele frequencies of the pseudo-control Spanish population can be obtained for diseases belonging to the category removed. Interestingly, in addition to pseudo-control studies, some population studies can be made, as, for example, prevalence of pharmacogenomic variants, etc. In addition, this genomic data has been used to define the first Spanish Genome Reference Panel (SGRP1.0) for imputation. This is the first local repository of variability entirely produced by a crowdsourcing effort and constitutes an example for future initiatives to characterize local variability worldwide. CSVS is also part of the GA4GH Beacon network. CSVS can be accessed at: http://csvs.babelomics.org/.

}, keywords = {Alleles, Chromosome Mapping, Crowdsourcing, Databases, Genetic, Exome, Gene Frequency, Genetic Variation, Genetics, Population, Genome, Human, Genomics, Humans, Internet, Precision Medicine, Software, Spain}, issn = {1362-4962}, doi = {10.1093/nar/gkaa794}, author = {Pe{\~n}a-Chilet, Maria and Rold{\'a}n, Gema and Perez-Florido, Javier and Ortuno, Francisco M and Carmona, Rosario and Aquino, Virginia and L{\'o}pez-L{\'o}pez, Daniel and Loucera, Carlos and Fernandez-Rueda, Jose L and Gallego, Asunci{\'o}n and Garcia-Garcia, Francisco and Gonz{\'a}lez-Neira, Anna and Pita, Guillermo and N{\'u}{\~n}ez-Torres, Roc{\'\i}o and Santoyo-L{\'o}pez, Javier and Ayuso, Carmen and Minguez, Pablo and Avila-Fernandez, Almudena and Corton, Marta and Moreno-Pelayo, Miguel {\'A}ngel and Morin, Mat{\'\i}as and Gallego-Martinez, Alvaro and Lopez-Escamez, Jose A and Borrego, Salud and Anti{\v n}olo, Guillermo and Amigo, Jorge and Salgado-Garrido, Josefa and Pasalodos-Sanchez, Sara and Morte, Beatriz and Carracedo, {\'A}ngel and Alonso, {\'A}ngel and Dopazo, Joaquin} } @article {731, title = {De novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects.}, journal = {Am J Med Genet A}, volume = {185}, year = {2021}, month = {2021 03}, pages = {877-883}, abstract = {

Disruption of the autism susceptibility candidate 2 (AUTS2) gene through genomic rearrangements, copy number variations (CNVs), and intragenic deletions and mutations, has been recurrently involved in syndromic forms of developmental delay and intellectual disability, known as AUTS2 syndrome. The AUTS2 gene plays an important role in regulation of neuronal migration, and when altered, associates with a variable phenotype from severely to mildly affected patients. The more severe phenotypes significantly correlate with the presence of defects affecting the C-terminus part of the gene. This article reports a new patient with a syndromic neurodevelopmental disorder, who presents a deletion of 30 nucleotides in the exon 9 of the AUTS2 gene. Importantly, this deletion includes the transcription start site for the AUTS2 short transcript isoform, which has an important role in brain development. Gene expression analysis of AUTS2 full-length and short isoforms revealed that the deletion found in this patient causes a remarkable reduction in the expression level, not only of the short isoform, but also of the full AUTS2 transcripts. This report adds more evidence for the role of mutated AUTS2 short transcripts in the development of a severe phenotype in the AUTS2 syndrome.

}, keywords = {Child, Preschool, Cytoskeletal Proteins, Dwarfism, Exons, Gene Expression Regulation, Genetic Association Studies, Humans, Male, Neurodevelopmental Disorders, Protein Isoforms, RNA, Messenger, Sequence Deletion, Syndrome, Transcription Factors, Transcription Initiation Site, Transcription, Genetic}, issn = {1552-4833}, doi = {10.1002/ajmg.a.62017}, author = {Martinez-Delgado, Beatriz and Lopez-Martin, Estrella and Lara-Herguedas, Juli{\'a}n and Monzon, Sara and Cuesta, Isabel and Juli{\'a}, Miguel and Aquino, Virginia and Rodriguez-Martin, Carlos and Damian, Alejandra and Gonzalo, Irene and Gomez-Mariano, Gema and Baladron, Beatriz and Cazorla, Rosario and Iglesias, Gema and Roman, Enriqueta and Ros, Purificacion and Tutor, Pablo and Mellor, Susana and Jimenez, Carlos and Cabrejas, Maria Jose and Gonzalez-Vioque, Emiliano and Alonso, Javier and Bermejo-S{\'a}nchez, Eva and Posada, Manuel} } @article {720, title = {A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin.}, journal = {Mol Oncol}, volume = {15}, year = {2021}, month = {2021 12}, pages = {3691-3705}, abstract = {

Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.

}, issn = {1878-0261}, doi = {10.1002/1878-0261.12996}, author = {Moura, David S and Pe{\~n}a-Chilet, Maria and Cordero Varela, Juan Antonio and Alvarez-Alegret, Ramiro and Agra-Pujol, Carolina and Izquierdo, Francisco and Ramos, Rafael and Ortega-Medina, Luis and Martin-Davila, Francisco and Castilla-Ramirez, Carolina and Hernandez-Leon, Carmen Nieves and Romagosa, Cleofe and Vaz Salgado, Maria Angeles and Lavernia, Javier and Bagu{\'e}, Silvia and Mayodormo-Aranda, Empar and Vicioso, Luis and Hern{\'a}ndez Barcel{\'o}, Jose Emilio and Rubio-Casadevall, Jordi and de Juan, Ana and Fia{\~n}o-Valverde, Maria Concepcion and Hindi, Nadia and Lopez-Alvarez, Maria and Lacerenza, Serena and Dopazo, Joaquin and Gutierrez, Antonio and Alvarez, Rosa and Valverde, Claudia and Martinez-Trufero, Javier and Martin-Broto, Javier} } @article {724, title = {Genome-scale mechanistic modeling of signaling pathways made easy: A bioconductor/cytoscape/web server framework for the analysis of omic data}, journal = {Computational and Structural Biotechnology Journal}, volume = {19}, year = {2021}, month = {Jan-01-2021}, pages = {2968 - 2978}, issn = {20010370}, doi = {10.1016/j.csbj.2021.05.022}, url = {https://linkinghub.elsevier.com/retrieve/pii/S2001037021002038}, author = {Rian, Kinza and Hidalgo, Marta R. and Cubuk, Cankut and Falco, Matias M. and Loucera, Carlos and Esteban-Medina, Marina and Alamo-Alvarez, Inmaculada and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin} } @article {717, title = {Genome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system developmentAbstractBackgroundResultsConclusionsGraphic abstract}, journal = {Clinical Epigenetics}, volume = {13}, year = {2021}, month = {Jan-12-2021}, issn = {1868-7075}, doi = {10.1186/s13148-021-01040-6}, url = {http://link.springer.com/article/10.1186/s13148-021-01040-6/fulltext.html}, author = {Villalba-Benito, Leticia and L{\'o}pez-L{\'o}pez, Daniel and Torroglosa, Ana and Casimiro-Soriguer, Carlos S. and Luz{\'o}n-Toro, Berta and Fern{\'a}ndez, Raquel Mar{\'\i}a and Moya-Jim{\'e}nez, Mar{\'\i}a Jos{\'e} and Anti{\v n}olo, Guillermo and Dopazo, Joaquin and Borrego, Salud} } @article {714, title = {The NCI Genomic Data Commons}, journal = {Nature Genetics}, year = {2021}, month = {Oct-02-2022}, issn = {1061-4036}, doi = {10.1038/s41588-021-00791-5}, url = {http://www.nature.com/articles/s41588-021-00791-5}, author = {Heath, Allison P. and Ferretti, Vincent and Agrawal, Stuti and An, Maksim and Angelakos, James C. and Arya, Renuka and Bajari, Rosita and Baqar, Bilal and Barnowski, Justin H. B. and Burt, Jeffrey and Catton, Ann and Chan, Brandon F. and Chu, Fay and Cullion, Kim and Davidsen, Tanja and Do, Phuong-My and Dompierre, Christian and Ferguson, Martin L. and Fitzsimons, Michael S. and Ford, Michael and Fukuma, Miyuki and Gaheen, Sharon and Ganji, Gajanan L. and Garcia, Tzintzuni I. and George, Sameera S. and Gerhard, Daniela S. and Gerthoffert, Francois and Gomez, Fauzi and Han, Kang and Hernandez, Kyle M. and Issac, Biju and Jackson, Richard and Jensen, Mark A. and Joshi, Sid and Kadam, Ajinkya and Khurana, Aishmit and Kim, Kyle M. J. and Kraft, Victoria E. and Li, Shenglai and Lichtenberg, Tara M. and Lodato, Janice and Lolla, Laxmi and Martinov, Plamen and Mazzone, Jeffrey A. and Miller, Daniel P. and Miller, Ian and Miller, Joshua S. and Miyauchi, Koji and Murphy, Mark W. and Nullet, Thomas and Ogwara, Rowland O. and Ortu{\~n}o, Francisco M. and Pedrosa, Jes{\'u}s and Pham, Phuong L. and Popov, Maxim Y. and Porter, James J. and Powell, Raymond and Rademacher, Karl and Reid, Colin P. and Rich, Samantha and Rogel, Bessie and Sahni, Himanso and Savage, Jeremiah H. and Schmitt, Kyle A. and Simmons, Trevar J. and Sislow, Joseph and Spring, Jonathan and Stein, Lincoln and Sullivan, Sean and Tang, Yajing and Thiagarajan, Mathangi and Troyer, Heather D. and Wang, Chang and Wang, Zhining and West, Bedford L. and Wilmer, Alex and Wilson, Shane and Wu, Kaman and Wysocki, William P. and Xiang, Linda and Yamada, Joseph T. and Yang, Liming and Yu, Christine and Yung, Christina K. and Zenklusen, Jean Claude and Zhang, Junjun and Zhang, Zhenyu and Zhao, Yuanheng and Zubair, Ariz and Staudt, Louis M. and Grossman, Robert L.} } @article {742, title = {Reporting guidelines for human microbiome research: the STORMS checklist.}, journal = {Nat Med}, volume = {27}, year = {2021}, month = {2021 11}, pages = {1885-1892}, abstract = {

The particularly interdisciplinary nature of human microbiome research makes the organization and reporting of results spanning epidemiology, biology, bioinformatics, translational medicine and statistics a challenge. Commonly used reporting guidelines for observational or genetic epidemiology studies lack key features specific to microbiome studies. Therefore, a multidisciplinary group of microbiome epidemiology researchers adapted guidelines for observational and genetic studies to culture-independent human microbiome studies, and also developed new reporting elements for laboratory, bioinformatics and statistical analyses tailored to microbiome studies. The resulting tool, called {\textquoteright}Strengthening The Organization and Reporting of Microbiome Studies{\textquoteright} (STORMS), is composed of a 17-item checklist organized into six sections that correspond to the typical sections of a scientific publication, presented as an editable table for inclusion in supplementary materials. The STORMS checklist provides guidance for concise and complete reporting of microbiome studies that will facilitate manuscript preparation, peer review, and reader comprehension of publications and comparative analysis of published results.

}, keywords = {Computational Biology, Dysbiosis, Humans, Microbiota, Observational Studies as Topic, Research Design, Translational Science, Biomedical}, issn = {1546-170X}, doi = {10.1038/s41591-021-01552-x}, author = {Mirzayi, Chloe and Renson, Audrey and Zohra, Fatima and Elsafoury, Shaimaa and Geistlinger, Ludwig and Kasselman, Lora J and Eckenrode, Kelly and van de Wijgert, Janneke and Loughman, Amy and Marques, Francine Z and MacIntyre, David A and Arumugam, Manimozhiyan and Azhar, Rimsha and Beghini, Francesco and Bergstrom, Kirk and Bhatt, Ami and Bisanz, Jordan E and Braun, Jonathan and Bravo, Hector Corrada and Buck, Gregory A and Bushman, Frederic and Casero, David and Clarke, Gerard and Collado, Maria Carmen and Cotter, Paul D and Cryan, John F and Demmer, Ryan T and Devkota, Suzanne and Elinav, Eran and Escobar, Juan S and Fettweis, Jennifer and Finn, Robert D and Fodor, Anthony A and Forslund, Sofia and Franke, Andre and Furlanello, Cesare and Gilbert, Jack and Grice, Elizabeth and Haibe-Kains, Benjamin and Handley, Scott and Herd, Pamela and Holmes, Susan and Jacobs, Jonathan P and Karstens, Lisa and Knight, Rob and Knights, Dan and Koren, Omry and Kwon, Douglas S and Langille, Morgan and Lindsay, Brianna and McGovern, Dermot and McHardy, Alice C and McWeeney, Shannon and Mueller, Noel T and Nezi, Luigi and Olm, Matthew and Palm, Noah and Pasolli, Edoardo and Raes, Jeroen and Redinbo, Matthew R and R{\"u}hlemann, Malte and Balfour Sartor, R and Schloss, Patrick D and Schriml, Lynn and Segal, Eran and Shardell, Michelle and Sharpton, Thomas and Smirnova, Ekaterina and Sokol, Harry and Sonnenburg, Justin L and Srinivasan, Sujatha and Thingholm, Louise B and Turnbaugh, Peter J and Upadhyay, Vaibhav and Walls, Ramona L and Wilmes, Paul and Yamada, Takuji and Zeller, Georg and Zhang, Mingyu and Zhao, Ni and Zhao, Liping and Bao, Wenjun and Culhane, Aedin and Devanarayan, Viswanath and Dopazo, Joaquin and Fan, Xiaohui and Fischer, Matthias and Jones, Wendell and Kusko, Rebecca and Mason, Christopher E and Mercer, Tim R and Sansone, Susanna-Assunta and Scherer, Andreas and Shi, Leming and Thakkar, Shraddha and Tong, Weida and Wolfinger, Russ and Hunter, Christopher and Segata, Nicola and Huttenhower, Curtis and Dowd, Jennifer B and Jones, Heidi E and Waldron, Levi} } @article {722, title = {Schuurs{\textendash}Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review}, journal = {Genes}, volume = {12}, year = {2021}, month = {Jan-05-2021}, pages = {738}, doi = {10.3390/genes12050738}, url = {https://www.mdpi.com/2073-4425/12/5/738https://www.mdpi.com/2073-4425/12/5/738/pdf}, author = {Tenorio-Casta{\~n}o, Jair and Morte, Beatriz and Nevado, Juli{\'a}n and Mart{\'\i}nez-Glez, V{\'\i}ctor and Santos-Simarro, Fernando and Garc{\'\i}a-Mi{\~n}aur, Sixto and Palomares-Bralo, Mar{\'\i}a and Pacio-M{\'\i}guez, Marta and G{\'o}mez, Beatriz and Arias, Pedro and Alcochea, Alba and Carri{\'o}n, Juan and Arias, Patricia and Almoguera, Berta and L{\'o}pez-Grondona, Fermina and Lorda-Sanchez, Isabel and Gal{\'a}n-G{\'o}mez, Enrique and Valenzuela, Irene and M{\'e}ndez Perez, Mar{\'\i}a and Cusc{\'o}, Iv{\'o}n and Barros, Francisco and Pi{\'e}, Juan and Ramos, Sergio and Ramos, Feliciano and Kuechler, Alma and Tizzano, Eduardo and Ayuso, Carmen and Kaiser, Frank and P{\'e}rez-Jurado, Luis and Carracedo, {\'A}ngel and Lapunzina, Pablo} } @article {715, title = {Uniform genomic data analysis in the NCI Genomic Data CommonsAbstract}, journal = {Nature Communications}, volume = {12}, year = {2021}, month = {Jan-12-2021}, doi = {10.1038/s41467-021-21254-9}, url = {http://www.nature.com/articles/s41467-021-21254-9}, author = {Zhang, Zhenyu and Hernandez, Kyle and Savage, Jeremiah and Li, Shenglai and Miller, Dan and Agrawal, Stuti and Ortuno, Francisco and Staudt, Louis M. and Heath, Allison and Grossman, Robert L.} } @article {611, title = {Association of a single nucleotide polymorphism in the ubxn6 gene with long-term non-progression phenotype in HIV-positive individuals.}, journal = {Clin Microbiol Infect}, volume = {26}, year = {2020}, month = {2020 Jan}, pages = {107-114}, abstract = {

OBJECTIVES: The long-term non-progressors (LTNPs) are a heterogeneous group of HIV-positive individuals characterized by their ability to maintain high CD4 T-cell counts and partially control viral replication for years in the absence of antiretroviral therapy. The present study aims to identify host single nucleotide polymorphisms (SNPs) associated with non-progression in a cohort of 352 individuals.

METHODS: DNA microarrays and exome sequencing were used for genotyping about 240~000 functional polymorphisms throughout more than 20~000 human genes. The allele frequencies of 85 LTNPs were compared with a control population. SNPs associated with LTNPs were confirmed in a population of typical progressors. Functional analyses in the affected gene were carried out through knockdown experiments in HeLa-P4, macrophages and dendritic cells.

RESULTS: Several SNPs located within the major histocompatibility complex region previously related to LTNPs were confirmed in this new cohort. The SNP rs1127888 (UBXN6) surpassed the statistical significance of these markers after Bonferroni correction (q~=~2.11~{\texttimes}~10). An uncommon allelic frequency of rs1127888 among LTNPs was confirmed by comparison with typical progressors and other publicly available populations. UBXN6 knockdown experiments caused an increase in CAV1 expression and its accumulation in the plasma membrane. In~vitro infection of different cell types with HIV-1 replication-competent recombinant viruses caused a reduction of the viral replication capacity compared with their corresponding wild-type cells expressing UBXN6.

CONCLUSIONS: A higher prevalence of Ala31Thr in UBXN6 was found among LTNPs within its N-terminal region, which is crucial for UBXN6/VCP protein complex formation. UBXN6 knockdown affected CAV1 turnover and HIV-1 replication capacity.

}, keywords = {Adaptor Proteins, Vesicular Transport, Autophagy-Related Proteins, Caveolin 1, Cohort Studies, Dendritic Cells, Disease Progression, Gene Frequency, Gene Knockdown Techniques, Genetic Association Studies, HeLa Cells, HIV Infections, HIV Long-Term Survivors, HIV-1, Humans, Macrophages, Oligonucleotide Array Sequence Analysis, Phenotype, Polymorphism, Single Nucleotide, whole exome sequencing}, issn = {1469-0691}, doi = {10.1016/j.cmi.2019.05.015}, author = {D{\'\i}ez-Fuertes, F and De La Torre-Tarazona, H E and Calonge, E and Pernas, M and Bermejo, M and Garc{\'\i}a-P{\'e}rez, J and {\'A}lvarez, A and Capa, L and Garc{\'\i}a-Garc{\'\i}a, F and Saumoy, M and Riera, M and Boland-Auge, A and L{\'o}pez-Gal{\'\i}ndez, C and Lathrop, M and Dopazo, J and Sakuntabhai, A and Alcam{\'\i}, J} } @article {689, title = {COVID-19 Disease Map, building a computational repository of SARS-CoV-2 virus-host interaction mechanisms.}, journal = {Sci Data}, volume = {7}, year = {2020}, month = {2020 05 05}, pages = {136}, keywords = {Betacoronavirus, Computational Biology, Coronavirus Infections, COVID-19, Databases, Factual, Host Microbial Interactions, Host-Pathogen Interactions, Humans, International Cooperation, Models, Biological, Pandemics, Pneumonia, Viral, SARS-CoV-2}, issn = {2052-4463}, doi = {10.1038/s41597-020-0477-8}, author = {Ostaszewski, Marek and Mazein, Alexander and Gillespie, Marc E and Kuperstein, Inna and Niarakis, Anna and Hermjakob, Henning and Pico, Alexander R and Willighagen, Egon L and Evelo, Chris T and Hasenauer, Jan and Schreiber, Falk and Dr{\"a}ger, Andreas and Demir, Emek and Wolkenhauer, Olaf and Furlong, Laura I and Barillot, Emmanuel and Dopazo, Joaquin and Orta-Resendiz, Aurelio and Messina, Francesco and Valencia, Alfonso and Funahashi, Akira and Kitano, Hiroaki and Auffray, Charles and Balling, Rudi and Schneider, Reinhard} } @article {729, title = {The ELIXIR Human Copy Number Variations Community: building bioinformatics infrastructure for research.}, journal = {F1000Res}, volume = {9}, year = {2020}, month = {2020}, chapter = {1229}, abstract = {

Copy number variations (CNVs) are major causative contributors both in the genesis of genetic diseases and human neoplasias. While "High-Throughput" sequencing technologies are increasingly becoming the primary choice for genomic screening analysis, their ability to efficiently detect CNVs is still heterogeneous and remains to be developed. The aim of this white paper is to provide a guiding framework for the future contributions of ELIXIR{\textquoteright}s recently established with implications beyond human disease diagnostics and population genomics. This white paper is the direct result of a strategy meeting that took place in September 2018 in Hinxton (UK) and involved representatives of 11 ELIXIR Nodes. The meeting led to the definition of priority objectives and tasks, to address a wide range of CNV-related challenges ranging from detection and interpretation to sharing and training. Here, we provide suggestions on how to align these tasks within the ELIXIR Platforms strategy, and on how to frame the activities of this new ELIXIR Community in the international context.

}, keywords = {Computational Biology, DNA Copy Number Variations, High-Throughput Nucleotide Sequencing, Humans}, issn = {2046-1402}, doi = {10.12688/f1000research.24887.1}, author = {Salgado, David and Armean, Irina M and Baudis, Michael and Beltran, Sergi and Capella-Gut{\'\i}errez, Salvador and Carvalho-Silva, Denise and Dominguez Del Angel, Victoria and Dopazo, Joaquin and Furlong, Laura I and Gao, Bo and Garcia, Leyla and Gerloff, Dietlind and Gut, Ivo and Gyenesei, Attila and Habermann, Nina and Hancock, John M and Hanauer, Marc and Hovig, Eivind and Johansson, Lennart F and Keane, Thomas and Korbel, Jan and Lauer, Katharina B and Laurie, Steve and Lesko{\v s}ek, Brane and Lloyd, David and Marqu{\'e}s-Bonet, Tom{\'a}s and Mei, Hailiang and Monostory, Katalin and Pi{\~n}ero, Janet and Poterlowicz, Krzysztof and Rath, Ana and Samarakoon, Pubudu and Sanz, Ferran and Saunders, Gary and Sie, Daoud and Swertz, Morris A and Tsukanov, Kirill and Valencia, Alfonso and Vidak, Marko and Yenyxe Gonz{\'a}lez, Cristina and Ylstra, Bauke and B{\'e}roud, Christophe} } @article {693, title = {Immune Cell Associations with Cancer Risk.}, journal = {iScience}, volume = {23}, year = {2020}, month = {2020 Jul 24}, pages = {101296}, abstract = {

Proper immune system function hinders cancer development, but little is known about whether genetic variants linked to cancer risk alter immune cells. Here, we report 57 cancer risk loci associated with differences in immune and/or stromal cell contents in the corresponding tissue. Predicted target genes show expression and regulatory associations with immune features. Polygenic risk scores also reveal associations with immune and/or stromal cell contents, and breast cancer scores show consistent results in normal and tumor tissue. SH2B3 links peripheral alterations of several immune cell types to the risk of this malignancy. Pleiotropic SH2B3 variants are associated with breast cancer risk in BRCA1/2 mutation carriers. A retrospective case-cohort study indicates a positive association between blood counts of basophils, leukocytes, and monocytes and age at breast cancer diagnosis. These findings broaden our knowledge of the role of the immune system in cancer and highlight promising prevention strategies for individuals at high risk.

}, issn = {2589-0042}, doi = {10.1016/j.isci.2020.101296}, author = {Palomero, Luis and Galv{\'a}n-Femen{\'\i}a, Ivan and de Cid, Rafael and Esp{\'\i}n, Roderic and Barnes, Daniel R and Blommaert, Eline and Gil-Gil, Miguel and Falo, Catalina and Stradella, Agostina and Ouchi, Dan and Roso-Llorach, Albert and Violan, Concepci{\'o} and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin and Extremera, Ana Isabel and Garc{\'\i}a-Valero, Mar and Herranz, Carmen and Mateo, Francesca and Mereu, Elisabetta and Beesley, Jonathan and Chenevix-Trench, Georgia and Roux, Cecilia and Mak, Tak and Brunet, Joan and Hakem, Razq and Gorrini, Chiara and Antoniou, Antonis C and L{\'a}zaro, Conxi and Pujana, Miquel Angel} } @article {665, title = {Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies.}, journal = {J Med Genet}, volume = {57}, year = {2020}, month = {2020 04}, pages = {258-268}, abstract = {

PURPOSE: Patients with Fanconi anaemia (FA), a rare DNA repair genetic disease, exhibit chromosome fragility, bone marrow failure, malformations and cancer susceptibility. FA molecular diagnosis is challenging since FA is caused by point mutations and large deletions in 22 genes following three heritability patterns. To optimise FA patients{\textquoteright} characterisation, we developed a simplified but effective methodology based on whole exome sequencing (WES) and functional studies.

METHODS: 68 patients with FA were analysed by commercial WES services. Copy number variations were evaluated by sequencing data analysis with RStudio. To test missense variants, wt FANCA cDNA was cloned and variants were introduced by site-directed mutagenesis. Vectors were then tested for their ability to complement DNA repair defects of a FANCA-KO human cell line generated by TALEN technologies.

RESULTS: We identified 93.3\% of mutated alleles including large deletions. We determined the pathogenicity of three FANCA missense variants and demonstrated that two variants reported in mutations databases as {\textquoteright}affecting functions{\textquoteright} are SNPs. Deep analysis of sequencing data revealed patients{\textquoteright} true mutations, highlighting the importance of functional analysis. In one patient, no pathogenic variant could be identified in any of the 22 known FA genes, and in seven patients, only one deleterious variant could be identified (three patients each with FANCA and FANCD2 and one patient with FANCE mutations) CONCLUSION: WES and proper bioinformatics analysis are sufficient to effectively characterise patients with FA regardless of the rarity of their complementation group, type of mutations, mosaic condition and DNA source.

}, keywords = {Cell Line, DNA Copy Number Variations, DNA Repair, DNA-Binding Proteins, Fanconi Anemia, Fanconi Anemia Complementation Group A Protein, Female, Gene Knockout Techniques, Genetic Predisposition to Disease, Humans, Male, Mutation, Missense, Polymorphism, Single Nucleotide, whole exome sequencing}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2019-106249}, author = {Bogliolo, Massimo and Pujol, Roser and Aza-Carmona, Miriam and Mu{\~n}oz-Subirana, N{\'u}ria and Rodriguez-Santiago, Benjamin and Casado, Jos{\'e} Antonio and Rio, Paula and Bauser, Christopher and Reina-Castill{\'o}n, Judith and Lopez-Sanchez, Marcos and Gonzalez-Quereda, Lidia and Gallano, Pia and Catal{\'a}, Albert and Ruiz-Llobet, Ana and Badell, Isabel and Diaz-Heredia, Cristina and Hladun, Raquel and Senent, Leonort and Argiles, Bienvenida and Bergua Burgues, Juan Miguel and Ba{\~n}ez, Fatima and Arrizabalaga, Beatriz and L{\'o}pez Almaraz, Ricardo and Lopez, Monica and Figuera, {\'A}ngela and Molin{\'e}s, Antonio and P{\'e}rez de Soto, Inmaculada and Hernando, In{\'e}s and Mu{\~n}oz, Juan Antonio and Del Rosario Marin, Maria and Balma{\~n}a, Judith and Stjepanovic, Neda and Carrasco, Estela and Cuesta, Isabel and Cosuelo, Jos{\'e} Miguel and Regueiro, Alexandra and Moraleda Jimenez, Jos{\'e} and Galera-Mi{\~n}arro, Ana Maria and Rosi{\~n}ol, Laura and Carri{\'o}, Anna and Bel{\'e}ndez-Bieler, Cristina and Escudero Soto, Antonio and Cela, Elena and de la Mata, Gregorio and Fern{\'a}ndez-Delgado, Rafael and Garcia-Pardos, Maria Carmen and S{\'a}ez-Villaverde, Raquel and Barraga{\~n}o, Marta and Portugal, Raquel and Lendinez, Francisco and Hernadez, Ines and Vagace, Jos{\'e} Manue and Tapia, Maria and Nieto, Jos{\'e} and Garcia, Marta and Gonzalez, Macarena and Vicho, Cristina and Galvez, Eva and Valiente, Alberto and Antelo, Maria Luisa and Ancliff, Phil and Garc{\'\i}a, Francisco and Dopazo, Joaquin and Sevilla, Julian and Paprotka, Tobias and P{\'e}rez-Jurado, Luis Alberto and Bueren, Juan and Surralles, Jordi} } @article {694, title = {Platform to study intracellular polystyrene nanoplastic pollution and clinical outcomes.}, journal = {Stem Cells}, volume = {38}, year = {2020}, month = {2020 10 01}, pages = {1321-1325}, abstract = {

Increased pollution by plastics has become a serious global environmental problem, but the concerns for human health have been raised after reported presence of microplastics (MPs) and nanoplastics (NPs) in food and beverages. Unfortunately, few studies have investigate the potentially harmful effects of MPs/NPs on early human development and human health. Therefore, we used a new platform to study possible effects of polystyrene NPs (PSNPs) on the transcription profile of preimplantation human embryos and human induced pluripotent stem cells (hiPSCs). Two pluripotency genes, LEFTY1 and LEFTY2, which encode secreted ligands of the transforming growth factor-beta, were downregulated, while CA4 and OCLM, which are related to eye development, were upregulated in both samples. The gene set enrichment analysis showed that the development of atrioventricular heart valves and the dysfunction of cellular components, including extracellular matrix, were significantly affected after exposure of hiPSCs to PSNPs. Finally, using the HiPathia method, which uncovers disease mechanisms and predicts clinical outcomes, we determined the APOC3 circuit, which is responsible for increased risk for ischemic cardiovascular disease. These results clearly demonstrate that better understanding of NPs bioactivities and its implications for human health is of extreme importance. Thus, the presented platform opens further aspects to study interactions between different environmental and intracellular pollutions with the aim to decipher the mechanism and origin of human diseases.

}, keywords = {Environmental Pollution, Humans, Induced Pluripotent Stem Cells, Intracellular Space, Nanoparticles, Plastics, Polystyrenes, Transcriptome, Treatment Outcome}, issn = {1549-4918}, doi = {10.1002/stem.3244}, author = {Bojic, Sanja and Falco, Matias M and Stojkovic, Petra and Ljujic, Biljana and Gazdic Jankovic, Marina and Armstrong, Lyle and Markovic, Nebojsa and Dopazo, Joaquin and Lako, Majlinda and Bauer, Roman and Stojkovic, Miodrag} } @article {705, title = {SMN1 copy-number and sequence variant analysis from next-generation sequencing data.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 12}, pages = {2073-2077}, abstract = {

Spinal muscular atrophy (SMA) is a severe neuromuscular autosomal recessive disorder affecting 1/10,000 live births. Most SMA patients present homozygous deletion of SMN1, while the vast majority of SMA carriers present only a single SMN1 copy. The sequence similarity between SMN1 and SMN2, and the complexity of the SMN locus makes the estimation of the SMN1 copy-number by next-generation sequencing (NGS) very difficult. Here, we present SMAca, the first python tool to detect SMA carriers and estimate the absolute SMN1 copy-number using NGS data. Moreover, SMAca takes advantage of the knowledge of certain variants specific to SMN1 duplication to also identify silent carriers. This tool has been validated with a cohort of 326 samples from the Navarra 1000 Genomes Project (NAGEN1000). SMAca was developed with a focus on execution speed and easy installation. This combination makes it especially suitable to be integrated into production NGS pipelines. Source code and documentation are available at https://www.github.com/babelomics/SMAca.

}, keywords = {Base Sequence, DNA Copy Number Variations, High-Throughput Nucleotide Sequencing, Humans, Reproducibility of Results, Software, Survival of Motor Neuron 1 Protein}, issn = {1098-1004}, doi = {10.1002/humu.24120}, author = {L{\'o}pez-L{\'o}pez, Daniel and Loucera, Carlos and Carmona, Rosario and Aquino, Virginia and Salgado, Josefa and Pasalodos, Sara and Miranda, Mar{\'\i}a and Alonso, {\'A}ngel and Dopazo, Joaquin} } @article {710, title = {Transcriptomic Analysis of a Diabetic Skin-Humanized Mouse Model Dissects Molecular Pathways Underlying the Delayed Wound Healing Response.}, journal = {Genes (Basel)}, volume = {12}, year = {2020}, month = {2020 12 31}, abstract = {

Defective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients{\textquoteright} quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.

}, keywords = {Animals, Diabetes Mellitus, Experimental, Gene Expression Profiling, Gene Expression Regulation, Gene ontology, Humans, Metabolic Networks and Pathways, Mice, Mice, Nude, Microarray Analysis, Molecular Sequence Annotation, Principal Component Analysis, Signal Transduction, Skin, Skin Transplantation, Skin Ulcer, Streptozocin, Tissue Engineering, Transcriptome, Transplantation, Heterologous, Wound Healing}, issn = {2073-4425}, doi = {10.3390/genes12010047}, author = {Le{\'o}n, Carlos and Garcia-Garcia, Francisco and Llames, Sara and Garc{\'\i}a-P{\'e}rez, Eva and Carretero, Marta and Arriba, Mar{\'\i}a Del Carmen and Dopazo, Joaquin and Del Rio, Marcela and Escamez, Maria Jos{\'e} and Mart{\'\i}nez-Santamar{\'\i}a, Luc{\'\i}a} } @article {704, title = {Transparency and reproducibility in artificial intelligence.}, journal = {Nature}, volume = {586}, year = {2020}, month = {2020 10}, pages = {E14-E16}, keywords = {Algorithms, Artificial Intelligence, Reproducibility of Results}, issn = {1476-4687}, doi = {10.1038/s41586-020-2766-y}, author = {Haibe-Kains, Benjamin and Adam, George Alexandru and Hosny, Ahmed and Khodakarami, Farnoosh and Waldron, Levi and Wang, Bo and McIntosh, Chris and Goldenberg, Anna and Kundaje, Anshul and Greene, Casey S and Broderick, Tamara and Hoffman, Michael M and Leek, Jeffrey T and Korthauer, Keegan and Huber, Wolfgang and Brazma, Alvis and Pineau, Joelle and Tibshirani, Robert and Hastie, Trevor and Ioannidis, John P A and Quackenbush, John and Aerts, Hugo J W L} } @article {612, title = {Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 06 17}, pages = {2674}, abstract = {

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca{\textquoteright}s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60\% of combinations. However, 20\% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.

}, keywords = {ADAM17 Protein, Antineoplastic Combined Chemotherapy Protocols, Benchmarking, Biomarkers, Tumor, Cell Line, Tumor, Computational Biology, Datasets as Topic, Drug Antagonism, Drug Resistance, Neoplasm, Drug Synergism, Genomics, Humans, Molecular Targeted Therapy, mutation, Neoplasms, pharmacogenetics, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Treatment Outcome}, issn = {2041-1723}, doi = {10.1038/s41467-019-09799-2}, author = {Menden, Michael P and Wang, Dennis and Mason, Mike J and Szalai, Bence and Bulusu, Krishna C and Guan, Yuanfang and Yu, Thomas and Kang, Jaewoo and Jeon, Minji and Wolfinger, Russ and Nguyen, Tin and Zaslavskiy, Mikhail and Jang, In Sock and Ghazoui, Zara and Ahsen, Mehmet Eren and Vogel, Robert and Neto, Elias Chaibub and Norman, Thea and Tang, Eric K Y and Garnett, Mathew J and Veroli, Giovanni Y Di and Fawell, Stephen and Stolovitzky, Gustavo and Guinney, Justin and Dry, Jonathan R and Saez-Rodriguez, Julio} } @article {403, title = {A comparison of mechanistic signaling pathway activity analysis methods.}, journal = {Brief Bioinform}, volume = {20}, year = {2019}, month = {2019 09 27}, pages = {1655-1668}, abstract = {

Understanding the aspects of cell functionality that account for disease mechanisms or drug modes of action is a main challenge for precision medicine. Classical gene-based approaches ignore the modular nature of most human traits, whereas conventional pathway enrichment approaches produce only illustrative results of limited practical utility. Recently, a family of new methods has emerged that change the focus from the whole pathways to the definition of elementary subpathways within them that have any mechanistic significance and to the study of their activities. Thus, mechanistic pathway activity (MPA) methods constitute a new paradigm that allows recoding poorly informative genomic measurements into cell activity quantitative values and relate them to phenotypes. Here we provide a review on the MPA methods available and explain their contribution to systems medicine approaches for addressing challenges in the diagnostic and treatment of complex diseases.

}, keywords = {Algorithms, Humans, Postmortem Changes, Signal Transduction, Systems biology, Transcriptome}, issn = {1477-4054}, doi = {10.1093/bib/bby040}, author = {Amadoz, Alicia and Hidalgo, Marta R and Cubuk, Cankut and Carbonell-Caballero, Jos{\'e} and Dopazo, Joaquin} } @article {422, title = {Differential metabolic activity and discovery of therapeutic targets using summarized metabolic pathway models.}, journal = {NPJ Syst Biol Appl}, volume = {5}, year = {2019}, month = {2019}, pages = {7}, abstract = {

In spite of the increasing availability of genomic and transcriptomic data, there is still a gap between the detection of perturbations in gene expression and the understanding of their contribution to the molecular mechanisms that ultimately account for the phenotype studied. Alterations in the metabolism are behind the initiation and progression of many diseases, including cancer. The wealth of available knowledge on metabolic processes can therefore be used to derive mechanistic models that link gene expression perturbations to changes in metabolic activity that provide relevant clues on molecular mechanisms of disease and drug modes of action (MoA). In particular, pathway modules, which recapitulate the main aspects of metabolism, are especially suitable for this type of modeling. We present Metabolizer, a web-based application that offers an intuitive, easy-to-use interactive interface to analyze differences in pathway metabolic module activities that can also be used for class prediction and in silico prediction of knock-out (KO) effects. Moreover, Metabolizer can automatically predict the optimal KO intervention for restoring a diseased phenotype. We provide different types of validations of some of the predictions made by Metabolizer. Metabolizer is a web tool that allows understanding molecular mechanisms of disease or the MoA of drugs within the context of the metabolism by using gene expression measurements. In addition, this tool automatically suggests potential therapeutic targets for individualized therapeutic interventions.

}, keywords = {Computational Biology, Computer Simulation, Drug discovery, Gene Regulatory Networks, Humans, Internet, Metabolic Networks and Pathways, Models, Biological, Neoplasms, Phenotype, Software, Transcriptome}, issn = {2056-7189}, doi = {10.1038/s41540-019-0087-2}, author = {Cubuk, Cankut and Hidalgo, Marta R and Amadoz, Alicia and Rian, Kinza and Salavert, Francisco and Pujana, Miguel A and Mateo, Francesca and Herranz, Carmen and Carbonell-Caballero, Jos{\'e} and Dopazo, Joaquin} } @article {389, title = {Precision medicine needs pioneering clinical bioinformaticians.}, journal = {Brief Bioinform}, volume = {20}, year = {2019}, month = {2019 05 21}, pages = {752-766}, abstract = {

Success in precision medicine depends on accessing high-quality genetic and molecular data from large, well-annotated patient cohorts that couple biological samples to comprehensive clinical data, which in conjunction can lead to effective therapies. From such a scenario emerges the need for a new professional profile, an expert bioinformatician with training in clinical areas who can make sense of multi-omics data to improve therapeutic interventions in patients, and the design of optimized basket trials. In this review, we first describe the main policies and international initiatives that focus on precision medicine. Secondly, we review the currently ongoing clinical trials in precision medicine, introducing the concept of {\textquoteright}precision bioinformatics{\textquoteright}, and we describe current pioneering bioinformatics efforts aimed at implementing tools and computational infrastructures for precision medicine in health institutions around the world. Thirdly, we discuss the challenges related to the clinical training of bioinformaticians, and the urgent need for computational specialists capable of assimilating medical terminologies and protocols to address real clinical questions. We also propose some skills required to carry out common tasks in clinical bioinformatics and some tips for emergent groups. Finally, we explore the future perspectives and the challenges faced by precision medicine bioinformatics.

}, keywords = {Cohort Studies, Computational Biology, Humans, Precision Medicine}, issn = {1477-4054}, doi = {10.1093/bib/bbx144}, author = {G{\'o}mez-L{\'o}pez, Gonzalo and Dopazo, Joaquin and Cigudosa, Juan C and Valencia, Alfonso and Al-Shahrour, F{\'a}tima} } @article {428, title = {A crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection}, journal = {Nature Communications}, volume = {9}, year = {2018}, month = {Jan-12-2018}, doi = {10.1038/s41467-018-06735-8}, url = {http://www.nature.com/articles/s41467-018-06735-8http://www.nature.com/articles/s41467-018-06735-8.pdfhttp://www.nature.com/articles/s41467-018-06735-8.pdfhttp://www.nature.com/articles/s41467-018-06735-8}, author = {Fourati, Slim and Talla, Aarthi and Mahmoudian, Mehrad and Burkhart, Joshua G. and Kl{\'e}n, Riku and Henao, Ricardo and Yu, Thomas and Ayd{\i}n, Zafer and Yeung, Ka Yee and Ahsen, Mehmet Eren and Almugbel, Reem and Jahandideh, Samad and Liang, Xiao and Nordling, Torbj{\"o}rn E. M. and Shiga, Motoki and Stanescu, Ana and Vogel, Robert and Pandey, Gaurav and Chiu, Christopher and McClain, Micah T. and Woods, Christopher W. and Ginsburg, Geoffrey S. and Elo, Laura L. and Tsalik, Ephraim L. and Mangravite, Lara M. and Sieberts, Solveig K.} } @article {397, title = {The effects of death and post-mortem cold ischemia on human tissue transcriptomes.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 02 13}, pages = {490}, abstract = {

Post-mortem tissues samples are a key resource for investigating patterns of gene expression. However, the processes triggered by death and the post-mortem interval (PMI) can significantly alter physiologically normal RNA levels. We investigate the impact of PMI on gene expression using data from multiple tissues of post-mortem donors obtained from the GTEx project. We find that many genes change expression over relatively short PMIs in a tissue-specific manner, but this potentially confounding effect in a biological analysis can be minimized by taking into account appropriate covariates. By comparing ante- and post-mortem blood samples, we identify the cascade of transcriptional events triggered by death of the organism. These events do not appear to simply reflect stochastic variation resulting from mRNA degradation, but active and ongoing regulation of transcription. Finally, we develop a model to predict the time since death from the analysis of the transcriptome of a few readily accessible tissues.

}, keywords = {Blood, Cold Ischemia, Death, Female, gene expression, Humans, Models, Biological, Postmortem Changes, RNA, Messenger, Stochastic Processes, Transcriptome}, issn = {2041-1723}, doi = {10.1038/s41467-017-02772-x}, author = {Ferreira, Pedro G and Mu{\~n}oz-Aguirre, Manuel and Reverter, Ferran and S{\'a} Godinho, Caio P and Sousa, Abel and Amadoz, Alicia and Sodaei, Reza and Hidalgo, Marta R and Pervouchine, Dmitri and Carbonell-Caballero, Jos{\'e} and Nurtdinov, Ramil and Breschi, Alessandra and Amador, Raziel and Oliveira, Patr{\'\i}cia and Cubuk, Cankut and Curado, Jo{\~a}o and Aguet, Fran{\c c}ois and Oliveira, Carla and Dopazo, Joaquin and Sammeth, Michael and Ardlie, Kristin G and Guig{\'o}, Roderic} } @article {405, title = {Gene Expression Integration into Pathway Modules Reveals a Pan-Cancer Metabolic Landscape.}, journal = {Cancer Res}, volume = {78}, year = {2018}, month = {2018 11 01}, pages = {6059-6072}, abstract = {

Metabolic reprogramming plays an important role in cancer development and progression and is a well-established hallmark of cancer. Despite its inherent complexity, cellular metabolism can be decomposed into functional modules that represent fundamental metabolic processes. Here, we performed a pan-cancer study involving 9,428 samples from 25 cancer types to reveal metabolic modules whose individual or coordinated activity predict cancer type and outcome, in turn highlighting novel therapeutic opportunities. Integration of gene expression levels into metabolic modules suggests that the activity of specific modules differs between cancers and the corresponding tissues of origin. Some modules may cooperate, as indicated by the positive correlation of their activity across a range of tumors. The activity of many metabolic modules was significantly associated with prognosis at a stronger magnitude than any of their constituent genes. Thus, modules may be classified as tumor suppressors and oncomodules according to their potential impact on cancer progression. Using this modeling framework, we also propose novel potential therapeutic targets that constitute alternative ways of treating cancer by inhibiting their reprogrammed metabolism. Collectively, this study provides an extensive resource of predicted cancer metabolic profiles and dependencies. Combining gene expression with metabolic modules identifies molecular mechanisms of cancer undetected on an individual gene level and allows discovery of new potential therapeutic targets. .

}, keywords = {Cell Line, Tumor, Cluster Analysis, Disease Progression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Humans, Kaplan-Meier Estimate, Metabolome, mutation, Neoplasms, Oncogenes, Phenotype, Prognosis, RNA, Small Interfering, Sequence Analysis, RNA, Transcriptome, Treatment Outcome}, issn = {1538-7445}, doi = {10.1158/0008-5472.CAN-17-2705}, author = {Cubuk, Cankut and Hidalgo, Marta R and Amadoz, Alicia and Pujana, Miguel A and Mateo, Francesca and Herranz, Carmen and Carbonell-Caballero, Jos{\'e} and Dopazo, Joaquin} } @article {398, title = {Genomics of the origin and evolution of Citrus.}, journal = {Nature}, volume = {554}, year = {2018}, month = {2018 02 15}, pages = {311-316}, abstract = {

The genus Citrus, comprising some of the most widely cultivated fruit crops worldwide, includes an uncertain number of species. Here we describe ten natural citrus species, using genomic, phylogenetic and biogeographic analyses of 60 accessions representing diverse citrus germ plasms, and propose that citrus diversified during the late Miocene epoch through a rapid southeast Asian radiation that correlates with a marked weakening of the monsoons. A second radiation enabled by migration across the Wallace line gave rise to the Australian limes in the early Pliocene epoch. Further identification and analyses of hybrids and admixed genomes provides insights into the genealogy of major commercial cultivars of citrus. Among mandarins and sweet orange, we find an extensive network of relatedness that illuminates the domestication of these groups. Widespread pummelo admixture among these mandarins and its correlation with fruit size and acidity suggests a plausible role of pummelo introgression in the selection of palatable mandarins. This work provides a new evolutionary framework for the genus Citrus.

}, keywords = {Asia, Southeastern, Biodiversity, citrus, Crop Production, Evolution, Molecular, Genetic Speciation, Genome, Plant, Genomics, Haplotypes, Heterozygote, History, Ancient, Human Migration, Hybridization, Genetic, Phylogeny}, issn = {1476-4687}, doi = {10.1038/nature25447}, author = {Wu, Guohong Albert and Terol, Javier and Iba{\~n}ez, Victoria and L{\'o}pez-Garc{\'\i}a, Antonio and P{\'e}rez-Rom{\'a}n, Estela and Borred{\'a}, Carles and Domingo, Concha and Tadeo, Francisco R and Carbonell-Caballero, Jos{\'e} and Alonso, Roberto and Curk, Franck and Du, Dongliang and Ollitrault, Patrick and Roose, Mikeal L and Dopazo, Joaquin and Gmitter, Frederick G and Rokhsar, Daniel S and Talon, Manuel} } @article {404, title = {Models of cell signaling uncover molecular mechanisms of high-risk neuroblastoma and predict disease outcome.}, journal = {Biol Direct}, volume = {13}, year = {2018}, month = {2018 08 22}, pages = {16}, abstract = {

BACKGROUND: Despite the progress in neuroblastoma therapies the mortality of high-risk patients is still high (40-50\%) and the molecular basis of the disease remains poorly known. Recently, a mathematical model was used to demonstrate that the network regulating stress signaling by the c-Jun N-terminal kinase pathway played a crucial role in survival of patients with neuroblastoma irrespective of their MYCN amplification status. This demonstrates the enormous potential of computational models of biological modules for the discovery of underlying molecular mechanisms of diseases.

RESULTS: Since signaling is known to be highly relevant in cancer, we have used a computational model of the whole cell signaling network to understand the molecular determinants of bad prognostic in neuroblastoma. Our model produced a comprehensive view of the molecular mechanisms of neuroblastoma tumorigenesis and progression.

CONCLUSION: We have also shown how the activity of signaling circuits can be considered a reliable model-based prognostic biomarker.

REVIEWERS: This article was reviewed by Tim Beissbarth, Wenzhong Xiao and Joanna Polanska. For the full reviews, please go to the Reviewers{\textquoteright} comments section.

}, keywords = {Computational Biology, Gene Expression Regulation, Neoplastic, Humans, JNK Mitogen-Activated Protein Kinases, Models, Theoretical, Neuroblastoma, Signal Transduction}, issn = {1745-6150}, doi = {10.1186/s13062-018-0219-4}, author = {Hidalgo, Marta R and Amadoz, Alicia and Cubuk, Cankut and Carbonell-Caballero, Jos{\'e} and Dopazo, Joaquin} } @article {407, title = {The modular network structure of the mutational landscape of Acute Myeloid Leukemia.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0202926}, abstract = {

Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50\% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML. Novel candidate-genes, together with others previously described, were targeted resequenced in an independent cohort of 100 de novo AML patients classified in the cytogenetic intermediate-risk (IR) category. A mean of 4.89 mutations per sample were detected in 73 genes, 35 of which were mutated in more than one patient. After a network enrichment analysis, we defined a single in silico model and established a set of seed-genes that may trigger leukemogenesis in patients with normal karyotype. The high heterogeneity of gene mutations observed in AML patients suggested that a specific alteration could not be as essential as the interaction of deregulated pathways.

}, keywords = {Adult, Aged, Cytodiagnosis, Female, Gene Regulatory Networks, Genetic Association Studies, Genetic Heterogeneity, Humans, Karyotype, Leukemia, Myeloid, Acute, Male, Middle Aged, mutation, Neoplasm Proteins, Nucleophosmin, Prognosis, whole exome sequencing}, issn = {1932-6203}, doi = {10.1371/journal.pone.0202926}, author = {Ib{\'a}{\~n}ez, Mariam and Carbonell-Caballero, Jos{\'e} and Such, Esperanza and Garc{\'\i}a-Alonso, Luz and Liquori, Alessandro and L{\'o}pez-Pav{\'\i}a, Mar{\'\i}a and LLop, Marta and Alonso, Carmen and Barrag{\'a}n, Eva and G{\'o}mez-Segu{\'\i}, In{\'e}s and Neef, Alexander and Herv{\'a}s, David and Montesinos, Pau and Sanz, Guillermo and Sanz, Miguel Angel and Dopazo, Joaquin and Cervera, Jos{\'e}} } @article {386, title = {GGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonates.}, journal = {N Engl J Med}, volume = {376}, year = {2017}, month = {2017 05 04}, pages = {1794-1795}, keywords = {Aged, Amino Acid Sequence, Bone Density Conservation Agents, Dimethylallyltranstransferase, Diphosphonates, Exome, Farnesyltranstransferase, Female, Femoral Fractures, Geranyltranstransferase, Humans, Middle Aged, mutation}, issn = {1533-4406}, doi = {10.1056/NEJMc1612804}, url = {http://www.nejm.org/doi/full/10.1056/NEJMc1612804}, author = {Roca-Ayats, Neus and Balcells, Susana and Garcia-Giralt, Nat{\`a}lia and Falc{\'o}-Mascar{\'o}, Maite and Mart{\'\i}nez-Gil, N{\'u}ria and Abril, Josep F and Urreizti, Roser and Dopazo, Joaquin and Quesada-G{\'o}mez, Jos{\'e} M and Nogu{\'e}s, Xavier and Mellibovsky, Leonardo and Prieto-Alhambra, Daniel and Dunford, James E and Javaid, Muhammad K and Russell, R Graham and Grinberg, Daniel and D{\'\i}ez-P{\'e}rez, Adolfo} } @article {434, title = {High throughput estimation of functional cell activities reveals disease mechanisms and predicts relevant clinical outcomes.}, journal = {Oncotarget}, volume = {8}, year = {2017}, month = {2017 Jan 17}, pages = {5160-5178}, abstract = {

Understanding the aspects of the cell functionality that account for disease or drug action mechanisms is a main challenge for precision medicine. Here we propose a new method that models cell signaling using biological knowledge on signal transduction. The method recodes individual gene expression values (and/or gene mutations) into accurate measurements of changes in the activity of signaling circuits, which ultimately constitute high-throughput estimations of cell functionalities caused by gene activity within the pathway. Moreover, such estimations can be obtained either at cohort-level, in case/control comparisons, or personalized for individual patients. The accuracy of the method is demonstrated in an extensive analysis involving 5640 patients from 12 different cancer types. Circuit activity measurements not only have a high diagnostic value but also can be related to relevant disease outcomes such as survival, and can be used to assess therapeutic interventions.

}, keywords = {Computational Biology, gene expression, Gene Regulatory Networks, Humans, mutation, Neoplasms, Precision Medicine, Sequence Analysis, RNA, Signal Transduction}, issn = {1949-2553}, doi = {10.18632/oncotarget.14107}, author = {Hidalgo, Marta R and Cubuk, Cankut and Amadoz, Alicia and Salavert, Francisco and Carbonell-Caballero, Jos{\'e} and Dopazo, Joaquin} } @article {388, title = {Reference genome assessment from a population scale perspective: an accurate profile of variability and noise.}, journal = {Bioinformatics}, volume = {33}, year = {2017}, month = {2017 Nov 15}, pages = {3511-3517}, abstract = {

Motivation: Current plant and animal genomic studies are often based on newly assembled genomes that have not been properly consolidated. In this scenario, misassembled regions can easily lead to false-positive findings. Despite quality control scores are included within genotyping protocols, they are usually employed to evaluate individual sample quality rather than reference sequence reliability. We propose a statistical model that combines quality control scores across samples in order to detect incongruent patterns at every genomic region. Our model is inherently robust since common artifact signals are expected to be shared between independent samples over misassembled regions of the genome.

Results: The reliability of our protocol has been extensively tested through different experiments and organisms with accurate results, improving state-of-the-art methods. Our analysis demonstrates synergistic relations between quality control scores and allelic variability estimators, that improve the detection of misassembled regions, and is able to find strong artifact signals even within the human reference assembly. Furthermore, we demonstrated how our model can be trained to properly rank the confidence of a set of candidate variants obtained from new independent samples.

Availability and implementation: This tool is freely available at http://gitlab.com/carbonell/ces.

Contact: jcarbonell.cipf@gmail.com or joaquin.dopazo@juntadeandalucia.es.

Supplementary information: Supplementary data are available at Bioinformatics online.

}, keywords = {Animals, Genetic Variation, Genome, Genomics, Genotype, Humans, Models, Statistical, Quality Control, Reproducibility of Results, Software}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btx482}, url = {https://academic.oup.com/bioinformatics/article-lookup/doi/10.1093/bioinformatics/btx482}, author = {Carbonell-Caballero, Jos{\'e} and Amadoz, Alicia and Alonso, Roberto and Hidalgo, Marta R and Cubuk, Cankut and Conesa, David and L{\'o}pez-Qu{\'\i}lez, Antonio and Dopazo, Joaquin} } @article {382, title = {VISMapper: ultra-fast exhaustive cartography of viral insertion sites for gene therapy.}, journal = {BMC Bioinformatics}, volume = {18}, year = {2017}, month = {2017 Sep 20}, pages = {421}, abstract = {

BACKGROUND: The possibility of integrating viral vectors to become a persistent part of the host genome makes them a crucial element of clinical gene therapy. However, viral integration has associated risks, such as the unintentional activation of oncogenes that can result in cancer. Therefore, the analysis of integration sites of retroviral vectors is a crucial step in developing safer vectors for therapeutic use.

RESULTS: Here we present VISMapper, a vector integration site analysis web server, to analyze next-generation sequencing data for retroviral vector integration sites. VISMapper can be found at: http://vismapper.babelomics.org .

CONCLUSIONS: Because it uses novel mapping algorithms VISMapper is remarkably faster than previous available programs. It also provides a useful graphical interface to analyze the integration sites found in the genomic context.

}, keywords = {Base Sequence, Genetic Therapy, Genetic Vectors, High-Throughput Nucleotide Sequencing, Humans, Internet, User-Computer Interface, Virus Integration}, issn = {1471-2105}, doi = {10.1186/s12859-017-1837-z}, author = {Juanes, Jos{\'e} M and Gallego, Asunci{\'o}n and T{\'a}rraga, Joaqu{\'\i}n and Chaves, Felipe J and Marin-Garcia, Pablo and Medina, Ignacio and Arnau, Vicente and Dopazo, Joaquin} } @article {431, title = {Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes}, journal = {Genome Biology}, volume = {18}, year = {2017}, month = {Jan-12-2017}, doi = {10.1186/s13059-017-1174-6}, url = {http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-6http://link.springer.com/content/pdf/10.1186/s13059-017-1174-6.pdf}, author = {Gui, Hongsheng and Schriemer, Duco and Cheng, William W. and Chauhan, Rajendra K. and Anti{\v n}olo, Guillermo and Berrios, Courtney and Bleda, Marta and Brooks, Alice S. and Brouwer, Rutger W. W. and Burns, Alan J. and Cherny, Stacey S. and Dopazo, Joaquin and Eggen, Bart J. L. and Griseri, Paola and Jalloh, Binta and Le, Thuy-Linh and Lui, Vincent C. H. and Luz{\'o}n-Toro, Berta and Matera, Ivana and Ngan, Elly S. W. and Pelet, Anna and Ruiz-Ferrer, Macarena and Sham, Pak C. and Shepherd, Iain T. and So, Man-Ting and Sribudiani, Yunia and Tang, Clara S. M. and van den Hout, Mirjam C. G. N. and van der Linde, Herma C. and van Ham, Tjakko J. and van IJcken, Wilfred F. J. and Verheij, Joke B. G. M. and Amiel, Jeanne and Borrego, Salud and Ceccherini, Isabella and Chakravarti, Aravinda and Lyonnet, Stanislas and Tam, Paul K. H. and Garcia-Barcel{\'o}, Maria-Merc{\`e} and Hofstra, Robert M. W.} } @article {1231, title = {Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes.}, journal = {Genome biology}, volume = {18}, year = {2017}, month = {2017 Mar 08}, pages = {48}, abstract = {BACKGROUND: Hirschsprung disease (HSCR), which is congenital obstruction of the bowel, results from a failure of enteric nervous system (ENS) progenitors to migrate, proliferate, differentiate, or survive within the distal intestine. Previous studies that have searched for genes underlying HSCR have focused on ENS-related pathways and genes not fitting the current knowledge have thus often been ignored. We identify and validate novel HSCR genes using whole exome sequencing (WES), burden tests, in silico prediction, unbiased in vivo analyses of the mutated genes in zebrafish, and expression analyses in zebrafish, mouse, and human. RESULTS: We performed de novo mutation (DNM) screening on 24 HSCR trios. We identify 28 DNMs in 21 different genes. Eight of the DNMs we identified occur in RET, the main HSCR gene, and the remaining 20 DNMs reside in genes not reported in the ENS. Knockdown of all 12 genes with missense or loss-of-function DNMs showed that the orthologs of four genes (DENND3, NCLN, NUP98, and TBATA) are indispensable for ENS development in zebrafish, and these results were confirmed by CRISPR knockout. These genes are also expressed in human and mouse gut and/or ENS progenitors. Importantly, the encoded proteins are linked to neuronal processes shared by the central nervous system and the ENS. CONCLUSIONS: Our data open new fields of investigation into HSCR pathology and provide novel insights into the development of the ENS. Moreover, the study demonstrates that functional analyses of genes carrying DNMs are warranted to delineate the full genetic architecture of rare complex diseases.}, keywords = {Hirschprung, Rare Disease, WES}, issn = {1474-760X}, doi = {10.1186/s13059-017-1174-6}, url = {http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-6}, author = {Gui, Hongsheng and Schriemer, Duco and Cheng, William W and Chauhan, Rajendra K and Anti{\v n}olo, Guillermo and Berrios, Courtney and Bleda, Marta and Brooks, Alice S and Brouwer, Rutger W W and Burns, Alan J and Cherny, Stacey S and Dopazo, Joaquin and Eggen, Bart J L and Griseri, Paola and Jalloh, Binta and Le, Thuy-Linh and Lui, Vincent C H and Luz{\'o}n-Toro, Berta and Matera, Ivana and Ngan, Elly S W and Pelet, Anna and Ruiz-Ferrer, Macarena and Sham, Pak C and Shepherd, Iain T and So, Man-Ting and Sribudiani, Yunia and Tang, Clara S M and van den Hout, Mirjam C G N and van der Linde, Herma C and van Ham, Tjakko J and van IJcken, Wilfred F J and Verheij, Joke B G M and Amiel, Jeanne and Borrego, Salud and Ceccherini, Isabella and Chakravarti, Aravinda and Lyonnet, Stanislas and Tam, Paul K H and Garcia-Barcel{\'o}, Maria-Merc{\`e} and Hofstra, Robert Mw} } @article {1184, title = {267 Spanish exomes reveal population-specific differences in disease-related genetic variation.}, journal = {Molecular biology and evolution}, year = {2016}, month = {2016 Jan 13}, abstract = {Recent results from large-scale genomic projects suggest that allele frequencies, which are highly relevant for medical purposes, differ considerably across different populations. The need for a detailed catalogue of local variability motivated the whole exome sequencing of 267 unrelated individuals, representative of the healthy Spanish population. Like in other studies, a considerable number of rare variants were found (almost one third of the described variants). There were also relevant differences in allelic frequencies in polymorphic variants, including about 10,000 polymorphisms private to the Spanish population. The allelic frequencies of variants conferring susceptibility to complex diseases (including cancer, schizophrenia, Alzheimer disease, type 2 diabetes and other pathologies) were overall similar to those of other populations. However, the trend is the opposite for variants linked to Mendelian and rare diseases (including several retinal degenerative dystrophies and cardiomyopathies) that show marked frequency differences between populations. Interestingly, a correspondence between differences in allelic frequencies and disease prevalence was found, highlighting the relevance of frequency differences in disease risk. These differences are also observed in variants that disrupt known drug binding sites, suggesting an important role for local variability in population-specific drug resistances or adverse effects. We have made the Spanish population variant server web page that contains population frequency information for the complete list of 170,888 variant positions we found publicly available (http://spv.babelomics.org/), We show that it if fundamental to determine population-specific variant frequencies in order to distinguish real disease associations from population-specific polymorphisms.}, keywords = {disease, NGS, polymorphisms, Population genomics, prioritization, SNP}, issn = {1537-1719}, doi = {10.1093/molbev/msw005}, url = {https://mbe.oxfordjournals.org/content/early/2016/02/17/molbev.msw005.full}, author = {Joaqu{\'\i}n Dopazo and Amadoz, Alicia and Bleda, Marta and Garc{\'\i}a-Alonso, Luz and Alem{\'a}n, Alejandro and Garcia-Garcia, Francisco and Rodriguez, Juan A and Daub, Josephine T and Muntan{\'e}, Gerard and Antonio Rueda and Vela-Boza, Alicia and L{\'o}pez-Domingo, Francisco J and Florido, Javier P and Arce, Pablo and Ruiz-Ferrer, Macarena and M{\'e}ndez-Vidal, Cristina and Arnold, Todd E and Spleiss, Olivia and Alvarez-Tejado, Miguel and Navarro, Arcadi and Bhattacharya, Shomi S and Borrego, Salud and Santoyo-L{\'o}pez, Javier and Anti{\v n}olo, Guillermo} } @article {1203, title = {Actionable pathways: interactive discovery of therapeutic targets using signaling pathway models.}, journal = {Nucleic acids research}, year = {2016}, month = {2016 May 2}, abstract = {The discovery of actionable targets is crucial for targeted therapies and is also a constituent part of the drug discovery process. The success of an intervention over a target depends critically on its contribution, within the complex network of gene interactions, to the cellular processes responsible for disease progression or therapeutic response. Here we present PathAct, a web server that predicts the effect that interventions over genes (inhibitions or activations that simulate knock-outs, drug treatments or over-expressions) can have over signal transmission within signaling pathways and, ultimately, over the cell functionalities triggered by them. PathAct implements an advanced graphical interface that provides a unique interactive working environment in which the suitability of potentially actionable genes, that could eventually become drug targets for personalized or individualized therapies, can be easily tested. The PathAct tool can be found at: http://pathact.babelomics.org.}, keywords = {actionable genes, Disease mechanism, drug action mechanism, Drug discovery, pathway analysis, personalized medicine, signalling, therapeutic targets}, issn = {1362-4962}, doi = {10.1093/nar/gkw369}, url = {http://nar.oxfordjournals.org/content/early/2016/05/02/nar.gkw369.full}, author = {Salavert, Francisco and Hidago, Marta R and Amadoz, Alicia and Cubuk, Cankut and Medina, Ignacio and Crespo, Daniel and Carbonell-Caballero, Jos{\'e} and Joaqu{\'\i}n Dopazo} } @article {1182, title = {Assessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy.}, journal = {The Journal of molecular diagnostics : JMD}, year = {2016}, month = {2016 Jan 2}, abstract = {Charcot-Marie-Tooth disease is characterized by broad genetic heterogeneity with >50 known disease-associated genes. Mutations in some of these genes can cause a pure motor form of hereditary motor neuropathy, the genetics of which are poorly characterized. We designed a panel comprising 56 genes associated with Charcot-Marie-Tooth disease/hereditary motor neuropathy. We validated this diagnostic tool by first testing 11 patients with pathological mutations. A cohort of 33 affected subjects was selected for this study. The DNAJB2 c.352+1G>A mutation was detected in two cases; novel changes and/or variants with low frequency (<1\%) were found in 12 cases. There were no candidate variants in 18 cases, and amplification failed for one sample. The DNAJB2 c.352+1G>A mutation was also detected in three additional families. On haplotype analysis, all of the patients from these five families shared the same haplotype; therefore, the DNAJB2 c.352+1G>A mutation may be a founder event. Our gene panel allowed us to perform a very rapid and cost-effective screening of genes involved in Charcot-Marie-Tooth disease/hereditary motor neuropathy. Our diagnostic strategy was robust in terms of both coverage and read depth for all of the genes and patient samples. These findings demonstrate the difficulty in achieving a definitive molecular diagnosis because of the complexity of interpreting new variants and the genetic heterogeneity that is associated with these neuropathies.}, keywords = {Charcot-Marie-Tooth, CMT, Diagnostic, NGS, Panels, rare diseases, Targeted resequencing}, issn = {1943-7811}, doi = {10.1016/j.jmoldx.2015.10.005}, url = {http://www.sciencedirect.com/science/article/pii/S1525157815002615}, author = {Lupo, Vincenzo and Garcia-Garcia, Francisco and Sancho, Paula and Tello, Cristina and Garc{\'\i}a-Romero, Mar and Villarreal, Liliana and Alberti, Antonia and Sivera, Rafael and Joaqu{\'\i}n Dopazo and Pascual-Pascual, Samuel I and M{\'a}rquez-Infante, Celedonio and Casasnovas, Carlos and Sevilla, Teresa and Espin{\'o}s, Carmen} } @article {560, title = {HPG pore: an efficient and scalable framework for nanopore sequencing data}, journal = {BMC Bioinformatics}, volume = {17}, year = {2016}, month = {Jan-12-2016}, doi = {10.1186/s12859-016-0966-0}, url = {http://www.biomedcentral.com/1471-2105/17/107http://link.springer.com/content/pdf/10.1186/s12859-016-0966-0}, author = {T{\'a}rraga, Joaqu{\'\i}n and Gallego, Asunci{\'o}n and Arnau, Vicente and Medina, Ignacio and Dopazo, Joaquin} } @article {1195, title = {HPG pore: an efficient and scalable framework for nanopore sequencing data.}, journal = {BMC bioinformatics}, volume = {17}, year = {2016}, month = {2016}, pages = {107}, abstract = {BACKGROUND: The use of nanopore technologies is expected to spread in the future because they are portable and can sequence long fragments of DNA molecules without prior amplification. The first nanopore sequencer available, the MinION{\texttrademark} from Oxford Nanopore Technologies, is a USB-connected, portable device that allows real-time DNA analysis. In addition, other new instruments are expected to be released soon, which promise to outperform the current short-read technologies in terms of throughput. Despite the flood of data expected from this technology, the data analysis solutions currently available are only designed to manage small projects and are not scalable. RESULTS: Here we present HPG Pore, a toolkit for exploring and analysing nanopore sequencing data. HPG Pore can run on both individual computers and in the Hadoop distributed computing framework, which allows easy scale-up to manage the large amounts of data expected to result from extensive use of nanopore technologies in the future. CONCLUSIONS: HPG Pore allows for virtually unlimited sequencing data scalability, thus guaranteeing its continued management in near future scenarios. HPG Pore is available in GitHub at http://github.com/opencb/hpg-pore .}, keywords = {hadoop, HPC, nanopore, NGS}, issn = {1471-2105}, doi = {10.1186/s12859-016-0966-0}, url = {http://www.biomedcentral.com/1471-2105/17/107}, author = {T{\'a}rraga, Joaqu{\'\i}n and Gallego, Asunci{\'o}n and Arnau, Vicente and Medina, Ignacio and Dopazo, Joaquin} } @article {561, title = {Human DNA methylomes of neurodegenerative diseases show common epigenomic patterns.}, journal = {Transl Psychiatry}, volume = {6}, year = {2016}, month = {2016 Jan 19}, pages = {e718}, abstract = {

Different neurodegenerative disorders often show similar lesions, such as the presence of amyloid plaques, TAU-neurotangles and synuclein inclusions. The genetically inherited forms are rare, so we wondered whether shared epigenetic aberrations, such as those affecting DNA methylation, might also exist. The studied samples were gray matter samples from the prefrontal cortex of control and neurodegenerative disease-associated cases. We performed the DNA methylation analyses of Alzheimer{\textquoteright}s disease, dementia with Lewy bodies, Parkinson{\textquoteright}s disease and Alzheimer-like neurodegenerative profile associated with Down{\textquoteright}s syndrome samples. The DNA methylation landscapes obtained show that neurodegenerative diseases share similar aberrant CpG methylation shifts targeting a defined gene set. Our findings suggest that neurodegenerative disorders might have similar pathogenetic mechanisms that subsequently evolve into different clinical entities. The identified aberrant DNA methylation changes can be used as biomarkers of the disorders and as potential new targets for the development of new therapies.

}, keywords = {Adult, Aged, Aged, 80 and over, DNA Methylation, Epigenomics, Female, Humans, Male, Middle Aged, neurodegenerative diseases, Prefrontal Cortex, Tissue Array Analysis}, issn = {2158-3188}, doi = {10.1038/tp.2015.214}, author = {Sanchez-Mut, J V and Heyn, H and Vidal, E and Moran, S and Sayols, S and Delgado-Morales, R and Schultz, M D and Ansoleaga, B and Garcia-Esparcia, P and Pons-Espinal, M and de Lagran, M M and Dopazo, J and Rabano, A and Avila, J and Dierssen, M and Lott, I and Ferrer, I and Ecker, J R and Esteller, M} } @article {437, title = {Identification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa.}, journal = {Sci Rep}, volume = {6}, year = {2016}, month = {2016 10 13}, pages = {35370}, abstract = {

Retinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors.

}, keywords = {Aged, Animals, Co-Repressor Proteins, Codon, Nonsense, Cohort Studies, Comparative Genomic Hybridization, Consanguinity, DNA Mutational Analysis, Exome, Eye Proteins, Female, Gene Expression Regulation, Genes, Recessive, Homeodomain Proteins, Homozygote, Humans, Male, Mice, Middle Aged, Polymorphism, Single Nucleotide, Protein Interaction Mapping, Retina, Retinal Dystrophies, Retinal Rod Photoreceptor Cells, Retinitis pigmentosa, Spain, Trans-Activators, Transcription Factors}, issn = {2045-2322}, doi = {10.1038/srep35370}, author = {Corton, M and Avila-Fern{\'a}ndez, A and Campello, L and S{\'a}nchez, M and Benavides, B and L{\'o}pez-Molina, M I and Fern{\'a}ndez-S{\'a}nchez, L and S{\'a}nchez-Alcudia, R and da Silva, L R J and Reyes, N and Mart{\'\i}n-Garrido, E and Zurita, O and Fern{\'a}ndez-San Jos{\'e}, P and P{\'e}rez-Carro, R and Garc{\'\i}a-Garc{\'\i}a, F and Dopazo, J and Garc{\'\i}a-Sandoval, B and Cuenca, N and Ayuso, C} } @article {452, title = {Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel.}, journal = {Sci Rep}, volume = {6}, year = {2016}, month = {2016 Apr 01}, pages = {23910}, abstract = {

Next-generation sequencing (NGS) has overcome important limitations to the molecular diagnosis of Inherited Retinal Dystrophies (IRD) such as the high clinical and genetic heterogeneity and the overlapping phenotypes. The purpose of this study was the identification of the genetic defect in 32 Spanish families with different forms of IRD. With that aim, we implemented a custom NGS panel comprising 64 IRD-associated genes in our population, and three disease-associated intronic regions. A total of 37 pathogenic mutations (14 novels) were found in 73\% of IRD patients ranging from 50\% for autosomal dominant cases, 75\% for syndromic cases, 83\% for autosomal recessive cases, and 100\% for X-linked cases. Additionally, unexpected phenotype-genotype correlations were found in 6 probands, which led to the refinement of their clinical diagnoses. Furthermore, intra- and interfamilial phenotypic variability was observed in two cases. Moreover, two cases unsuccessfully analysed by exome sequencing were resolved by applying this panel. Our results demonstrate that this hypothesis-free approach based on frequently mutated, population-specific loci is highly cost-efficient for the routine diagnosis of this heterogeneous condition and allows the unbiased analysis of a miscellaneous cohort. The molecular information found here has aid clinical diagnosis and has improved genetic counselling and patient management.

}, keywords = {Alleles, Computer Simulation, DNA Copy Number Variations, DNA Mutational Analysis, Eye Proteins, Gene Library, Genetic Association Studies, Genetic Heterogeneity, Genetic Therapy, High-Throughput Nucleotide Sequencing, Humans, mutation, Phenotype, Retinal Dystrophies}, issn = {2045-2322}, doi = {10.1038/srep23910}, author = {Bravo-Gil, Nereida and M{\'e}ndez-Vidal, Cristina and Romero-P{\'e}rez, Laura and Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Rodr{\'\i}guez-de la R{\'u}a, Enrique and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {450, title = {Screening of CD96 and ASXL1 in 11 patients with Opitz C or Bohring-Opitz syndromes.}, journal = {Am J Med Genet A}, volume = {170A}, year = {2016}, month = {2016 Jan}, pages = {24-31}, abstract = {

Opitz C trigonocephaly (or Opitz C syndrome, OTCS) and Bohring-Opitz syndrome (BOS or C-like syndrome) are two rare genetic disorders with phenotypic overlap. The genetic causes of these diseases are not understood. However, two genes have been associated with OTCS or BOS with dominantly inherited de novo mutations. Whereas CD96 has been related to OTCS (one case) and to BOS (one case), ASXL1 has been related to BOS only (several cases). In this study we analyze CD96 and ASXL1 in a group of 11 affected individuals, including 2 sibs, 10 of them were diagnosed with OTCS, and one had a BOS phenotype. Exome sequences were available on six patients with OTCS and three parent pairs. Thus, we could analyze the CD96 and ASXL1 sequences in these patients bioinformatically. Sanger sequencing of all exons of CD96 and ASXL1 was carried out in the remaining patients. Detailed scrutiny of the sequences and assessment of variants allowed us to exclude putative pathogenic and private mutations in all but one of the patients. In this patient (with BOS) we identified a de novo mutation in ASXL1 (c.2100dupT). By nature and location within the gene, this mutation resembles those previously described in other BOS patients and we conclude that it may be responsible for the condition. Our results indicate that in 10 of 11, the disease (OTCS or BOS) cannot be explained by small changes in CD96 or ASXL1. However, the cohort is too small to make generalizations about the genetic etiology of these diseases.

}, keywords = {Adolescent, Antigens, CD, Child, Child, Preschool, Craniosynostoses, Exome, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Intellectual Disability, Male, mutation, Pedigree, Phenotype, Prognosis, Repressor Proteins}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37418}, author = {Urreizti, Roser and Roca-Ayats, Neus and Trepat, Judith and Garcia-Garcia, Francisco and Alem{\'a}n, Alejandro and Orteschi, Daniela and Marangi, Giuseppe and Neri, Giovanni and Opitz, John M and Dopazo, Joaquin and Cormand, Bru and Vilageliu, Llu{\"\i}sa and Balcells, Susana and Grinberg, Daniel} } @article {438, title = {Web-based network analysis and visualization using CellMaps.}, journal = {Bioinformatics}, volume = {32}, year = {2016}, month = {2016 10 01}, pages = {3041-3}, abstract = {

UNLABELLED: : CellMaps is an HTML5 open-source web tool that allows displaying, editing, exploring and analyzing biological networks as well as integrating metadata into them. Computations and analyses are remotely executed in high-end servers, and all the functionalities are available through RESTful web services. CellMaps can easily be integrated in any web page by using an available JavaScript API.

AVAILABILITY AND IMPLEMENTATION: The application is available at: http://cellmaps.babelomics.org/ and the code can be found in: https://github.com/opencb/cell-maps The client is implemented in JavaScript and the server in C and Java.

CONTACT: jdopazo@cipf.es

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

}, keywords = {Biochemical Phenomena, Internet, Software}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btw332}, author = {Salavert, Francisco and Garc{\'\i}a-Alonso, Luz and S{\'a}nchez, Rub{\'e}n and Alonso, Roberto and Bleda, Marta and Medina, Ignacio and Dopazo, Joaquin} } @article {558, title = {Whole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype.}, journal = {Hum Genet}, volume = {135}, year = {2016}, month = {2016 12}, pages = {1343-1354}, abstract = {

Classical Rett syndrome (RTT) is a neurodevelopmental disorder where most of cases carry MECP2 mutations. Atypical RTT variants involve mutations in CDKL5 and FOXG1. However, a subset of RTT patients remains that do not carry any mutation in the described genes. Whole exome sequencing was carried out in a cohort of 21 female probands with clinical features overlapping with those of RTT, but without mutations in the customarily studied genes. Candidates were functionally validated by assessing the appearance of a neurological phenotype in Caenorhabditis elegans upon disruption of the corresponding ortholog gene. We detected pathogenic variants that accounted for the RTT-like phenotype in 14 (66.6~\%) patients. Five patients were carriers of mutations in genes already known to be associated with other syndromic neurodevelopmental disorders. We determined that the other patients harbored mutations in genes that have not previously been linked to RTT or other neurodevelopmental syndromes, such as the ankyrin repeat containing protein ANKRD31 or the neuronal acetylcholine receptor subunit alpha-5 (CHRNA5). Furthermore, worm assays demonstrated that mutations in the studied candidate genes caused locomotion defects. Our findings indicate that mutations in a variety of genes contribute to the development of RTT-like phenotypes.

}, keywords = {Adolescent, Adult, Animals, Caenorhabditis elegans, Carrier Proteins, Cell Cycle Proteins, Child, Child, Preschool, DNA Mutational Analysis, Exome, Female, Forkhead Transcription Factors, Genetic Variation, High-Throughput Nucleotide Sequencing, Humans, Methyl-CpG-Binding Protein 2, mutation, Nerve Tissue Proteins, Protein Serine-Threonine Kinases, Receptors, Nicotinic, Rett Syndrome}, issn = {1432-1203}, doi = {10.1007/s00439-016-1721-3}, author = {Lucariello, Mario and Vidal, Enrique and Vidal, Silvia and Saez, Mauricio and Roa, Laura and Huertas, Dori and Pineda, Merc{\`e} and Dalf{\'o}, Esther and Dopazo, Joaquin and Jurado, Paola and Armstrong, Judith and Esteller, Manel} } @article {1128, title = {Assessing the impact of mutations found in next generation sequencing data over human signaling pathways.}, journal = {Nucleic acids research}, volume = {43}, number = {W1}, year = {2015}, month = {2015 Apr 16}, pages = {W270-W275}, abstract = {Modern sequencing technologies produce increasingly detailed data on genomic variation. However, conventional methods for relating either individual variants or mutated genes to phenotypes present known limitations given the complex, multigenic nature of many diseases or traits. Here we present PATHiVar, a web-based tool that integrates genomic variation data with gene expression tissue information. PATHiVar constitutes a new generation of genomic data analysis methods that allow studying variants found in next generation sequencing experiment in the context of signaling pathways. Simple Boolean models of pathways provide detailed descriptions of the impact of mutations in cell functionality so as, recurrences in functionality failures can easily be related to diseases, even if they are produced by mutations in different genes. Patterns of changes in signal transmission circuits, often unpredictable from individual genes mutated, correspond to patterns of affected functionalities that can be related to complex traits such as disease progression, drug response, etc. PATHiVar is available at: http://pathivar.babelomics.org.}, keywords = {NGS, pathways, signalling, Systems biology}, issn = {1362-4962}, doi = {10.1093/nar/gkv349}, url = {http://nar.oxfordjournals.org/content/43/W1/W270}, author = {Hernansaiz-Ballesteros, Rosa D and Salavert, Francisco and Sebasti{\'a}n-Leon, Patricia and Alem{\'a}n, Alejandro and Medina, Ignacio and Joaqu{\'\i}n Dopazo} } @article {1129, title = {Babelomics 5.0: functional interpretation for new generations of genomic data.}, journal = {Nucleic acids research}, volume = {43}, number = {W1}, year = {2015}, month = {2015 Apr 20}, pages = {W117-W121}, abstract = {Babelomics has been running for more than one decade offering a user-friendly interface for the functional analysis of gene expression and genomic data. Here we present its fifth release, which includes support for Next Generation Sequencing data including gene expression (RNA-seq), exome or genome resequencing. Babelomics has simplified its interface, being now more intuitive. Improved visualization options, such as a genome viewer as well as an interactive network viewer, have been implemented. New technical enhancements at both, client and server sides, makes the user experience faster and more dynamic. Babelomics offers user-friendly access to a full range of methods that cover: (i) primary data analysis, (ii) a variety of tests for different experimental designs and (iii) different enrichment and network analysis algorithms for the interpretation of the results of such tests in the proper functional context. In addition to the public server, local copies of Babelomics can be downloaded and installed. Babelomics is freely available at: http://www.babelomics.org.}, keywords = {babelomics, data integration, gene set analysis, interactome, network analysis, NGS, RNA-seq, Systems biology, transcriptomics}, issn = {1362-4962}, doi = {10.1093/nar/gkv384}, url = {http://nar.oxfordjournals.org/content/43/W1/W117}, author = {Alonso, Roberto and Salavert, Francisco and Garcia-Garcia, Francisco and Carbonell-Caballero, Jos{\'e} and Bleda, Marta and Garc{\'\i}a-Alonso, Luz and Sanchis-Juan, Alba and Perez-Gil, Daniel and Marin-Garcia, Pablo and S{\'a}nchez, Rub{\'e}n and Cubuk, Cankut and Hidalgo, Marta R and Amadoz, Alicia and Hernansaiz-Ballesteros, Rosa D and Alem{\'a}n, Alejandro and T{\'a}rraga, Joaqu{\'\i}n and Montaner, David and Medina, Ignacio and Dopazo, Joaquin} } @article {1126, title = {BRCA1 Alternative splicing landscape in breast tissue samples.}, journal = {BMC cancer}, volume = {15}, year = {2015}, month = {2015}, pages = {219}, abstract = {BACKGROUND: BRCA1 is a key protein in cell network, involved in DNA repair pathways and cell cycle. Recently, the ENIGMA consortium has reported a high number of alternative splicing (AS) events at this locus in blood-derived samples. However, BRCA1 splicing pattern in breast tissue samples is unknown. Here, we provide an accurate description of BRCA1 splicing events distribution in breast tissue samples. METHODS: BRCA1 splicing events were scanned in 70 breast tumor samples, 4 breast samples from healthy individuals and in 72 blood-derived samples by capillary electrophoresis (capillary EP). Molecular subtype was identified in all tumor samples. Splicing events were considered predominant if their relative expression level was at least the 10\% of the full-length reference signal. RESULTS: 54 BRCA1 AS events were identified, 27 of them were annotated as predominant in at least one sample. Δ5q, Δ13, Δ9, Δ5 and ▼1aA were significantly more frequently annotated as predominant in breast tumor samples than in blood-derived samples. Predominant splicing events were, on average, more frequent in tumor samples than in normal breast tissue samples (P = 0.010). Similarly, likely inactivating splicing events (PTC-NMDs, Non-Coding, Δ5 and Δ18) were more frequently annotated as predominant in tumor than in normal breast samples (P = 0.020), whereas there were no significant differences for other splicing events (No-Fs) frequency distribution between tumor and normal breast samples (P = 0.689). CONCLUSIONS: Our results complement recent findings by the ENIGMA consortium, demonstrating that BRCA1 AS, despite its tremendous complexity, is similar in breast and blood samples, with no evidences for tissue specific AS events. Further on, we conclude that somatic inactivation of BRCA1 through spliciogenic mutations is, at best, a rare mechanism in breast carcinogenesis, albeit our data detects an excess of likely inactivating AS events in breast tumor samples.}, issn = {1471-2407}, doi = {10.1186/s12885-015-1145-9}, url = {http://www.biomedcentral.com/1471-2407/15/219}, author = {Romero, Atocha and Garcia-Garcia, Francisco and L{\'o}pez-Perolio, Irene and Ruiz de Garibay, Gorka and Garc{\'\i}a-S{\'a}enz, Jos{\'e} A and Garre, Pilar and Ayll{\'o}n, Patricia and Benito, Esperanza and Joaqu{\'\i}n Dopazo and D{\'\i}az-Rubio, Eduardo and Cald{\'e}s, Trinidad and de la Hoya, Miguel} } @article {1160, title = {Comparative gene expression study of the vestibular organ of the Igf1 deficient mouse using whole-transcript arrays.}, journal = {Hearing research}, year = {2015}, month = {2015 Sep 1}, abstract = {The auditory and vestibular organs form the inner ear and have a common developmental origin. Insulin like growth factor 1 (IGF-1) has a central role in the development of the cochlea and maintenance of hearing. Its deficiency causes sensorineural hearing loss in man and mice. During chicken early development, IGF-1 modulates neurogenesis of the cochleovestibular ganglion but no further studies have been conducted to explore the potential role of IGF-1 in the vestibular system. In this study we have compared the whole transcriptome of the vestibular organ from wild type and Igf1(-/-) mice at different developmental and postnatal times. RNA was prepared from E18.5, P15 and P90 vestibular organs of Igf1(-/-) and Igf1(+/+) mice and the transcriptome analysed in triplicates using Affymetrix{\textregistered} Mouse Gene 1.1 ST Array Plates. These plates are whole-transcript arrays that include probes to measure both messenger (mRNA) and long intergenic non-coding RNA transcripts (lincRNA), with a coverage of over 28 thousand coding transcripts and over 7 thousands non-coding transcripts. Given the complexity of the data we used two different methods VSN-RMA and mmBGX to analyse and compare the data. This is to better evaluate the number of false positives and to quantify uncertainty of low signals. We identified a number of differentially expressed genes that we described using functional analysis and validated using RT-qPCR. The morphology of the vestibular organ did not show differences between genotypes and no evident alterations were observed in the vestibular sensory areas of the null mice. However, well-defined cellular alterations were found in the vestibular neurons with respect their number and size. Although these mice did not show a dramatic vestibular phenotype, we conducted a functional analysis on differentially expressed genes between genotypes and across time. This was with the aim to identify new pathways that are involved in the development of the vestibular organ as well as pathways that maybe affected by the lack of IGF-1 and be associated to the morphological changes of the vestibular neurons that we observed in the Igf1(-/-) mice.}, issn = {1878-5891}, doi = {10.1016/j.heares.2015.08.016}, url = {http://www.sciencedirect.com/science/article/pii/S0378595515001835}, author = {Rodr{\'\i}guez-de la Rosa, Lourdes and S{\'a}nchez-Calder{\'o}n, Hortensia and Contreras, Julio and Murillo-Cuesta, Silvia and Falagan, Sandra and Avenda{\~n}o, Carlos and Joaqu{\'\i}n Dopazo and Varela-Nieto, Isabel and Milo, Marta} } @article {458, title = {Deregulation of key signaling pathways involved in oocyte maturation in FMR1 premutation carriers with Fragile X-associated primary ovarian insufficiency.}, journal = {Gene}, volume = {571}, year = {2015}, month = {2015 Oct 15}, pages = {52-7}, abstract = {

FMR1 premutation female carriers are at risk for Fragile X-associated primary ovarian insufficiency (FXPOI). Insights from knock-in mouse model have recently demonstrated that FXPOI is due to an increased rate of follicle depletion or an impaired development of the growing follicles. Molecular mechanisms responsible for this reduced viability are still unknown. In an attempt to provide new data on the mechanisms that lead to FXPOI, we report the first investigation involving transcription profiling of total blood from FMR1 premutation female carriers with and without FXPOI. A total of 16 unrelated female individuals (6 FMR1 premutated females with FXPOI; 6 FMR1 premutated females without FXPOI; and 4 no-FXPOI females) were studied by whole human genome oligonucleotide microarray (Agilent Technologies). Fold change analysis did not show any genes with significant differential gene expression. However, functional profiling by gene set analysis showed large number of statistically significant deregulated GO annotations as well as numerous KEGG pathways in FXPOI females. These results suggest that the impairment of fertility in these females might be due to a generalized deregulation of key signaling pathways involved in oocyte maturation. In particular, the vasoendotelial growth factor signaling, the inositol phosphate metabolism, the cell cycle, and the MAPK signaling pathways were found to be down-regulated in FXPOI females. Furthermore, a high statistical enrichment of biological processes involved in cell death and survival were found deregulated among FXPOI females. Our results provide new strategic approaches to further investigate the molecular mechanisms and potential therapeutic targets for FXPOI not focused in a single gene but rather in the set of genes involved in these pathways.

}, keywords = {Adult, Aged, Female, Fragile X Mental Retardation Protein, Fragile X Syndrome, Gene Expression Profiling, Gene Expression Regulation, Developmental, Gene ontology, Genome-Wide Association Study, Heterozygote, Humans, Middle Aged, Models, Genetic, mutation, Oligonucleotide Array Sequence Analysis, Oocytes, Primary Ovarian Insufficiency, Signal Transduction}, issn = {1879-0038}, doi = {10.1016/j.gene.2015.06.039}, author = {Alvarez-Mora, M I and Rodriguez-Revenga, L and Madrigal, I and Garc{\'\i}a-Garc{\'\i}a, F and Duran, M and Dopazo, J and Estivill, X and Mil{\`a}, M} } @article {471, title = {Exome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease}, journal = {Scientific Reports}, volume = {5}, year = {2015}, month = {Jan-12-2015}, doi = {10.1038/srep16473}, url = {http://www.nature.com/articles/srep16473http://www.nature.com/articles/srep16473.pdfhttp://www.nature.com/articles/srep16473.pdfhttp://www.nature.com/articles/srep16473}, author = {Luz{\'o}n-Toro, Berta and Gui, Hongsheng and Ruiz-Ferrer, Macarena and Sze-Man Tang, Clara and Fern{\'a}ndez, Raquel M. and Sham, Pak-Chung and Torroglosa, Ana and Kwong-Hang Tam, Paul and Espino-Pais{\'a}n, Laura and Cherny, Stacey S. and Bleda, Marta and Enguix-Riego, Mar{\'\i}a Del Valle and Dopazo, Joaquin and Anti{\v n}olo, Guillermo and Garcia-Barcel{\'o}, Maria-Merc{\`e} and Borrego, Salud} } @article {1171, title = {Exome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease.}, journal = {Scientific reports}, volume = {5}, year = {2015}, month = {2015}, pages = {16473}, abstract = {Hirschsprung disease (HSCR; OMIM 142623) is a developmental disorder characterized by aganglionosis along variable lengths of the distal gastrointestinal tract, which results in intestinal obstruction. Interactions among known HSCR genes and/or unknown disease susceptibility loci lead to variable severity of phenotype. Neither linkage nor genome-wide association studies have efficiently contributed to completely dissect the genetic pathways underlying this complex genetic disorder. We have performed whole exome sequencing of 16 HSCR patients from 8 unrelated families with SOLID platform. Variants shared by affected relatives were validated by Sanger sequencing. We searched for genes recurrently mutated across families. Only variations in the FAT3 gene were significantly enriched in five families. Within-family analysis identified compound heterozygotes for AHNAK and several genes (N = 23) with heterozygous variants that co-segregated with the phenotype. Network and pathway analyses facilitated the discovery of polygenic inheritance involving FAT3, HSCR known genes and their gene partners. Altogether, our approach has facilitated the detection of more than one damaging variant in biologically plausible genes that could jointly contribute to the phenotype. Our data may contribute to the understanding of the complex interactions that occur during enteric nervous system development and the etiopathology of familial HSCR.}, keywords = {babelomics, Hirschprung, NGS, prioritization}, issn = {2045-2322}, doi = {10.1038/srep16473}, url = {http://www.nature.com/articles/srep16473}, author = {Luz{\'o}n-Toro, Berta and Gui, Hongsheng and Ruiz-Ferrer, Macarena and Sze-Man Tang, Clara and Fern{\'a}ndez, Raquel M and Sham, Pak-Chung and Torroglosa, Ana and Kwong-Hang Tam, Paul and Espino-Pais{\'a}n, Laura and Cherny, Stacey S and Bleda, Marta and Enguix-Riego, Mar{\'\i}a Del Valle and Joaqu{\'\i}n Dopazo and Anti{\v n}olo, Guillermo and Garcia-Barcel{\'o}, Maria-Merc{\`e} and Borrego, Salud} } @article {1179, title = {Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas.}, journal = {BMC medical genomics}, volume = {8}, year = {2015}, month = {2015}, pages = {83}, abstract = {BACKGROUND: The molecular mechanisms leading to sporadic medullary thyroid carcinoma (sMTC) and juvenile papillary thyroid carcinoma (PTC), two rare tumours of the thyroid gland, remain poorly understood. Genetic studies on thyroid carcinomas have been conducted, although just a few loci have been systematically associated. Given the difficulties to obtain single-loci associations, this work expands its scope to the study of epistatic interactions that could help to understand the genetic architecture of complex diseases and explain new heritable components of genetic risk. METHODS: We carried out the first screening for epistasis by Multifactor-Dimensionality Reduction (MDR) in genome-wide association study (GWAS) on sMTC and juvenile PTC, to identify the potential simultaneous involvement of pairs of variants in the disease. RESULTS: We have identified two significant epistatic gene interactions in sMTC (CHFR-AC016582.2 and C8orf37-RNU1-55P) and three in juvenile PTC (RP11-648k4.2-DIO1, RP11-648k4.2-DMGDH and RP11-648k4.2-LOXL1). Interestingly, each interacting gene pair included a non-coding RNA, providing thus support to the relevance that these elements are increasingly gaining to explain carcinoma development and progression. CONCLUSIONS: Overall, this study contributes to the understanding of the genetic basis of thyroid carcinoma susceptibility in two different case scenarios such as sMTC and juvenile PTC.}, keywords = {epistasis, GWAS, Thyroid cancer}, issn = {1755-8794}, doi = {10.1186/s12920-015-0160-7}, url = {http://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-015-0160-7}, author = {Luz{\'o}n-Toro, Berta and Bleda, Marta and Navarro, Elena and Garc{\'\i}a-Alonso, Luz and Ruiz-Ferrer, Macarena and Medina, Ignacio and Mart{\'\i}n-S{\'a}nchez, Marta and Gonzalez, Cristina Y and Fern{\'a}ndez, Raquel M and Torroglosa, Ana and Anti{\v n}olo, Guillermo and Dopazo, Joaquin and Borrego, Salud} } @article {562, title = {Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas}, journal = {BMC Medical Genomics}, volume = {8}, year = {2015}, month = {Dec}, pages = {83}, abstract = {The molecular mechanisms leading to sporadic medullary thyroid carcinoma (sMTC) and juvenile papillary thyroid carcinoma (PTC), two rare tumours of the thyroid gland, remain poorly understood. Genetic studies on thyroid carcinomas have been conducted, although just a few loci have been systematically associated. Given the difficulties to obtain single-loci associations, this work expands its scope to the study of epistatic interactions that could help to understand the genetic architecture of complex diseases and explain new heritable components of genetic risk.}, issn = {1755-8794}, doi = {10.1186/s12920-015-0160-7}, url = {https://doi.org/10.1186/s12920-015-0160-7}, author = {Luz{\'o}n-Toro, Berta and Bleda, Marta and Navarro, Elena and Garc{\'\i}a-Alonso, Luz and Ruiz-Ferrer, Macarena and Medina, Ignacio and Mart{\'\i}n-S{\'a}nchez, Marta and Gonzalez, Cristina Y. and Fern{\'a}ndez, Raquel M. and Torroglosa, Ana and Anti{\v n}olo, Guillermo and Dopazo, Joaquin and Borrego, Salud} } @article {1115, title = {Involvement of a citrus meiotic recombination TTC-repeat motif in the formation of gross deletions generated by ionizing radiation and MULE activation.}, journal = {BMC genomics}, volume = {16}, year = {2015}, month = {2015 Feb 13}, pages = {69}, abstract = {BACKGROUND: Transposable-element mediated chromosomal rearrangements require the involvement of two transposons and two double-strand breaks (DSB) located in close proximity. In radiobiology, DSB proximity is also a major factor contributing to rearrangements. However, the whole issue of DSB proximity remains virtually unexplored. RESULTS: Based on DNA sequencing analysis we show that the genomes of 2 derived mutations, Arrufatina (sport) and Nero (irradiation), share a similar 2 Mb deletion of chromosome 3. A 7 kb Mutator-like element found in Clemenules was present in Arrufatina in inverted orientation flanking the 5{\textquoteright} end of the deletion. The Arrufatina Mule displayed "dissimilar" 9-bp target site duplications separated by 2 Mb. Fine-scale single nucleotide variant analyses of the deleted fragments identified a TTC-repeat sequence motif located in the center of the deletion responsible of a meiotic crossover detected in the citrus reference genome. CONCLUSIONS: Taken together, this information is compatible with the proposal that in both mutants, the TTC-repeat motif formed a triplex DNA structure generating a loop that brought in close proximity the originally distinct reactive ends. In Arrufatina, the loop brought the Mule ends nearby the 2 distinct insertion target sites and the inverted insertion of the transposable element between these target sites provoked the release of the in-between fragment. This proposal requires the involvement of a unique transposon and sheds light on the unresolved question of how two distinct sites become located in close proximity. These observations confer a crucial role to the TTC-repeats in fundamental plant processes as meiotic recombination and chromosomal rearrangements.}, issn = {1471-2164}, doi = {10.1186/s12864-015-1280-3}, url = {http://www.biomedcentral.com/1471-2164/16/69}, author = {Terol, Javier and Iba{\~n}ez, Victoria and Carbonell, Jos{\'e} and Alonso, Roberto and Estornell, Leandro H and Licciardello, Concetta and Gut, Ivo G and Joaqu{\'\i}n Dopazo and Talon, Manuel} } @article {563, title = {Involvement of a citrus meiotic recombination TTC-repeat motif in the formation of gross deletions generated by ionizing radiation and MULE activation}, journal = {BMC Genomics}, volume = {16}, year = {2015}, month = {Feb}, pages = {69}, abstract = {Transposable-element mediated chromosomal rearrangements require the involvement of two transposons and two double-strand breaks (DSB) located in close proximity. In radiobiology, DSB proximity is also a major factor contributing to rearrangements. However, the whole issue of DSB proximity remains virtually unexplored.}, issn = {1471-2164}, doi = {10.1186/s12864-015-1280-3}, url = {https://doi.org/10.1186/s12864-015-1280-3}, author = {Terol, Javier and Iba{\~n}ez, Victoria and Carbonell, Jos{\'e} and Alonso, Roberto and Estornell, Leandro H. and Licciardello, Concetta and Gut, Ivo G. and Dopazo, Joaquin and Talon, Manuel} } @article {1121, title = {A phylogenetic analysis of 34 chloroplast genomes elucidates the relationships between wild and domestic species within the genus Citrus.}, journal = {Molecular biology and evolution}, volume = {32}, number = {8}, year = {2015}, month = {2015 Apr 14}, pages = {2015-2035}, abstract = {Citrus genus includes some of the most important cultivated fruit trees worldwide. Despite being extensively studied because of its commercial relevance, the origin of cultivated citrus species and the history of its domestication still remain an open question. Here we present a phylogenetic analysis of the chloroplast genomes of 34 citrus genotypes which constitutes the most comprehensive and detailed study to date on the evolution and variability of the genus Citrus. A statistical model was used to estimate divergence times between the major citrus groups. Additionally, a complete map of the variability across the genome of different citrus species was produced, including single nucleotide variants, heteroplasmic positions, indels and large structural variants. The distribution of all these variants provided further independent support to the phylogeny obtained. An unexpected finding was the high level of heteroplasmy found in several of the analysed genomes. The use of the complete chloroplast DNA not only paves the way for a better understanding of the phylogenetic relationships within the Citrus genus, but also provides original insights into other elusive evolutionary processes such as chloroplast inheritance, heteroplasmy and gene selection.}, keywords = {chloroplast, citrus, Phylogeny, WGS}, issn = {1537-1719}, doi = {10.1093/molbev/msv082}, url = {http://mbe.oxfordjournals.org/content/early/2015/04/27/molbev.msv082.full}, author = {Carbonell-Caballero, Jos{\'e} and Alonso, Roberto and Iba{\~n}ez, Victoria and Terol, Javier and Talon, Manuel and Dopazo, Joaquin} } @article {1155, title = {Prediction of human population responses to toxic compounds by a collaborative competition.}, journal = {Nature biotechnology}, year = {2015}, month = {2015 Aug 10}, abstract = {The ability to computationally predict the effects of toxic compounds on humans could help address the deficiencies of current chemical safety testing. Here, we report the results from a community-based DREAM challenge to predict toxicities of environmental compounds with potential adverse health effects for human populations. We measured the cytotoxicity of 156 compounds in 884 lymphoblastoid cell lines for which genotype and transcriptional data are available as part of the Tox21 1000 Genomes Project. The challenge participants developed algorithms to predict interindividual variability of toxic response from genomic profiles and population-level cytotoxicity data from structural attributes of the compounds. 179 submitted predictions were evaluated against an experimental data set to which participants were blinded. Individual cytotoxicity predictions were better than random, with modest correlations (Pearson{\textquoteright}s r < 0.28), consistent with complex trait genomic prediction. In contrast, predictions of population-level response to different compounds were higher (r < 0.66). The results highlight the possibility of predicting health risks associated with unknown compounds, although risk estimation accuracy remains suboptimal.}, issn = {1546-1696}, doi = {10.1038/nbt.3299}, url = {http://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.3299.html}, author = {Eduati, Federica and Mangravite, Lara M and Wang, Tao and Tang, Hao and Bare, J Christopher and Huang, Ruili and Norman, Thea and Kellen, Mike and Menden, Michael P and Yang, Jichen and Zhan, Xiaowei and Zhong, Rui and Xiao, Guanghua and Xia, Menghang and Abdo, Nour and Kosyk, Oksana} } @article {467, title = {Re-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F.}, journal = {Am J Med Genet A}, volume = {167}, year = {2015}, month = {2015 Jul}, pages = {1597-600}, abstract = {

Mutations in USH2A are a common cause of Retinitis Pigmentosa (RP). Among the most frequently reported USH2A variants, c.2276G>T (p.C759F) has been found in both affected and healthy individuals. The pathogenicity of this variant remains controversial since it was detected in homozygosity in two healthy siblings of a Spanish family (S23), eleven years ago. The fact that these individuals remain asymptomatic today, prompted us to study the presence of other pathogenic variants in this family using targeted resequencing of 26 retinal genes in one of the affected individuals. This approach allowed us to identify one novel pathogenic homozygous mutation in exon 13 of PDE6B (c.1678C>T; p.R560C). This variant cosegregated with the disease and was absent in 200 control individuals. Remarkably, the identified variant in PDE6B corresponds to the mutation responsible of the retinal degeneration in the naturally occurring rd10 mutant mice. To our knowledge, this is the first report of the identification of the rd10 mice mutation in a RP family. These findings, together with a review of the literature, support the hypothesis that homozygous p.C759F mutations are not pathogenic and led us to exclude the implication of p.C759F in the RP of family S23. Our results indicate the need of re-evaluating all families genetically diagnosed with this mutation.

}, keywords = {Base Sequence, Cyclic Nucleotide Phosphodiesterases, Type 6, Extracellular Matrix Proteins, Gene Library, Humans, Molecular Sequence Data, Mutation, Missense, Pedigree, Retinitis pigmentosa, Sequence Analysis, DNA, Spain}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37003}, author = {Pozo, Mar{\'\i}a Gonz{\'a}lez-Del and Bravo-Gil, Nereida and M{\'e}ndez-Vidal, Cristina and Montero-de-Espinosa, Ignacio and Mill{\'a}n, Jos{\'e} M and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {1111, title = {Therapeutic targets for olive pollen allergy defined by gene markers modulated by Ole e 1-derived peptides.}, journal = {Molecular immunology}, volume = {64}, year = {2015}, month = {2015 Apr}, pages = {252-61}, abstract = {Two regions of Ole e 1, the major olive-pollen allergen, have been characterized as T-cell epitopes, one as immunodominant region (aa91-130) and the other, as mainly recognized by non-allergic subjects (aa10-31). This report tries to characterize the specific relevance of these epitopes in the allergic response to olive pollen by analyzing the secreted cytokines and the gene expression profiles induced after specific stimulation of peripheral blood mononuclear cells (PBMCs). PBMCs from olive pollen-allergic and non-allergic control subjects were stimulated with olive-pollen extract and Ole e 1 dodecapeptides containing relevant T-cell epitopes. Levels of cytokines were measured in cellular supernatants and gene expression was determined by microarrays, on the RNAs extracted from PBMCs. One hundred eighty-nine differential genes (fold change >2 or <-2, P<0.05) were validated by qRT-PCR in a large population. It was not possible to define a pattern of response according the overall cytokine results but interesting differences were observed, mainly in the regulatory cytokines. Principal component (PCA) gene-expression analysis defined clusters that correlated with the experimental conditions in the group of allergic subjects. Gene expression and functional analyses revealed differential genes and pathways among the experimental conditions. A set of 51 genes (many essential to T-cell tolerance and homeostasis) correlated with the response to aa10-31 of Ole e 1. In conclusion, two peptides derived from Ole e 1 could regulate the immune response in allergic patients, by gene-expression modification of several regulation-related genes. These results open new research ways to the regulation of allergy by Oleaceae family members.}, issn = {1872-9142}, doi = {10.1016/j.molimm.2014.12.002}, url = {http://www.sciencedirect.com/science/article/pii/S0161589014003356}, author = {Calzada, David and Aguerri, Miriam and Baos, Selene and Montaner, David and Mata, Manuel and Joaqu{\'\i}n Dopazo and Quiralte, Joaqu{\'\i}n and Florido, Fernando and Lahoz, Carlos and C{\'a}rdaba, Blanca} } @article {474, title = {Using activation status of signaling pathways as mechanism-based biomarkers to predict drug sensitivity.}, journal = {Sci Rep}, volume = {5}, year = {2015}, month = {2015 Dec 18}, pages = {18494}, abstract = {

Many complex traits, as drug response, are associated with changes in biological pathways rather than being caused by single gene alterations. Here, a predictive framework is presented in which gene expression data are recoded into activity statuses of signal transduction circuits (sub-pathways within signaling pathways that connect receptor proteins to final effector proteins that trigger cell actions). Such activity values are used as features by a prediction algorithm which can efficiently predict a continuous variable such as the IC50 value. The main advantage of this prediction method is that the features selected by the predictor, the signaling circuits, are themselves rich-informative, mechanism-based biomarkers which provide insight into or drug molecular mechanisms of action (MoA).

}, keywords = {Algorithms, Antineoplastic Agents, biomarkers, Cell Line, Tumor, Cell Survival, gene expression, Humans, Lethal Dose 50, Neoplasms, Phosphorylation, Proteins, Signal Transduction}, issn = {2045-2322}, doi = {10.1038/srep18494}, author = {Amadoz, Alicia and Sebasti{\'a}n-Leon, Patricia and Vidal, Enrique and Salavert, Francisco and Dopazo, Joaquin} } @article {1127, title = {Whole Exome Sequencing Reveals ZNF408 as a New Gene Associated With Autosomal Recessive Retinitis Pigmentosa with Vitreal Alterations.}, journal = {Human molecular genetics}, volume = {24}, number = {14}, year = {2015}, month = {2015 Apr 16}, pages = {4037-4048}, abstract = {Retinitis Pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors ten predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina.}, issn = {1460-2083}, doi = {10.1093/hmg/ddv140}, url = {http://hmg.oxfordjournals.org/content/early/2015/04/16/hmg.ddv140.abstract}, author = {Avila-Fernandez, Almudena and Perez-Carro, Raquel and Corton, Marta and Lopez-Molina, Maria Isabel and Campello, Laura and Garanto, Alex and Fernadez-Sanchez, Laura and Duijkers, Lonneke and Lopez-Martinez, Miguel Angel and Riveiro-Alvarez, Rosa and da Silva, Luciana Rodrigues Jacy and Sanchez-Alcudia, Roc{\'\i}o and Martin-Garrido, Esther and Reyes, Noelia and Garcia-Garcia, Francisco and Dopazo, Joaquin and Garcia-Sandoval, Blanca and Collin, Rob W and Cuenca, Nicolas and Ayuso, Carmen} } @article {463, title = {Whole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Jul 15}, pages = {4037-48}, abstract = {

Retinitis pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole-exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors 10 predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina.

}, keywords = {Amino Acid Sequence, Animals, Chlorocebus aethiops, Chromosome Mapping, COS Cells, DNA-Binding Proteins, Exome, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Molecular Sequence Data, Mutant Proteins, Pedigree, Retina, Retinal Cone Photoreceptor Cells, Retinal Rod Photoreceptor Cells, Retinitis pigmentosa, Transcription Factors}, issn = {1460-2083}, doi = {10.1093/hmg/ddv140}, author = {Avila-Fernandez, Almudena and Perez-Carro, Raquel and Corton, Marta and Lopez-Molina, Maria Isabel and Campello, Laura and Garanto, Alejandro and Fernandez-Sanchez, Laura and Duijkers, Lonneke and Lopez-Martinez, Miguel Angel and Riveiro-Alvarez, Rosa and da Silva, Luciana Rodrigues Jacy and Sanchez-Alcudia, Roc{\'\i}o and Martin-Garrido, Esther and Reyes, Noelia and Garcia-Garcia, Francisco and Dopazo, Joaquin and Garcia-Sandoval, Blanca and Collin, Rob W J and Cuenca, Nicolas and Ayuso, Carmen} } @article {1076, title = {Acceleration of short and long DNA read mapping without loss of accuracy using suffix array.}, journal = {Bioinformatics (Oxford, England)}, volume = {30}, year = {2014}, month = {2014 Aug 20}, pages = {3396-3398}, abstract = {HPG Aligner applies suffix arrays for DNA read mapping. This implementation produces a highly sensitive and extremely fast mapping of DNA reads that scales up almost linearly with read length. The approach presented here is faster (over 20x for long reads) and more sensitive (over 98\% in a wide range of read lengths) than the current, state-of-the-art mappers. HPG Aligner is not only an optimal alternative for current sequencers but also the only solution available to cope with longer reads and growing throughputs produced by forthcoming sequencing technologies.}, keywords = {NGS, short read mapping. HPC. suffix arrays}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btu553}, url = {http://bioinformatics.oxfordjournals.org/content/early/2014/08/19/bioinformatics.btu553.long}, author = {T{\'a}rraga, Joaqu{\'\i}n and Arnau, Vicente and Martinez, Hector and Moreno, Raul and Cazorla, Diego and Salavert-Torres, Jos{\'e} and Blanquer-Espert, Ignacio and Joaqu{\'\i}n Dopazo and Medina, Ignacio} } @article {493, title = {The Activation of the Sox2 RR2 Pluripotency Transcriptional Reporter in Human Breast Cancer Cell Lines is Dynamic and Labels Cells with Higher Tumorigenic Potential.}, journal = {Front Oncol}, volume = {4}, year = {2014}, month = {2014}, pages = {308}, abstract = {

The striking similarity displayed at the mechanistic level between tumorigenesis and the generation of induced pluripotent stem cells and the fact that genes and pathways relevant for embryonic development are reactivated during tumor progression highlights the link between pluripotency and cancer. Based on these observations, we tested whether it is possible to use a pluripotency-associated transcriptional reporter, whose activation is driven by the SRR2 enhancer from the Sox2 gene promoter (named S4+ reporter), to isolate cancer stem cells (CSCs) from breast cancer cell lines. The S4+ pluripotency transcriptional reporter allows the isolation of cells with enhanced tumorigenic potential and its activation was switched on and off in the cell lines studied, reflecting a plastic cellular process. Microarray analysis comparing the populations in which the reporter construct is active versus inactive showed that positive cells expressed higher mRNA levels of cytokines (IL-8, IL-6, TNF) and genes (such as ATF3, SNAI2, and KLF6) previously related with the CSC phenotype in breast cancer.

}, issn = {2234-943X}, doi = {10.3389/fonc.2014.00308}, author = {Iglesias, Juan Manuel and Leis, Olatz and P{\'e}rez Ruiz, Est{\'\i}baliz and Gumuzio Barrie, Juan and Garcia-Garcia, Francisco and Aduriz, Ariane and Beloqui, Izaskun and Hernandez-Garcia, Susana and Lopez-Mato, Maria Paz and Dopazo, Joaquin and Pandiella, Atanasio and Menendez, Javier A and Martin, Angel Garcia} } @article {486, title = {Deciphering intrafamilial phenotypic variability by exome sequencing in a Bardet-Biedl family.}, journal = {Mol Genet Genomic Med}, volume = {2}, year = {2014}, month = {2014 Mar}, pages = {124-33}, abstract = {

Bardet-Biedl syndrome (BBS) is a model ciliopathy characterized by a wide range of clinical variability. The heterogeneity of this condition is reflected in the number of underlying gene defects and the epistatic interactions between the proteins encoded. BBS is generally inherited in an autosomal recessive trait. However, in some families, mutations across different loci interact to modulate the expressivity of the phenotype. In order to investigate the magnitude of epistasis in one BBS family with remarkable intrafamilial phenotypic variability, we designed an exome sequencing-based approach using SOLID 5500xl platform. This strategy allowed the reliable detection of the primary causal mutations in our family consisting of two novel compound heterozygous mutations in McKusick-Kaufman syndrome (MKKS) gene (p.D90G and p.V396F). Additionally, exome sequencing enabled the detection of one novel heterozygous NPHP4 variant which is predicted to activate a cryptic acceptor splice site and is only present in the most severely affected patient. Here, we provide an exome sequencing analysis of a BBS family and show the potential utility of this tool, in combination with network analysis, to detect disease-causing mutations and second-site modifiers. Our data demonstrate how next-generation sequencing (NGS) can facilitate the dissection of epistatic phenomena, and shed light on the genetic basis of phenotypic variability.

}, issn = {2324-9269}, doi = {10.1002/mgg3.50}, author = {Gonz{\'a}lez-del Pozo, Mar{\'\i}a and M{\'e}ndez-Vidal, Cristina and Santoyo-L{\'o}pez, Javier and Vela-Boza, Alicia and Bravo-Gil, Nereida and Rueda, Antonio and Garc{\'\i}a-Alonso, Luz and V{\'a}zquez-Marouschek, Carmen and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {1035, title = {Deciphering intrafamilial phenotypic variability by exome sequencing in a Bardet{\textendash}Biedl family}, journal = {Molecular Genetics \& Genomic Medicine}, volume = {2}, number = {2}, year = {2014}, pages = {124-133}, abstract = {Bardet{\textendash}Biedl syndrome (BBS) is a model ciliopathy characterized by a wide range of clinical variability. The heterogeneity of this condition is reflected in the number of underlying gene defects and the epistatic interactions between the proteins encoded. BBS is generally inherited in an autosomal recessive trait. However, in some families, mutations across different loci interact to modulate the expressivity of the phenotype. In order to investigate the magnitude of epistasis in one BBS family with remarkable intrafamilial phenotypic variability, we designed an exome sequencing{\textendash}based approach using SOLID 5500xl platform. This strategy allowed the reliable detection of the primary causal mutations in our family consisting of two novel compound heterozygous mutations in McKusick{\textendash}Kaufman syndrome (MKKS) gene (p.D90G and p.V396F). Additionally, exome sequencing enabled the detection of one novel heterozygous NPHP4 variant which is predicted to activate a cryptic acceptor splice site and is only present in the most severely affected patient. Here, we provide an exome sequencing analysis of a BBS family and show the potential utility of this tool, in combination with network analysis, to detect disease-causing mutations and second-site modifiers. Our data demonstrate how next-generation sequencing (NGS) can facilitate the dissection of epistatic phenomena, and shed light on the genetic basis of phenotypic variability.}, doi = {10.1002/mgg3.50}, url = {http://onlinelibrary.wiley.com/doi/10.1002/mgg3.50/full}, author = {Gonz{\'a}lez-del Pozo, Mar{\'\i}a and M{\'e}ndez-Vidal, Cristina and Santoyo-L{\'o}pez, Javier and Vela-Boza, Alicia and Nereida Bravo-Gil and Antonio Rueda and Garc{\'\i}a-Alonso, Luz and V{\'a}zquez-Marouschek, Carmen and Joaqu{\'\i}n Dopazo and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {489, title = {Exome sequencing reveals novel and recurrent mutations with clinical significance in inherited retinal dystrophies.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e116176}, abstract = {

This study aimed to identify the underlying molecular genetic cause in four Spanish families clinically diagnosed of Retinitis Pigmentosa (RP), comprising one autosomal dominant RP (adRP), two autosomal recessive RP (arRP) and one with two possible modes of inheritance: arRP or X-Linked RP (XLRP). We performed whole exome sequencing (WES) using NimbleGen SeqCap EZ Exome V3 sample preparation kit and SOLID 5500xl platform. All variants passing filter criteria were validated by Sanger sequencing to confirm familial segregation and the absence in local control population. This strategy allowed the detection of: (i) one novel heterozygous splice-site deletion in RHO, c.937-2_944del, (ii) one rare homozygous mutation in C2orf71, c.1795T>C; p.Cys599Arg, not previously associated with the disease, (iii) two heterozygous null mutations in ABCA4, c.2041C>T; p.R681* and c.6088C>T; p.R2030*, and (iv) one mutation, c.2405-2406delAG; p.Glu802Glyfs*31 in the ORF15 of RPGR. The molecular findings for RHO and C2orf71 confirmed the initial diagnosis of adRP and arRP, respectively, while patients with the two ABCA4 mutations, both previously associated with Stargardt disease, presented symptoms of RP with early macular involvement. Finally, the X-Linked inheritance was confirmed for the family with the RPGR mutation. This latter finding allowed the inclusion of carrier sisters in our preimplantational genetic diagnosis program.

}, keywords = {Adolescent, Adult, Amino Acid Sequence, Base Sequence, Child, Chromosome Segregation, DNA Mutational Analysis, Exome, Family, Female, Humans, Inheritance Patterns, Male, Middle Aged, Molecular Sequence Data, mutation, Pedigree, Retinal Dystrophies, Rhodopsin}, issn = {1932-6203}, doi = {10.1371/journal.pone.0116176}, author = {Gonz{\'a}lez-del Pozo, Mar{\'\i}a and M{\'e}ndez-Vidal, Cristina and Bravo-Gil, Nereida and Vela-Boza, Alicia and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {1083, title = {A New Overgrowth Syndrome is Due to Mutations in RNF125.}, journal = {Human mutation}, volume = {35}, year = {2014}, month = {2014 Sep 5}, pages = {1436{\textendash}1441}, abstract = {Overgrowth syndromes (OGS) are a group of disorders in which all parameters of growth and physical development are above the mean for age and sex. We evaluated a series of 270 families from the Spanish Overgrowth Syndrome Registry with no known overgrowth syndrome. We identified one de novo deletion and three missense mutations in RNF125 in six patients from 4 families with overgrowth, macrocephaly, intellectual disability, mild hydrocephaly, hypoglycaemia and inflammatory diseases resembling Sj{\"o}gren syndrome. RNF125 encodes an E3 ubiquitin ligase and is a novel gene of OGS. Our studies of the RNF125 pathway point to upregulation of RIG-I-IPS1-MDA5 and/or disruption of the PI3K-AKT and interferon signaling pathways as the putative final effectors. This article is protected by copyright. All rights reserved.}, keywords = {NGS, prioritization, Rare Disease}, issn = {1098-1004}, doi = {10.1002/humu.22689}, url = {http://onlinelibrary.wiley.com/doi/10.1002/humu.22689/abstract}, author = {Tenorio, Jair and Mansilla, Alicia and Valencia, Mar{\'\i}a and Mart{\'\i}nez-Glez, V{\'\i}ctor and Romanelli, Valeria and Arias, Pedro and Castrej{\'o}n, Nerea and Poletta, Fernando and Guill{\'e}n-Navarro, Encarna and Gordo, Gema and Mansilla, Elena and Garc{\'\i}a-Santiago, F{\'e} and Gonz{\'a}lez-Casado, Isabel and Vallesp{\'\i}n, Elena and Palomares, Mar{\'\i}a and Mori, Mar{\'\i}a A and Santos-Simarro, Fernando and Garc{\'\i}a-Mi{\~n}aur, Sixto and Fern{\'a}ndez, Luis and Mena, Roc{\'\i}o and Benito-Sanz, Sara and Del Pozo, Angela and Silla, Juan Carlos and Iba{\~n}ez, Kristina and L{\'o}pez-Granados, Eduardo and Mart{\'\i}n-Trujillo, Alex and Montaner, David and Heath, Karen E and Campos-Barros, Angel and Joaqu{\'\i}n Dopazo and Nevado, Juli{\'a}n and Monk, David and Ruiz-P{\'e}rez, V{\'\i}ctor L and Lapunzina, Pablo} } @article {1066, title = {A novel locus for a hereditary recurrent neuropathy on chromosome 21q21.}, journal = {Neuromuscular disorders : NMD}, volume = {24}, number = {8}, year = {2014}, month = {2014 May 9}, pages = {660-5}, abstract = {Hereditary recurrent neuropathies are uncommon. Disorders with a known molecular basis falling within this group include hereditary neuropathy with liability to pressure palsies (HNPP) due to the deletion of the PMP22 gene or to mutations in this same gene, and hereditary neuralgic amyotrophy (HNA) caused by mutations in the SEPT9 gene. We report a three-generation family presenting a hereditary recurrent neuropathy without pathological changes in either PMP22 or SEPT9 genes. We performed a genome-wide mapping, which yielded a locus of 12.4Mb on chromosome 21q21. The constructed haplotype fully segregated with the disease and we found significant evidence of linkage. After mutational screening of genes located within this locus, encoding for proteins and microRNAs, as well as analysis of large deletions/insertions, we identified 71 benign polymorphisms. Our findings suggest a novel genetic locus for a recurrent hereditary neuropathy of which the molecular defect remains elusive. Our results further underscore the clinical and genetic heterogeneity of this group of neuropathies.}, issn = {1873-2364}, doi = {10.1016/j.nmd.2014.04.004}, url = {http://www.sciencedirect.com/science/article/pii/S0960896614001060$\#$}, author = {Calpena, E and Mart{\'\i}nez-Rubio, D and Arpa, J and Garc{\'\i}a-Pe{\~n}as, J J and Montaner, D. and Dopazo, J. and Palau, F and Espin{\'o}s, C} } @article {490, title = {Novel RP1 mutations and a recurrent BBS1 variant explain the co-existence of two distinct retinal phenotypes in the same pedigree.}, journal = {BMC Genet}, volume = {15}, year = {2014}, month = {2014 Dec 14}, pages = {143}, abstract = {

BACKGROUND: Molecular diagnosis of Inherited Retinal Dystrophies (IRD) has long been challenging due to the extensive clinical and genetic heterogeneity present in this group of disorders. Here, we describe the clinical application of an integrated next-generation sequencing approach to determine the underlying genetic defects in a Spanish family with a provisional clinical diagnosis of autosomal recessive Retinitis Pigmentosa (arRP).

RESULTS: Exome sequencing of the index patient resulted in the identification of the homozygous BBS1 p.M390R mutation. Sanger sequencing of additional members of the family showed lack of co-segregation of the p.M390R variant in some individuals. Clinical reanalysis indicated co-ocurrence of two different phenotypes in the same family: Bardet-Biedl syndrome in the individual harboring the BBS1 mutation and non-syndromic arRP in extended family members. To identify possible causative mutations underlying arRP, we conducted disease-targeted gene sequencing using a panel of 26 IRD genes. The in-house custom panel was validated using 18 DNA samples known to harbor mutations in relevant genes. All variants were redetected, indicating a high mutation detection rate. This approach allowed the identification of two novel heterozygous null mutations in RP1 (c.4582_4585delATCA; p.I1528Vfs*10 and c.5962dupA; p.I1988Nfs*3) which co-segregated with the disease in arRP patients. Additionally, a mutational screening in 96 patients of our cohort with genetically unresolved IRD revealed the presence of the c.5962dupA mutation in one unrelated family.

CONCLUSIONS: The combination of molecular findings for RP1 and BBS1 genes through exome and gene panel sequencing enabled us to explain the co-existence of two different retinal phenotypes in a family. The identification of two novel variants in RP1 suggests that the use of panels containing the prevalent genes of a particular population, together with an optimized data analysis pipeline, is an efficient and cost-effective approach that can be reliably implemented into the routine diagnostic process of diverse inherited retinal disorders. Moreover, the identification of these novel variants in two unrelated families supports the relatively high prevalence of RP1 mutations in Spanish population and the role of private mutations for commonly mutated genes, while extending the mutational spectrum of RP1.

}, keywords = {Bardet-Biedl Syndrome, Base Sequence, Case-Control Studies, DNA Mutational Analysis, Eye Proteins, Genes, Recessive, Genetic Association Studies, Humans, Microsatellite Repeats, Microtubule-Associated Proteins, Mutation, Missense, Pedigree, Phenotype, Retina, Retinitis pigmentosa}, issn = {1471-2156}, doi = {10.1186/s12863-014-0143-2}, author = {M{\'e}ndez-Vidal, Cristina and Bravo-Gil, Nereida and Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Vela-Boza, Alicia and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {492, title = {Permanent cardiac sarcomere changes in a rabbit model of intrauterine growth restriction.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e113067}, abstract = {

BACKGROUND: Intrauterine growth restriction (IUGR) induces fetal cardiac remodelling and dysfunction, which persists postnatally and may explain the link between low birth weight and increased cardiovascular mortality in adulthood. However, the cellular and molecular bases for these changes are still not well understood. We tested the hypothesis that IUGR is associated with structural and functional gene expression changes in the fetal sarcomere cytoarchitecture, which remain present in adulthood.

METHODS AND RESULTS: IUGR was induced in New Zealand pregnant rabbits by selective ligation of the utero-placental vessels. Fetal echocardiography demonstrated more globular hearts and signs of cardiac dysfunction in IUGR. Second harmonic generation microscopy (SHGM) showed shorter sarcomere length and shorter A-band and thick-thin filament interaction lengths, that were already present in utero and persisted at 70 postnatal days (adulthood). Sarcomeric M-band (GO: 0031430) functional term was over-represented in IUGR fetal hearts.

CONCLUSION: The results suggest that IUGR induces cardiac dysfunction and permanent changes on the sarcomere.

}, keywords = {Animals, biomarkers, Blood Pressure, Body Weight, Disease Models, Animal, Echocardiography, Female, Fetal Growth Retardation, Fetal Heart, Fetus, Gene Expression Profiling, Organ Size, Placenta, Pregnancy, Rabbits, Sarcomeres}, issn = {1932-6203}, doi = {10.1371/journal.pone.0113067}, author = {Torre, Iratxe and Gonz{\'a}lez-Tendero, Anna and Garc{\'\i}a-Ca{\~n}adilla, Patricia and Crispi, F{\'a}tima and Garcia-Garcia, Francisco and Bijnens, Bart and Iruretagoyena, Igor and Dopazo, Joaquin and Amat-Rold{\'a}n, Ivan and Gratac{\'o}s, Eduard} } @article {1049, title = {Programmed cell death activated by Rose Bengal in Arabidopsis thaliana cell suspension cultures requires functional chloroplasts.}, journal = {Journal of experimental botany}, year = {2014}, month = {2014 Apr 10}, abstract = {Light-grown Arabidopsis thaliana cell suspension culture (ACSC) were subjected to mild photooxidative damage with Rose Bengal (RB) with the aim of gaining a better understanding of singlet oxygen-mediated defence responses in plants. Additionally, ACSC were treated with H2O2 at concentrations that induced comparable levels of protein oxidation damage. Under low to medium light conditions, both RB and H2O2 treatments activated transcriptional defence responses and inhibited photosynthetic activity, but they differed in that programmed cell death (PCD) was only observed in cells treated with RB. When dark-grown ACSC were subjected to RB in the light, PCD was suppressed, indicating that the singlet oxygen-mediated signalling pathway in ACSC requires functional chloroplasts. Analysis of up-regulated transcripts in light-grown ACSC, treated with RB in the light, showed that both singlet oxygen-responsive transcripts and transcripts with a key role in hormone-activated PCD (i.e. ethylene and jasmonic acid) were present. A co-regulation analysis proved that ACSC treated with RB exhibited higher correlation with the conditional fluorescence (flu) mutant than with other singlet oxygen-producing mutants or wild-type plants subjected to high light. However, there was no evidence for the up-regulation of EDS1, suggesting that activation of PCD was not associated with the EXECUTER- and EDS1-dependent signalling pathway described in the flu mutant. Indigo Carmine and Methylene Violet, two photosensitizers unable to enter chloroplasts, did not activate transcriptional defence responses in ACSC; however, whether this was due to their location or to their inherently low singlet oxygen quantum efficiencies was not determined.}, issn = {1460-2431}, doi = {10.1093/jxb/eru151}, url = {http://jxb.oxfordjournals.org/content/early/2014/04/09/jxb.eru151.long}, author = {Guti{\'e}rrez, Jorge and Gonz{\'a}lez-P{\'e}rez, Sergio and Garcia-Garcia, Francisco and Daly, Cara T and Lorenzo, Oscar and Revuelta, Jos{\'e} L and McCabe, Paul F and Arellano, Juan B} } @article {494, title = {The role of the interactome in the maintenance of deleterious variability in human populations.}, journal = {Mol Syst Biol}, volume = {10}, year = {2014}, month = {2014 Sep 26}, pages = {752}, abstract = {

Recent genomic projects have revealed the existence of an unexpectedly large amount of deleterious variability in the human genome. Several hypotheses have been proposed to explain such an apparently high mutational load. However, the mechanisms by which deleterious mutations in some genes cause a pathological effect but are apparently innocuous in other genes remain largely unknown. This study searched for deleterious variants in the 1,000 genomes populations, as well as in a newly sequenced population of 252 healthy Spanish individuals. In addition, variants causative of monogenic diseases and somatic variants from 41 chronic lymphocytic leukaemia patients were analysed. The deleterious variants found were analysed in the context of the interactome to understand the role of network topology in the maintenance of the observed mutational load. Our results suggest that one of the mechanisms whereby the effect of these deleterious variants on the phenotype is suppressed could be related to the configuration of the protein interaction network. Most of the deleterious variants observed in healthy individuals are concentrated in peripheral regions of the interactome, in combinations that preserve their connectivity, and have a marginal effect on interactome integrity. On the contrary, likely pathogenic cancer somatic deleterious variants tend to occur in internal regions of the interactome, often with associated structural consequences. Finally, variants causative of monogenic diseases seem to occupy an intermediate position. Our observations suggest that the real pathological potential of a variant might be more a systems property rather than an intrinsic property of individual proteins.

}, keywords = {Alleles, Exome, Gene Library, Genetic Variation, Genetics, Population, Genome, Human, Genomics, Humans, Models, Genetic, mutation, Phenotype, Protein Conformation, Protein Interaction Maps, Sequence Analysis, DNA, Whites}, issn = {1744-4292}, doi = {10.15252/msb.20145222}, author = {Garc{\'\i}a-Alonso, Luz and Jim{\'e}nez-Almaz{\'a}n, Jorge and Carbonell-Caballero, Jos{\'e} and Vela-Boza, Alicia and Santoyo-L{\'o}pez, Javier and Anti{\v n}olo, Guillermo and Dopazo, Joaquin} } @article {484, title = {Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients.}, journal = {Hum Mutat}, volume = {35}, year = {2014}, month = {2014 Apr}, pages = {470-7}, abstract = {

Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain α-keto acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly, and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients{\textquoteright} clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention.

}, keywords = {Amino Acids, Branched-Chain, Developmental Disabilities, Fibroblasts, Humans, Male, Mutation, Missense, Nervous System Diseases, Pediatrics, Protein Kinases}, issn = {1098-1004}, doi = {10.1002/humu.22513}, author = {Garc{\'\i}a-Cazorla, Angels and Oyarzabal, Alfonso and Fort, Joana and Robles, Concepci{\'o}n and Castej{\'o}n, Esperanza and Ruiz-Sala, Pedro and Bodoy, Susanna and Merinero, Bego{\~n}a and Lopez-Sala, Anna and Dopazo, Joaquin and Nunes, Virginia and Ugarte, Magdalena and Artuch, Rafael and Palac{\'\i}n, Manuel and Rodr{\'\i}guez-Pombo, Pilar and Alcaide, Patricia and Navarrete, Rosa and Sanz, Paloma and Font-Llitj{\'o}s, Mariona and Vilaseca, Ma Antonia and Ormaizabal, Aida and Pristoupilova, Anna and Agull{\'o}, Sergi Beltran} } @article {1041, title = {Two Novel Mutations in the BCKDK Gene (Branched-Chain Keto-Acid Dehydrogenase Kinase) are Responsible of a Neurobehavioral Deficit in two Pediatric Unrelated Patients.}, journal = {Human mutation}, volume = {35}, number = {4}, year = {2014}, month = {2014 Jan 21}, pages = {470-7}, abstract = {Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain keto-acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients{\textquoteright} clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention. This article is protected by copyright. All rights reserved.}, issn = {1098-1004}, doi = {10.1002/humu.22513}, url = {http://onlinelibrary.wiley.com/doi/10.1002/humu.22513/abstract}, author = {Garc{\'\i}a-Cazorla, Angels and Oyarzabal, Alfonso and Fort, Joana and Robles, Concepci{\'o}n and Castej{\'o}n, Esperanza and Ruiz-Sala, Pedro and Bodoy, Susanna and Merinero, Bego{\~n}a and Lopez-Sala, Anna and Joaqu{\'\i}n Dopazo and Nunes, Virginia and Ugarte, Magdalena and Artuch, Rafael and Palac{\'\i}n, Manuel and Rodr{\'\i}guez-Pombo, Pilar} } @article {1093, title = {Understanding disease mechanisms with models of signaling pathway activities.}, journal = {BMC systems biology}, volume = {8}, year = {2014}, month = {2014 Oct 25}, pages = {121}, abstract = {BackgroundUnderstanding the aspects of the cell functionality that account for disease or drug action mechanisms is one of the main challenges in the analysis of genomic data and is on the basis of the future implementation of precision medicine.ResultsHere we propose a simple probabilistic model in which signaling pathways are separated into elementary sub-pathways or signal transmission circuits (which ultimately trigger cell functions) and then transforms gene expression measurements into probabilities of activation of such signal transmission circuits. Using this model, differential activation of such circuits between biological conditions can be estimated. Thus, circuit activation statuses can be interpreted as biomarkers that discriminate among the compared conditions. This type of mechanism-based biomarkers accounts for cell functional activities and can easily be associated to disease or drug action mechanisms. The accuracy of the proposed model is demonstrated with simulations and real datasets.ConclusionsThe proposed model provides detailed information that enables the interpretation disease mechanisms as a consequence of the complex combinations of altered gene expression values. Moreover, it offers a framework for suggesting possible ways of therapeutic intervention in a pathologically perturbed system.}, keywords = {Disease mechanism, pathway, signalling, Systems biology}, issn = {1752-0509}, doi = {10.1186/s12918-014-0121-3}, url = {http://www.biomedcentral.com/1752-0509/8/121/abstract}, author = {Sebasti{\'a}n-Leon, Patricia and Vidal, Enrique and Minguez, Pablo and Ana Conesa and Sonia Tarazona and Amadoz, Alicia and Armero, Carmen and Salavert, Francisco and Vidal-Puig, Antonio and Montaner, David and Joaqu{\'\i}n Dopazo} } @article {565, title = {Understanding disease mechanisms with models of signaling pathway activities}, journal = {BMC systems biology}, volume = {8}, year = {2014}, month = {10}, pages = {121}, doi = {10.1186/s12918-014-0121-3}, author = {Sebasti{\'a}n-Leon, Patricia and Vidal, Enrique and Minguez, Pablo and Conesa, Ana and Tarazona, Sonia and Amadoz, Alicia and Armero, Carmen and Salavert Torres, Francisco and Vidal-Puig, Antonio and Montaner, David and Dopazo, Joaquin} } @article {1058, title = {A web tool for the design and management of panels of genes for targeted enrichment and massive sequencing for clinical applications.}, journal = {Nucleic acids research}, volume = {42}, year = {2014}, month = {2014 May 26}, pages = {W83-W87}, abstract = {Disease targeted sequencing is gaining importance as a powerful and cost-effective application of high throughput sequencing technologies to the diagnosis. However, the lack of proper tools to process the data hinders its extensive adoption. Here we present TEAM, an intuitive and easy-to-use web tool that fills the gap between the predicted mutations and the final diagnostic in targeted enrichment sequencing analysis. The tool searches for known diagnostic mutations, corresponding to a disease panel, among the predicted patient{\textquoteright}s variants. Diagnostic variants for the disease are taken from four databases of disease-related variants (HGMD-public, HUMSAVAR, ClinVar and COSMIC.) If no primary diagnostic variant is found, then a list of secondary findings that can help to establish a diagnostic is produced. TEAM also provides with an interface for the definition of and customization of panels, by means of which, genes and mutations can be added or discarded to adjust panel definitions. TEAM is freely available at: http://team.babelomics.org.}, keywords = {Diagnostic, Targeted enrichment sequencing, WES}, issn = {1362-4962}, doi = {10.1093/nar/gku472}, url = {http://nar.oxfordjournals.org/cgi/pmidlookup?view=long\&pmid=24861626}, author = {Alem{\'a}n, Alejandro and Garcia-Garcia, Francisco and Medina, Ignacio and Joaqu{\'\i}n Dopazo} } @article {1051, title = {A web-based interactive framework to assist in the prioritization of disease candidate genes in whole-exome sequencing studies.}, journal = {Nucleic acids research}, volume = {42}, year = {2014}, month = {2014 May 6}, pages = {W88-W93.}, abstract = {Whole-exome sequencing has become a fundamental tool for the discovery of disease-related genes of familial diseases and the identification of somatic driver variants in cancer. However, finding the causal mutation among the enormous background of individual variability in a small number of samples is still a big challenge. Here we describe a web-based tool, BiERapp, which efficiently helps in the identification of causative variants in family and sporadic genetic diseases. The program reads lists of predicted variants (nucleotide substitutions and indels) in affected individuals or tumor samples and controls. In family studies, different modes of inheritance can easily be defined to filter out variants that do not segregate with the disease along the family. Moreover, BiERapp integrates additional information such as allelic frequencies in the general population and the most popular damaging scores to further narrow down the number of putative variants in successive filtering steps. BiERapp provides an interactive and user-friendly interface that implements the filtering strategy used in the context of a large-scale genomic project carried out by the Spanish Network for Research in Rare Diseases (CIBERER) in which more than 800 exomes have been analyzed. BiERapp is freely available at: http://bierapp.babelomics.org/}, keywords = {NGS. prioritization}, issn = {1362-4962}, doi = {10.1093/nar/gku407}, url = {http://nar.oxfordjournals.org/content/42/W1/W88}, author = {Alem{\'a}n, Alejandro and Garcia-Garcia, Francisco and Salavert, Francisco and Medina, Ignacio and Joaqu{\'\i}n Dopazo} } @article {21919703, title = {Assessing Differential Expression Measurements by Highly Parallel Pyrosequencing and DNA Microarrays: A Comparative Study.}, journal = {Omics : a journal of integrative biology}, year = {2013}, month = {2011 Sep 15}, abstract = {

Abstract To explore the feasibility of pyrosequencing for quantitative differential gene expression analysis we have performed a comparative study of the results of the sequencing experiments to those obtained by a conventional DNA microarray platform. A conclusion from our analysis is that, over a threshold of 35 normalized reads per gene, the measurements of gene expression display a good correlation with the references. The observed concordance between pyrosequencing and DNA microarray platforms beyond the threshold was of 0.8, measured as a Pearson{\textquoteright}s correlation coefficient. In differential gene expression the initial aim is the quantification the differences among transcripts when comparing experimental conditions. Thus, even in a scenario of low coverage the concordance in the measurements is quite acceptable. On the other hand, the comparatively longer read size obtained by pyrosequencing allows detecting unconventional splicing forms.

}, doi = {10.1089/omi.2011.0065}, url = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545353/}, author = {Ari{\~n}o, Joaqu{\'\i}n and Casamayor, Antonio and P{\'e}rez, Juli{\'a}n Perez and Pedrola, Laia and Alvarez-Tejado, Miguel and Marb{\`a}, Martina and Santoyo, Javier and Joaqu{\'\i}n Dopazo} } @article {1047, title = {Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer.}, journal = {Oncotarget}, year = {2013}, month = {2013 Dec 16}, abstract = {Germline mutations in CDKN2A and/or red hair color variants in MC1R genes are associated with an increased susceptibility to develop cutaneous melanoma or non melanoma skin cancer. We studied the impact of the CDKN2A germinal mutation p.G101W and MC1R variants on gene expression and transcription profiles associated with skin cancer. To this end we set-up primary skin cell co-cultures from siblings of melanoma prone-families that were later analyzed using the expression array approach. As a result, we found that 1535 transcripts were deregulated in CDKN2A mutated cells, with over-expression of immunity-related genes (HLA-DPB1, CLEC2B, IFI44, IFI44L, IFI27, IFIT1, IFIT2, SP110 and IFNK) and down-regulation of genes playing a role in the Notch signaling pathway. 3570 transcripts were deregulated in MC1R variant carriers. In particular, genes related to oxidative stress and DNA damage pathways were up-regulated as well as genes associated with neurodegenerative diseases such as Parkinson{\textquoteright}s, Alzheimer and Huntington. Finally, we observed that the expression signatures indentified in phenotypically normal cells carrying CDKN2A mutations or MC1R variants are maintained in skin cancer tumors (melanoma and squamous cell carcinoma). These results indicate that transcriptome deregulation represents an early event critical for skin cancer development.}, issn = {1949-2553}, url = {http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget\&page=article\&op=view\&path\%5B\%5D=1444\&path\%5B\%5D=1824}, author = {Puig-Butille, Joan Anton and Escamez, Maria Jos{\'e} and Garcia-Garcia, Francisco and Tell-Marti, Gemma and Fabra, Angels and Mart{\'\i}nez-Santamar{\'\i}a, Luc{\'\i}a and Badenas, Celia and Aguilera, Paula and Pevida, Marta and Joaqu{\'\i}n Dopazo and Del Rio, Marcela and Puig, Susana} } @article {504, title = {Differential gene-expression analysis defines a molecular pattern related to olive pollen allergy.}, journal = {J Biol Regul Homeost Agents}, volume = {27}, year = {2013}, month = {2013 Apr-Jun}, pages = {337-50}, abstract = {

Analysis of gene-expression profiles by microarrays is useful for characterization of candidate genes, key regulatory networks, and to define phenotypes or molecular signatures which improve the diagnosis and/or classification of the allergic processes. We have used this approach in the study of olive pollen response in order to find differential molecular markers among responders and non-responders to this allergenic source. Five clinical groups, non-allergic, asymptomatic, allergic but not to olive pollen, untreated-olive-pollen allergic patients and olive-pollen allergic patients (under specific-immunotherapy), were assessed during and outside pollen seasons. Whole-genome gene expression analysis was performed in RNAs extracted from PBMCs. After assessment of data quality and principal components analysis (PCA), differential gene-expression, by multiple testing and, functional analyses by KEGG, for pathways and Gene-Ontology for biological processes were performed. Relevance was defined by fold change and corrected P values (less than 0.05). The most differential genes were validated by qRT-PCR in a larger set of individuals. Interestingly, gene-expression profiling obtained by PCA clearly showed five clusters of samples that correlated with the five clinical groups. Furthermore, differential gene expression and functional analyses revealed differential genes and pathways in the five clinical groups. The 93 most significant genes found were validated, and one set of 35 genes was able to discriminate profiles of olive pollen response. Our results, in addition to providing new information on allergic response, define a possible molecular signature for olive pollen allergy which could be useful for the diagnosis and treatment of this and other sensitizations.

}, keywords = {Adult, Female, Gene Expression Profiling, Humans, Male, Middle Aged, Olea, Principal Component Analysis, Rhinitis, Allergic, Seasonal}, issn = {0393-974X}, author = {Aguerri, M and Calzada, D and Montaner, D and Mata, M and Florido, F and Quiralte, J and Dopazo, J and Lahoz, C and Cardaba, B} } @article {1003, title = {Genome Maps, a new generation genome browser.}, journal = {Nucleic acids research}, volume = {41}, number = {W1}, year = {2013}, month = {2013 Jun 8}, pages = {W41-W46}, abstract = {Genome browsers have gained importance as more genomes and related genomic information become available. However, the increase of information brought about by new generation sequencing technologies is, at the same time, causing a subtle but continuous decrease in the efficiency of conventional genome browsers. Here, we present Genome Maps, a genome browser that implements an innovative model of data transfer and management. The program uses highly efficient technologies from the new HTML5 standard, such as scalable vector graphics, that optimize workloads at both server and client sides and ensure future scalability. Thus, data management and representation are entirely carried out by the browser, without the need of any Java Applet, Flash or other plug-in technology installation. Relevant biological data on genes, transcripts, exons, regulatory features, single-nucleotide polymorphisms, karyotype and so forth, are imported from web services and are available as tracks. In addition, several DAS servers are already included in Genome Maps. As a novelty, this web-based genome browser allows the local upload of huge genomic data files (e.g. VCF or BAM) that can be dynamically visualized in real time at the client side, thus facilitating the management of medical data affected by privacy restrictions. Finally, Genome Maps can easily be integrated in any web application by including only a few lines of code. Genome Maps is an open source collaborative initiative available in the GitHub repository (https://github.com/compbio-bigdata-viz/genome-maps). Genome Maps is available at: http://www.genomemaps.org.}, keywords = {BAM, genome viewer, HTML5, javascript, Next Generation Sequencing, NGS, SVG, VCF}, issn = {1362-4962}, doi = {10.1093/nar/gkt530}, url = {http://nar.oxfordjournals.org/content/41/W1/W41}, author = {Medina, Ignacio and Salavert, Francisco and S{\'a}nchez, Rub{\'e}n and De Maria, Alejandro and Alonso, Roberto and Escobar, Pablo and Bleda, Marta and Joaqu{\'\i}n Dopazo} } @article {953, title = {Novel genes detected by transcriptional profiling from whole-blood cells in patients with early onset of acute coronary syndrome: Transcriptional profiling of acute coronary syndrome.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, year = {2013}, month = {2013 Mar 24}, abstract = {{BACKGROUND: Genome-wide expression analysis using microarrays has been used as a research strategy to discovery new biomarkers and candidate genes for a number of diseases. We aim to find new biomarkers for the prediction of acute coronary syndrome (ACS) with a differentially expressed mRNA profiling approach using whole genomic expression analysis in a peripheral blood cell model from patients with early ACS. METHODS AND RESULTS: This study was carried out in two phases. On phase 1 a restricted clinical criteria (ACS-Ph1}, issn = {1873-3492}, doi = {10.1016/j.cca.2013.03.011}, author = {Silbiger, Vivian N and Luchessi, Andr{\'e} D and Hirata, Ros{\'a}rio D C and Lima-Neto, L{\'\i}dio G and Cavichioli, D{\'e}bora and Carracedo, {\'A}ngel and Bri{\'o}n, Maria and Joaqu{\'\i}n Dopazo and Garcia-Garcia, Francisco and Dos Santos, Elizabete S and Ramos, Rui F and Sampaio, Marcelo F and Armaganijan, Dikran and Sousa, Amanda G M R and Hirata, Mario H} } @article {507, title = {Novel genes detected by transcriptional profiling from whole-blood cells in patients with early onset of acute coronary syndrome.}, journal = {Clin Chim Acta}, volume = {421}, year = {2013}, month = {2013 Jun 05}, pages = {184-90}, abstract = {

BACKGROUND: Genome-wide expression analysis using microarrays has been used as a research strategy to discovery new biomarkers and candidate genes for a number of diseases. We aim to find new biomarkers for the prediction of acute coronary syndrome (ACS) with a differentially expressed mRNA profiling approach using whole genomic expression analysis in a peripheral blood cell model from patients with early ACS.

METHODS AND RESULTS: This study was carried out in two phases. On phase 1 a restricted clinical criteria (ACS-Ph1, n=9 and CG-Ph1, n=6) was used in order to select potential mRNA biomarkers candidates. A subsequent phase 2 study was performed using selected phase 1 markers analyzed by RT-qPCR using a larger and independent casuistic (ACS-Ph2, n=74 and CG-Ph2, n=41). A total of 549 genes were found to be differentially expressed in the first 48 h after the ACS-Ph1. Technical and biological validation further confirmed that ALOX15, AREG, BCL2A1, BCL2L1, CA1, COX7B, ECHDC3, IL18R1, IRS2, KCNE1, MMP9, MYL4 and TREML4, are differentially expressed in both phases of this study.

CONCLUSIONS: Transcriptomic analysis by microarray technology demonstrated differential expression during a 48 h time course suggesting a potential use of some of these genes as biomarkers for very early stages of ACS, as well as for monitoring early cardiac ischemic recovery.

}, keywords = {Acute Coronary Syndrome, Acute-Phase Proteins, Adult, biomarkers, Blood Cells, Early Diagnosis, gene expression, Gene Expression Profiling, Humans, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, RNA, Messenger, Transcriptome}, issn = {1873-3492}, doi = {10.1016/j.cca.2013.03.011}, author = {Silbiger, Vivian N and Luchessi, Andr{\'e} D and Hirata, Ros{\'a}rio D C and Lima-Neto, L{\'\i}dio G and Cavichioli, D{\'e}bora and Carracedo, {\'A}ngel and Bri{\'o}n, Maria and Dopazo, Joaquin and Garcia-Garcia, Francisco and Dos Santos, Elizabete S and Ramos, Rui F and Sampaio, Marcelo F and Armaganijan, Dikran and Sousa, Amanda G M R and Hirata, Mario H} } @article {1033, title = {Pathways systematically associated to Hirschsprung{\textquoteright}s disease.}, journal = {Orphanet journal of rare diseases}, volume = {8}, year = {2013}, month = {2013 Dec 2}, pages = {187}, abstract = {Despite it has been reported that several loci are involved in Hirschsprung{\textquoteright}s disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung{\textquoteright}s disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations.}, keywords = {GWAS, Hirschprung, network analysis, Pathway Based Analysis}, issn = {1750-1172}, doi = {10.1186/1750-1172-8-187}, url = {http://www.ojrd.com/content/8/1/187/abstract}, author = {Fern{\'a}ndez, Raquel M and Bleda, Marta and Luz{\'o}n-Toro, Berta and Garc{\'\i}a-Alonso, Luz and Arnold, Stacey and Sribudiani, Yunia and Besmond, Claude and Lantieri, Francesca and Doan, Betty and Ceccherini, Isabella and Lyonnet, Stanislas and Hofstra, Robert Mw and Chakravarti, Aravinda and Anti{\v n}olo, Guillermo and Joaqu{\'\i}n Dopazo and Borrego, Salud} } @article {495, title = {Pathways systematically associated to Hirschsprung{\textquoteright}s disease.}, journal = {Orphanet J Rare Dis}, volume = {8}, year = {2013}, month = {2013 Dec 02}, pages = {187}, abstract = {

Despite it has been reported that several loci are involved in Hirschsprung{\textquoteright}s disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung{\textquoteright}s disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations.

}, keywords = {Female, Genetic Predisposition to Disease, Genotype, Hirschsprung Disease, Humans, Male, Polymorphism, Single Nucleotide}, issn = {1750-1172}, doi = {10.1186/1750-1172-8-187}, author = {Fern{\'a}ndez, Raquel M and Bleda, Marta and Luz{\'o}n-Toro, Berta and Garc{\'\i}a-Alonso, Luz and Arnold, Stacey and Sribudiani, Yunia and Besmond, Claude and Lantieri, Francesca and Doan, Betty and Ceccherini, Isabella and Lyonnet, Stanislas and Hofstra, Robert Mw and Chakravarti, Aravinda and Anti{\v n}olo, Guillermo and Dopazo, Joaquin and Borrego, Salud} } @article {1032, title = {Whole-exome sequencing identifies novel compound heterozygous mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa.}, journal = {Molecular vision}, volume = {19}, year = {2013}, month = {2013}, pages = {2187-95}, abstract = {PURPOSE: Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by extreme genetic and clinical heterogeneity. Thus, the diagnosis is not always easily performed due to phenotypic and genetic overlap. Current clinical practices have focused on the systematic evaluation of a set of known genes for each phenotype, but this approach may fail in patients with inaccurate diagnosis or infrequent genetic cause. In the present study, we investigated the genetic cause of autosomal recessive RP (arRP) in a Spanish family in which the causal mutation has not yet been identified with primer extension technology and resequencing. METHODS: We designed a whole-exome sequencing (WES)-based approach using NimbleGen SeqCap EZ Exome V3 sample preparation kit and the SOLiD 5500{\texttimes}l next-generation sequencing platform. We sequenced the exomes of both unaffected parents and two affected siblings. Exome analysis resulted in the identification of 43,204 variants in the index patient. All variants passing filter criteria were validated with Sanger sequencing to confirm familial segregation and absence in the control population. In silico prediction tools were used to determine mutational impact on protein function and the structure of the identified variants. RESULTS: Novel Usher syndrome type 2A (USH2A) compound heterozygous mutations, c.4325T>C (p.F1442S) and c.15188T>G (p.L5063R), located in exons 20 and 70, respectively, were identified as probable causative mutations for RP in this family. Family segregation of the variants showed the presence of both mutations in all affected members and in two siblings who were apparently asymptomatic at the time of family ascertainment. Clinical reassessment confirmed the diagnosis of RP in these patients. CONCLUSIONS: Using WES, we identified two heterozygous novel mutations in USH2A as the most likely disease-causing variants in a Spanish family diagnosed with arRP in which the cause of the disease had not yet been identified with commonly used techniques. Our data reinforce the clinical role of WES in the molecular diagnosis of highly heterogeneous genetic diseases where conventional genetic approaches have previously failed in achieving a proper diagnosis.}, issn = {1090-0535}, url = {http://www.molvis.org/molvis/v19/2187/}, author = {M{\'e}ndez-Vidal, Cristina and Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Vela-Boza, Alicia and Santoyo-L{\'o}pez, Javier and L{\'o}pez-Domingo, Francisco J and V{\'a}zquez-Marouschek, Carmen and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {931, title = {Development, Characterization and Experimental Validation of a Cultivated Sunflower (Helianthus annuus L.) Gene Expression Oligonucleotide Microarray.}, journal = {PloS one}, volume = {7}, year = {2012}, month = {2012}, pages = {e45899}, abstract = {Oligonucleotide-based microarrays with accurate gene coverage represent a key strategy for transcriptional studies in orphan species such as sunflower, H. annuus L., which lacks full genome sequences. The goal of this study was the development and functional annotation of a comprehensive sunflower unigene collection and the design and validation of a custom sunflower oligonucleotide-based microarray. A large scale EST (>130,000 ESTs) curation, assembly and sequence annotation was performed using Blast2GO (www.blast2go.de). The EST assembly comprises 41,013 putative transcripts (12,924 contigs and 28,089 singletons). The resulting Sunflower Unigen Resource (SUR version 1.0) was used to design an oligonucleotide-based Agilent microarray for cultivated sunflower. This microarray includes a total of 42,326 features: 1,417 Agilent controls, 74 control probes for sunflower replicated 10 times (740 controls) and 40,169 different non-control probes. Microarray performance was validated using a model experiment examining the induction of senescence by water deficit. Pre-processing and differential expression analysis of Agilent microarrays was performed using the Bioconductor limma package. The analyses based on p-values calculated by eBayes (p<0.01) allowed the detection of 558 differentially expressed genes between water stress and control conditions; from these, ten genes were further validated by qPCR. Over-represented ontologies were identified using FatiScan in the Babelomics suite. This work generated a curated and trustable sunflower unigene collection, and a custom, validated sunflower oligonucleotide-based microarray using Agilent technology. Both the curated unigene collection and the validated oligonucleotide microarray provide key resources for sunflower genome analysis, transcriptional studies, and molecular breeding for crop improvement.}, issn = {1932-6203}, doi = {10.1371/journal.pone.0045899}, url = {http://www.plosone.org/article/info\%3Adoi\%2F10.1371\%2Fjournal.pone.0045899}, author = {Fernandez, Paula and Soria, Marcelo and Blesa, David and Dirienzo, Julio and Moschen, Sebasti{\'a}n and Rivarola, M{\'a}ximo and Clavijo, Bernardo Jose and Gonzalez, Sergio and Peluffo, Lucila and Pr{\'\i}ncipi, Dario and Dosio, Guillermo and Aguirrezabal, Luis and Garcia-Garcia, Francisco and Ana Conesa and Hopp, Esteban and Joaqu{\'\i}n Dopazo and Heinz, Ruth Amelia and Paniego, Norma} } @article {512, title = {Discovering the hidden sub-network component in a ranked list of genes or proteins derived from genomic experiments.}, journal = {Nucleic Acids Res}, volume = {40}, year = {2012}, month = {2012 Nov 01}, pages = {e158}, abstract = {

Genomic experiments (e.g. differential gene expression, single-nucleotide polymorphism association) typically produce ranked list of genes. We present a simple but powerful approach which uses protein-protein interaction data to detect sub-networks within such ranked lists of genes or proteins. We performed an exhaustive study of network parameters that allowed us concluding that the average number of components and the average number of nodes per component are the parameters that best discriminate between real and random networks. A novel aspect that increases the efficiency of this strategy in finding sub-networks is that, in addition to direct connections, also connections mediated by intermediate nodes are considered to build up the sub-networks. The possibility of using of such intermediate nodes makes this approach more robust to noise. It also overcomes some limitations intrinsic to experimental designs based on differential expression, in which some nodes are invariant across conditions. The proposed approach can also be used for candidate disease-gene prioritization. Here, we demonstrate the usefulness of the approach by means of several case examples that include a differential expression analysis in Fanconi Anemia, a genome-wide association study of bipolar disorder and a genome-scale study of essentiality in cancer genes. An efficient and easy-to-use web interface (available at http://www.babelomics.org) based on HTML5 technologies is also provided to run the algorithm and represent the network.

}, keywords = {Bipolar Disorder, Fanconi Anemia, Gene Regulatory Networks, Genes, Neoplasm, Genome-Wide Association Study, Genomics, Humans, Protein Interaction Mapping}, issn = {1362-4962}, doi = {10.1093/nar/gks699}, author = {Garc{\'\i}a-Alonso, Luz and Alonso, Roberto and Vidal, Enrique and Amadoz, Alicia and De Maria, Alejandro and Minguez, Pablo and Medina, Ignacio and Dopazo, Joaquin} } @article {902, title = {Evolutionary Genomics of Genes Involved in Olfactory Behavior in the Drosophila melanogaster Species Group.}, journal = {Evolutionary bioinformatics online}, volume = {8}, year = {2012}, month = {2012}, pages = {89-104}, abstract = {Previous comparative genomic studies of genes involved in olfactory behavior in Drosophila focused only on particular gene families such as odorant receptor and/or odorant binding proteins. However, olfactory behavior has a complex genetic architecture that is orchestrated by many interacting genes. In this paper, we present a comparative genomic study of olfactory behavior in Drosophila including an extended set of genes known to affect olfactory behavior. We took advantage of the recent burst of whole genome sequences and the development of powerful statistical tools to analyze genomic data and test evolutionary and functional hypotheses of olfactory genes in the six species of the Drosophila melanogaster species group for which whole genome sequences are available. Our study reveals widespread purifying selection and limited incidence of positive selection on olfactory genes. We show that the pace of evolution of olfactory genes is mostly independent of the life cycle stage, and of the number of life cycle stages, in which they participate in olfaction. However, we detected a relationship between evolutionary rates and the position that the gene products occupy in the olfactory system, genes occupying central positions tend to be more constrained than peripheral genes. Finally, we demonstrate that specialization to one host does not seem to be associated with bursts of adaptive evolution in olfactory genes in D. sechellia and D. erecta, the two specialists species analyzed, but rather different lineages have idiosyncratic evolutionary histories in which both historical and ecological factors have been involved.}, issn = {1176-9343}, doi = {10.4137/EBO.S8484}, url = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3273929/?tool=pubmed}, author = {Lavagnino, Nicol{\'a}s and Serra, Fran{\c c}ois and Arbiza, Leonardo and Dopazo, Hern{\'a}n and Hasson, Esteban} } @article {944, title = {Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung{\textquoteright}s disease.}, journal = {Orphanet journal of rare diseases}, volume = {7}, year = {2012}, month = {2012 Dec 28}, pages = {103}, abstract = {ABSTRACT: Finding gene associations in rare diseases is frequently hampered by the reduced numbers of patients accessible. Conventional gene-based association tests rely on the availability of large cohorts, which constitutes a serious limitation for its application in this scenario. To overcome this problem we have used here a combined strategy in which a pathway-based analysis (PBA) has been initially conducted to prioritize candidate genes in a Spanish cohort of 53 trios of short-segment Hirschsprung{\textquoteright}s disease. Candidate genes have been further validated in an independent population of 106 trios. The study revealed a strong association of 11 gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other HSCR-related processes. Among the preselected candidates, a total of 4 loci, RASGEF1A, IQGAP2, DLC1 and CHRNA7, related to signal transduction and migration processes, were found to be significantly associated to HSCR. Network analysis also confirms their involvement in the network of already known disease genes. This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases.}, issn = {1750-1172}, doi = {10.1186/1750-1172-7-103}, url = {http://www.ojrd.com/content/7/1/103/abstract}, author = {Fern{\'a}ndez, Raquel Ma and Bleda, Marta and N{\'u}{\~n}ez-Torres, Roc{\'\i}o and Medina, Ignacio and Luz{\'o}n-Toro, Berta and Garc{\'\i}a-Alonso, Luz and Torroglosa, Ana and Marb{\`a}, Martina and Enguix-Riego, Ma Valle and Montaner, David and Anti{\v n}olo, Guillermo and Joaqu{\'\i}n Dopazo and Borrego, Salud} } @article {515, title = {Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung{\textquoteright}s disease.}, journal = {Orphanet J Rare Dis}, volume = {7}, year = {2012}, month = {2012 Dec 28}, pages = {103}, abstract = {

Finding gene associations in rare diseases is frequently hampered by the reduced numbers of patients accessible. Conventional gene-based association tests rely on the availability of large cohorts, which constitutes a serious limitation for its application in this scenario. To overcome this problem we have used here a combined strategy in which a pathway-based analysis (PBA) has been initially conducted to prioritize candidate genes in a Spanish cohort of 53 trios of short-segment Hirschsprung{\textquoteright}s disease. Candidate genes have been further validated in an independent population of 106 trios. The study revealed a strong association of 11 gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other HSCR-related processes. Among the preselected candidates, a total of 4 loci, RASGEF1A, IQGAP2, DLC1 and CHRNA7, related to signal transduction and migration processes, were found to be significantly associated to HSCR. Network analysis also confirms their involvement in the network of already known disease genes. This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases.

}, keywords = {Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Hirschsprung Disease, Humans, Male}, issn = {1750-1172}, doi = {10.1186/1750-1172-7-103}, author = {Fern{\'a}ndez, Raquel Ma and Bleda, Marta and N{\'u}{\~n}ez-Torres, Roc{\'\i}o and Medina, Ignacio and Luz{\'o}n-Toro, Berta and Garc{\'\i}a-Alonso, Luz and Torroglosa, Ana and Marb{\`a}, Martina and Enguix-Riego, Ma Valle and Montaner, David and Anti{\v n}olo, Guillermo and Dopazo, Joaquin and Borrego, Salud} } @article {517, title = {Inferring the regulatory network behind a gene expression experiment.}, journal = {Nucleic Acids Res}, volume = {40}, year = {2012}, month = {2012 Jul}, pages = {W168-72}, abstract = {

Transcription factors (TFs) and miRNAs are the most important dynamic regulators in the control of gene expression in multicellular organisms. These regulatory elements play crucial roles in development, cell cycling and cell signaling, and they have also been associated with many diseases. The Regulatory Network Analysis Tool (RENATO) web server makes the exploration of regulatory networks easy, enabling a better understanding of functional modularity and network integrity under specific perturbations. RENATO is suitable for the analysis of the result of expression profiling experiments. The program analyses lists of genes and search for the regulators compatible with its activation or deactivation. Tests of single enrichment or gene set enrichment allow the selection of the subset of TFs or miRNAs significantly involved in the regulation of the query genes. RENATO also offers an interactive advanced graphical interface that allows exploring the regulatory network found.RENATO is available at: http://renato.bioinfo.cipf.es/.

}, keywords = {Binding Sites, Databases, Genetic, Fanconi Anemia, Gene Regulatory Networks, Internet, MicroRNAs, Software, Transcription Factors, Transcriptome}, issn = {1362-4962}, doi = {10.1093/nar/gks573}, author = {Bleda, Marta and Medina, Ignacio and Alonso, Roberto and De Maria, Alejandro and Salavert, Francisco and Dopazo, Joaquin} } @article {920, title = {A map of human microRNA variation uncovers unexpectedly high levels of variability.}, journal = {Genome medicine}, volume = {4}, year = {2012}, month = {2012 Aug 20}, pages = {62}, abstract = {ABSTRACT: BACKGROUND: MicroRNAs (miRNAs) are key components of the gene regulatory network in many species. During the past few years, these regulatory elements have been shown to be involved in an increasing number and range of diseases. Consequently, the compilation of a comprehensive map of natural variability in healthy population seems an obvious requirement for future research on miRNA-related pathologies. METHODS: Data on 14 populations from the 1000 Genomes Project were analysed, along with new data extracted from 60 exomes of healthy individuals from a southern Spain population, sequenced in the context of the Medical Genome Project, to derive an accurate map of miRNA variability. RESULTS: Despite the common belief that miRNAs are highly conserved elements, analysis of the sequences of the 1,152 individuals indicated that the observed level of variability is double what was expected. A total of 527 variants were found. Among these, 45 variants affected the recognition region of the corresponding miRNA and were found in 43 different miRNAs, 26 of which are known to be involved in 57 diseases. Different parts of the mature structure of the miRNA were affected to different degrees by variants, which suggests the existence of a selective pressure related to the relative functional impact of the change. Moreover, 41 variants showed a significant deviation from the Hardy-Weinberg equilibrium, which supports the existence of a selective process against some alleles. The average number of variants per individual in miRNAs was 28. CONCLUSIONS: Despite an expectation that miRNAs would be highly conserved genomic elements, our study reports a level of variability comparable to that observed for coding genes.}, keywords = {NGS}, issn = {1756-994X}, doi = {10.1186/gm363}, url = {http://genomemedicine.com/content/4/8/62/abstract}, author = {Carbonell, Jos{\'e} and Alloza, Eva and Arce, Pablo and Borrego, Salud and Santoyo, Javier and Ruiz-Ferrer, Macarena and Medina, Ignacio and Jim{\'e}nez-Almaz{\'a}n, Jorge and M{\'e}ndez-Vidal, Cristina and Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Vela, Alicia and Bhattacharya, Shomi S and Anti{\v n}olo, Guillermo and Dopazo, Joaquin} } @article {896, title = {Microarray analysis of Etrog citron (Citrus medica L.) reveals changes in chloroplast, cell wall, peroxidase and symporter activities in response to viroid infection.}, journal = {Molecular plant pathology}, year = {2012}, month = {2012 Mar 15}, abstract = {Viroids are small (246-401 nucleotides), single-stranded, circular RNA molecules that infect several crop plants and can cause diseases of economic importance. Citrus are the hosts in which the largest number of viroids have been identified. Citrus exocortis viroid (CEVd), the causal agent of citrus exocortis disease, induces considerable losses in citrus crops. Changes in the gene expression profile during the early (pre-symptomatic) and late (post-symptomatic) stages of Etrog citron infected with CEVd were investigated using a citrus cDNA microarray. MaSigPro analysis was performed and, on the basis of gene expression profiles as a function of the time after infection, the differentially expressed genes were classified into five clusters. FatiScan analysis revealed significant enrichment of functional categories for each cluster, indicating that viroid infection triggers important changes in chloroplast, cell wall, peroxidase and symporter activities.}, issn = {1364-3703}, doi = {10.1111/j.1364-3703.2012.00794.x}, author = {Rizza, Serena and Ana Conesa and Juarez, Jos{\'e} and Catara, Antonino and Navarro, Luis and Duran-Vila, Nuria and Ancillo, Gema} } @article {521, title = {The protease MT1-MMP drives a combinatorial proteolytic program in activated endothelial cells.}, journal = {FASEB J}, volume = {26}, year = {2012}, month = {2012 Nov}, pages = {4481-94}, abstract = {

The mechanism by which proteolytic events translate into biological responses is not well understood. To explore the link of pericellular proteolysis to events relevant to capillary sprouting within the inflammatory context, we aimed at the identification of the collection of substrates of the protease MT1-MMP in endothelial tip cells induced by inflammatory stimuli. We applied quantitative proteomics to endothelial cells (ECs) derived from wild-type and MT1-MMP-null mice to identify the substrate repertoire of this protease in TNF-α-activated ECs. Bioinformatics analysis revealed a combinatorial MT1-MMP proteolytic program, in which combined rather than single substrate processing would determine biological decisions by activated ECs, including chemotaxis, cell motility and adhesion, and vasculature development. MT1-MMP-deficient ECs inefficiently processed several of these substrates (TSP1, CYR61, NID1, and SEM3C), validating the model. This novel concept of MT1-MMP-driven combinatorial proteolysis in angiogenesis might be extendable to proteolytic actions in other cellular contexts.

}, keywords = {Animals, Blotting, Western, Combinatorial Chemistry Techniques, Computational Biology, Endothelial Cells, Gene Expression Regulation, Enzymologic, Inflammation, Matrix Metalloproteinase 14, Mice, Protein Array Analysis, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, RNA, Small Interfering, Transcriptome, Tumor Necrosis Factor-alpha}, issn = {1530-6860}, doi = {10.1096/fj.12-205906}, author = {Koziol, Agnieszka and Gonzalo, Pilar and Mota, Alba and Poll{\'a}n, Angela and Lorenzo, Cristina and Colom{\'e}, Nuria and Montaner, David and Dopazo, Joaquin and Arribas, Joaqu{\'\i}n and Canals, Francesc and Arroyo, Alicia G} } @article {939, title = {Select your SNPs (SYSNPs): a web tool for automatic and massive selection of SNPs.}, journal = {International journal of data mining and bioinformatics}, volume = {6}, year = {2012}, month = {2012}, pages = {324-34}, abstract = {Association studies are the choice approach in the discovery of the genomic basis of complex traits. To carry out such analysis, researchers frequently need to (1) select optimally informative sets of Single Nucleotide Polymorphisms (SNPs) in candidate regions and (2) annotate the results of associations found by means of genome-wide SNP arrays. These are complex tasks, since many criteria have to be considered, including the SNPs{\textquoteright} functional properties, technological information and haplotype frequencies in given populations. SYSNPs implements algorithms that allow for efficient and simultaneous consideration of all the relevant criteria to obtain sets of SNPs that properly cover arbitrarily large lists of genes or genomic regions. Complementarily, SYSNPs allows for comprehensive functional annotation of SNPs linked to any given marker SNP. SYSNPs dramatically reduces the effort needed for SNP selection from days of searching various databases to a few minutes using a simple browser.}, issn = {1748-5673}, url = {http://inderscience.metapress.com/content/f76740x8071u513n/}, author = {Lorente-Galdos, Bel{\'e}n and Medina, Ignacio and Morcillo-Suarez, Carlos and Heredia, Txema and Carre{\~n}o-Torres, Angel and Sangr{\'o}s, Ricardo and Alegre, Josep and Pita, Guillermo and Vellalta, Gemma and Malats, Nuria and Pisano, David G and Joaqu{\'\i}n Dopazo and Navarro, Arcadi} } @article {1028, title = {Transdifferentiation of MALME-3M and MCF-7 Cells toward Adipocyte-like Cells is Dependent on Clathrin-mediated Endocytosis.}, journal = {SpringerPlus}, volume = {1}, year = {2012}, month = {2012}, pages = {44}, abstract = {ABSTRACT: Enforced cell transdifferentiation of human cancer cells is a promising alternative to conventional chemotherapy. We previously identified albumin-associated lipid- and, more specifically, saturated fatty acid-induced transdifferentiation programs in human cancer cells (HCCLs). In this study, we further characterized the adipocyte-like cells, resulting from the transdifferentiation of human cancer cell lines MCF-7 and MALME-3M, and proposed a common mechanistic approach for these transdifferentiating programs. We showed the loss of pigmentation in MALME-3M cells treated with albumin-associated lipids, based on electron microscopic analysis, and the overexpression of perilipin 2 (PLIN2) by western blotting in MALME-3M and MCF-7 cells treated with unsaturated fatty acids. Comparing the gene expression profiles of naive melanoma MALME-3M cells and albumin-associated lipid-treated cells, based on RNA sequencing, we confirmed the transcriptional upregulation of some key adipogenic gene markers and also an alternative splicing of the adipogenic master regulator PPARG, that is probably related to the reported up regulated expression of the protein. Most importantly, these results also showed the upregulation of genes responsible for Clathrin (CLTC) and other adaptor-related proteins. An increase in CLTC expression in the transdifferentiated cells was confirmed by western blotting. Inactivation of CLTC by chlorpromazine (CHP), an inhibitor of CTLC mediated endocytosis (CME), and gene silencing by siRNAs, partially reversed the accumulation of neutral lipids observed in the transdifferentiated cells. These findings give a deeper insight into the phenotypic changes observed in HCCL to adipocyte-like transdifferentiation and point towards CME as a key pathway in distinct transdifferentiation programs. DISCLOSURES: Simon C and Aguilar-Gallardo C are co-inventors of the International Patent Application No. PCT/EP2011/004941 entitled "Methods for tumor treatment and adipogenesis differentiation".}, issn = {2193-1801}, doi = {10.1186/2193-1801-1-44}, url = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725915/}, author = {Carcel-Trullols, Jaime and Aguilar-Gallardo, Crist{\'o}bal and Garc{\'\i}a-Alcalde, Fernando and Pardo-Cea, Miguel Angel and Dopazo, Joaquin and Ana Conesa and Simon, Carlos} } @article {523, title = {VARIANT: Command Line, Web service and Web interface for fast and accurate functional characterization of variants found by Next-Generation Sequencing.}, journal = {Nucleic Acids Res}, volume = {40}, year = {2012}, month = {2012 Jul}, pages = {W54-8}, abstract = {

The massive use of Next-Generation Sequencing (NGS) technologies is uncovering an unexpected amount of variability. The functional characterization of such variability, particularly in the most common form of variation found, the Single Nucleotide Variants (SNVs), has become a priority that needs to be addressed in a systematic way. VARIANT (VARIant ANalyis Tool) reports information on the variants found that include consequence type and annotations taken from different databases and repositories (SNPs and variants from dbSNP and 1000 genomes, and disease-related variants from the Genome-Wide Association Study (GWAS) catalog, Online Mendelian Inheritance in Man (OMIM), Catalog of Somatic Mutations in Cancer (COSMIC) mutations, etc). VARIANT also produces a rich variety of annotations that include information on the regulatory (transcription factor or miRNA-binding sites, etc.) or structural roles, or on the selective pressures on the sites affected by the variation. This information allows extending the conventional reports beyond the coding regions and expands the knowledge on the contribution of non-coding or synonymous variants to the phenotype studied. Contrarily to other tools, VARIANT uses a remote database and operates through efficient RESTful Web Services that optimize search and transaction operations. In this way, local problems of installation, update or disk size limitations are overcome without the need of sacrifice speed (thousands of variants are processed per minute). VARIANT is available at: http://variant.bioinfo.cipf.es.

}, keywords = {Databases, Nucleic Acid, Genetic Variation, High-Throughput Nucleotide Sequencing, Internet, Molecular Sequence Annotation, mutation, Polymorphism, Single Nucleotide, Software, User-Computer Interface}, issn = {1362-4962}, doi = {10.1093/nar/gks572}, author = {Medina, Ignacio and De Maria, Alejandro and Bleda, Marta and Salavert, Francisco and Alonso, Roberto and Gonzalez, Cristina Y and Dopazo, Joaquin} } @article {21479216, title = {Analysis of normal-tumour tissue interaction in tumours: prediction of prostate cancer features from the molecular profile of adjacent normal cells.}, journal = {PloS one}, volume = {6}, year = {2011}, month = {2011}, pages = {e16492}, abstract = {

Statistical modelling, in combination with genome-wide expression profiling techniques, has demonstrated that the molecular state of the tumour is sufficient to infer its pathological state. These studies have been extremely important in diagnostics and have contributed to improving our understanding of tumour biology. However, their importance in in-depth understanding of cancer patho-physiology may be limited since they do not explicitly take into consideration the fundamental role of the tissue microenvironment in specifying tumour physiology. Because of the importance of normal cells in shaping the tissue microenvironment we formulate the hypothesis that molecular components of the profile of normal epithelial cells adjacent the tumour are predictive of tumour physiology. We addressed this hypothesis by developing statistical models that link gene expression profiles representing the molecular state of adjacent normal epithelial cells to tumour features in prostate cancer. Furthermore, network analysis showed that predictive genes are linked to the activity of important secreted factors, which have the potential to influence tumor biology, such as IL1, IGF1, PDGF BB, AGT, and TGF\β.

}, author = {Trevino, Victor and Tadesse, Mahlet G and Vannucci, Marina and Fatima Al-Shahrour and Antczak, Philipp and Durant, Sarah and Bikfalvi, Andreas and Dopazo, Joaquin and Campbell, Moray J and Falciani, Francesco} } @article {21335611, title = {B2G-FAR, a species centered GO annotation repository.}, journal = {Bioinformatics (Oxford, England)}, volume = {27}, number = {7}, year = {2011}, month = {2011 Feb 18}, pages = {919-924}, abstract = {

MOTIVATION: Functional genomics research has expanded enormously in the last decade thanks to the cost-reduction in high-throughput technologies and the development of computational tools that generate, standardize and share information on gene and protein function such as the Gene Ontology (GO). Nevertheless many biologists, especially working with non-model organisms, still suffer from non-existing or low coverage functional annotation, or simply struggle retrieving, summarizing and querying these data. RESULTS: The Blast2GO Functional Annotation Repository (B2G-FAR) is a bioinformatics resource envisaged to provide functional information for otherwise uncharacterized sequence-data and offers data-mining tools to analyze a larger repertoire of species than currently available. This new annotation resource has been created by applying the Blast2GO functional annotation engine in a strongly high-throughput manner to the entire space of public available sequences. The resulting repository contains GO term predictions for over 13.2 million non-redundant protein sequences based on BLAST search alignments from the SIMAP database. We generated GO annotation for approximately 150.000 different taxa making available the 2000 species with the highest coverage through B2G-FAR. A second section within B2G-FAR holds functional annotations for 17 non-model organism Affymetrix GeneChips. Conclusions: B2G-FAR provides easy access to exhaustive functional annotation for 2000 species offering a good balance between quality and quantity, thereby supporting functional genomics research especially in the case of non-model organisms. AVAILABILITY: The annotation resource is available at http://b2gfar.bioinfo.cipf.es. CONTACT: aconesa@cipf.es, sgoetz@cipf.es.

}, author = {G{\"o}tz, Stefan and Arnold, Roland and Sebasti{\'a}n-Leon, Patricia and Mart{\'\i}n-Rodr{\'\i}guez, Samuel and Tischler, Patrick and Jehl, Marc-Andr{\'e} and Joaqu{\'\i}n Dopazo and Rattei, Thomas and Ana Conesa} } @article {22112448, title = {Does singlet oxygen activate cell death in Arabidopsis cell suspension cultures? Analysis of the early transcriptional defence responses to high light stress.}, journal = {Plant signaling \& behavior}, volume = {6}, year = {2011}, month = {2011 Dec 1}, abstract = {

Can Arabidopsis cell suspension cultures (ACSC) provide a useful working model to investigate genetically-controlled defence responses with signalling cascades starting in chloroplasts? In order to provide a convincing answer, we analysed the early transcriptional profile of Arabidopsis cells at high light (HL). The results showed that ACSC respond to HL in a manner that resembles the singlet oxygen ( ( 1) O 2)-mediated defence responses described for the conditional fluorescent (flu) mutant of Arabidopsis thaliana. The flu mutant is characterized by the accumulation of free protochlorophyllide (Pchlide) in plastids when put into darkness and the subsequent production of ( 1) O 2 when the light is on. In ACSC, ( 1) O 2 is produced in chloroplasts at HL when excess excitation energy flows into photosystem II (PSII). Other reactive oxygen species are also produced in ACSC at HL, but to a lesser extent. When the HL stress ceases, ACSC recovers the initial rate of oxygen evolution and cell growth continues. We can conclude that chloroplasts of ACSC are both photosynthetically active and capable of initiating ( 1) O 2-mediated signalling cascades that activate a broad range of genetically-controlled defence responses. The up-regulation of transcripts associated with the biosynthesis and signalling pathways of OPDA (12-oxophytodienoic acid) and ethylene (ET) suggests that the activated defence responses at HL are governed by these two hormones. In contrast to the flu mutant, the ( 1) O 2-mediated defence responses were independent of the up-regulation of EDS1 (enhanced disease susceptibility) required for the accumulation of salicylic acid (SA) and genetically-controlled cell death.\ 

}, author = {Guti{\'e}rrez, Jorge and Gonz{\'a}lez-P{\'e}rez, Sergio and Garcia-Garcia, Francisco and Lorenzo, Oscar and Arellano, Juan B} } @article {21531897, title = {Early transcriptional defence responses in Arabidopsis cell suspension culture under high light conditions.}, journal = {Plant physiology}, volume = {156}, number = {3}, year = {2011}, month = {2011 Apr 29}, pages = {1439-56}, abstract = {

The early transcriptional defence responses and ROS production in Arabidopsis cell suspension culture (ACSC), containing functional chloroplasts, were examined at high light (HL). The transcriptional analysis revealed that most of the ROS markers identified among the 449 transcripts with significant differential expression were transcripts specifically up-regulated by singlet oxygen (1O2). On the contrary, minimal correlation was established with transcripts specifically up-regulated by superoxide radical (O2\•) or hydrogen peroxide (H2O2). The transcriptional analysis was supported by fluorescence microscopy experiments. The incubation of ACSC with the 1O2 sensor green reagent and 2{\textquoteright},7{\textquoteright}-dichlorofluorescein diacetate showed that the 30-min-HL-treated cultures emitted fluorescence that corresponded with the production of 1O2, but not of H2O2. Furthermore, the in vivo photodamage of the D1 protein of photosystem II (PSII) indicated that the photogeneration of 1O2 took place within the PSII reaction centre. Functional enrichment analyses identified transcripts that are key components of the ROS signalling transduction pathway in plants as well as others encoding transcription factors that regulate both ROS scavenging and water deficit stress. A meta-analysis examining the transcriptional profiles of mutants and hormone treatments in Arabidopsis showed a high correlation between ACSC at HL and the flu mutant family of Arabidopsis, a producer of 1O2 in plastids. Intriguingly, a high correlation was also observed with aba1 and max4, two mutants with defects in the biosynthesis pathways of two key (apo)carotenoid-derived plant hormones (i.e. ABA and strigolactones, respectively). ACSC has proven to be a valuable system for studying early transcriptional responses to HL stress.

}, url = {http://www.plantphysiol.org/content/early/2011/04/29/pp.111.177766.short?keytype=ref\&ijkey=ph5B6J2khjnqwzN}, author = {Gonz{\'a}lez-P{\'e}rez, Sergio and Guti{\'e}rrez, Jorge and Garcia-Garcia, Francisco and Osuna, Daniel and Joaqu{\'\i}n Dopazo and Lorenzo, Oscar and Revuelta, Jos{\'e} L and Arellano, Juan B} } @article {532, title = {Early transcriptional defense responses in Arabidopsis cell suspension culture under high-light conditions.}, journal = {Plant Physiol}, volume = {156}, year = {2011}, month = {2011 Jul}, pages = {1439-56}, abstract = {

The early transcriptional defense responses and reactive oxygen species (ROS) production in Arabidopsis (Arabidopsis thaliana) cell suspension culture (ACSC), containing functional chloroplasts, were examined at high light (HL). The transcriptional analysis revealed that most of the ROS markers identified among the 449 transcripts with significant differential expression were transcripts specifically up-regulated by singlet oxygen ((1)O(2)). On the contrary, minimal correlation was established with transcripts specifically up-regulated by superoxide radical or hydrogen peroxide. The transcriptional analysis was supported by fluorescence microscopy experiments. The incubation of ACSC with the (1)O(2) sensor green reagent and 2{\textquoteright},7{\textquoteright}-dichlorofluorescein diacetate showed that the 30-min-HL-treated cultures emitted fluorescence that corresponded with the production of (1)O(2) but not of hydrogen peroxide. Furthermore, the in vivo photodamage of the D1 protein of photosystem II indicated that the photogeneration of (1)O(2) took place within the photosystem II reaction center. Functional enrichment analyses identified transcripts that are key components of the ROS signaling transduction pathway in plants as well as others encoding transcription factors that regulate both ROS scavenging and water deficit stress. A meta-analysis examining the transcriptional profiles of mutants and hormone treatments in Arabidopsis showed a high correlation between ACSC at HL and the fluorescent mutant family of Arabidopsis, a producer of (1)O(2) in plastids. Intriguingly, a high correlation was also observed with ABA deficient1 and more axillary growth4, two mutants with defects in the biosynthesis pathways of two key (apo)carotenoid-derived plant hormones (i.e. abscisic acid and strigolactones, respectively). ACSC has proven to be a valuable system for studying early transcriptional responses to HL stress.

}, keywords = {Arabidopsis, Blotting, Western, Cell Culture Techniques, Cells, Cultured, Chloroplasts, Cluster Analysis, Gene Expression Profiling, Gene Expression Regulation, Plant, Hydrogen Peroxide, Light, mutation, Oligonucleotide Array Sequence Analysis, Photosystem II Protein Complex, Plant Growth Regulators, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Signal Transduction, Stress, Physiological, Transcription, Genetic}, issn = {1532-2548}, doi = {10.1104/pp.111.177766}, author = {Gonz{\'a}lez-P{\'e}rez, Sergio and Guti{\'e}rrez, Jorge and Garcia-Garcia, Francisco and Osuna, Daniel and Dopazo, Joaquin and Lorenzo, Oscar and Revuelta, Jos{\'e} L and Arellano, Juan B} } @article {21824869, title = {Genome-wide heterogeneity of nucleotide substitution model fit.}, journal = {Genome biology and evolution}, volume = {3}, year = {2011}, month = {2011}, pages = {896-908}, abstract = {

At a genomic scale, the patterns that have shaped molecular evolution are believed to be largely heterogeneous. Consequently, comparative analyses should use appropriate probabilistic substitution models that capture the main features under which different genomic regions have evolved. While efforts have concentrated in the development and understanding of model selection techniques, no descriptions of overall relative substitution model fit at the genome level have been reported. Here, we provide a characterization of best-fit substitution models across three genomic data sets including coding regions from mammals, vertebrates, and Drosophila (24,000 alignments). According to the Akaike Information Criterion (AIC), 82 of 88 models considered were selected as best-fit models at least in one occasion, although with very different frequencies. Most parameter estimates also varied broadly among genes. Patterns found for vertebrates and Drosophila were quite similar and often more complex than those found in mammals. Phylogenetic trees derived from models in the 95\% confidence interval set showed much less variance and were significantly closer to the tree estimated under the best-fit model than trees derived from models outside this interval. Although alternative criteria selected simpler models than the AIC, they suggested similar patterns. All together our results show that at a genomic scale, different gene alignments for the same set of taxa are best explained by a large variety of different substitution models and that model choice has implications on different parameter estimates including the inferred phylogenetic trees. After taking into account the differences related to sample size, our results suggest a noticeable diversity in the underlying evolutionary process. All together, we conclude that the use of model selection techniques is important to obtain consistent phylogenetic estimates from real data at a genomic scale.

}, author = {Arbiza, Leonardo and Patricio, Mateus and Dopazo, Hern{\'a}n and Posada, David} } @article {850, title = {A large scale survey reveals that chromosomal copy-number alterations significantly affect gene modules involved in cancer initiation and progression}, journal = {BMC Medical Genomics}, volume = {4}, year = {2011}, month = {06/05/2011}, pages = {37}, type = {Research article}, abstract = {

Background

Recent observations point towards the existence of a large number of neighborhoods composed of functionally-related gene modules that lie together in the genome. This local component in the distribution of the functionality across chromosomes is probably affecting the own chromosomal architecture by limiting the possibilities in which genes can be arranged and distributed across the genome. As a direct consequence of this fact it is therefore presumable that diseases such as cancer, harboring DNA copy number alterations (CNAs), will have a symptomatology strongly dependent on modules of functionally-related genes rather than on a unique \"important\" gene.

Methods

We carried out a systematic analysis of more than 140,000 observations of CNAs in cancers and searched by enrichments in gene functional modules associated to high frequencies of loss or gains.

Results

The analysis of CNAs in cancers clearly demonstrates the existence of a significant pattern of loss of gene modules functionally related to cancer initiation and progression along with the amplification of modules of genes related to unspecific defense against xenobiotics (probably chemotherapeutical agents). With the extension of this analysis to an Array-CGH dataset (glioblastomas) from The Cancer Genome Atlas we demonstrate the validity of this approach to investigate the functional impact of CNAs.

Conclusions

The presented results indicate promising clinical and therapeutic implications. Our findings also directly point out to the necessity of adopting a function-centric, rather a gene-centric, view in the understanding of phenotypes or diseases harboring CNAs.

}, issn = {1755-8794}, doi = {10.1186/1755-8794-4-37}, url = {http://www.biomedcentral.com/1755-8794/4/37}, author = {Alloza, E. and Fatima Al-Shahrour and Cigudosa, J. C. and Dopazo, J.} } @article {535, title = {Large-scale transcriptional profiling and functional assays reveal important roles for Rho-GTPase signalling and SCL during haematopoietic differentiation of human embryonic stem cells.}, journal = {Hum Mol Genet}, volume = {20}, year = {2011}, month = {2011 Dec 15}, pages = {4932-46}, abstract = {

Understanding the transcriptional cues that direct differentiation of human embryonic stem cells (hESCs) and human-induced pluripotent stem cells to defined and functional cell types is essential for future clinical applications. In this study, we have compared transcriptional profiles of haematopoietic progenitors derived from hESCs at various developmental stages of a feeder- and serum-free differentiation method and show that the largest transcriptional changes occur during the first 4 days of differentiation. Data mining on the basis of molecular function revealed Rho-GTPase signalling as a key regulator of differentiation. Inhibition of this pathway resulted in a significant reduction in the numbers of emerging haematopoietic progenitors throughout the differentiation window, thereby uncovering a previously unappreciated role for Rho-GTPase signalling during human haematopoietic development. Our analysis indicated that SCL was the 11th most upregulated transcript during the first 4 days of the hESC differentiation process. Overexpression of SCL in hESCs promoted differentiation to meso-endodermal lineages, the emergence of haematopoietic and erythro-megakaryocytic progenitors and accelerated erythroid differentiation. Importantly, intrasplenic transplantation of SCL-overexpressing hESC-derived haematopoietic cells enhanced recovery from induced acute anaemia without significant cell engraftment, suggesting a paracrine-mediated effect.

}, keywords = {Acute Disease, Anemia, Hemolytic, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Line, Cell Lineage, Cluster Analysis, Embryonic Stem Cells, Erythroid Cells, Flow Cytometry, Gene Expression Profiling, Hematopoietic Stem Cells, Humans, Mice, Myeloid Cells, Paracrine Communication, Proto-Oncogene Proteins, Reverse Transcriptase Polymerase Chain Reaction, rho GTP-Binding Proteins, Signal Transduction, Stem Cell Transplantation, T-Cell Acute Lymphocytic Leukemia Protein 1, Transcriptome}, issn = {1460-2083}, doi = {10.1093/hmg/ddr431}, author = {Yung, Sun and Ledran, Maria and Moreno-Gimeno, Inmaculada and Conesa, Ana and Montaner, David and Dopazo, Joaquin and Dimmick, Ian and Slater, Nicholas J and Marenah, Lamin and Real, Pedro J and Paraskevopoulou, Iliana and Bisbal, Viviana and Burks, Deborah and Santibanez-Koref, Mauro and Moreno, Ruben and Mountford, Joanne and Menendez, Pablo and Armstrong, Lyle and Lako, Majlinda} } @article {536, title = {Mutation screening of multiple genes in Spanish patients with autosomal recessive retinitis pigmentosa by targeted resequencing.}, journal = {PLoS One}, volume = {6}, year = {2011}, month = {2011}, pages = {e27894}, abstract = {

Retinitis Pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. RP is the leading cause of visual loss in individuals younger than 60 years, with a prevalence of about 1 in 4000. The molecular genetic diagnosis of autosomal recessive RP (arRP) is challenging due to the large genetic and clinical heterogeneity. Traditional methods for sequencing arRP genes are often laborious and not easily available and a screening technique that enables the rapid detection of the genetic cause would be very helpful in the clinical practice. The goal of this study was to develop and apply microarray-based resequencing technology capable of detecting both known and novel mutations on a single high-throughput platform. Hence, the coding regions and exon/intron boundaries of 16 arRP genes were resequenced using microarrays in 102 Spanish patients with clinical diagnosis of arRP. All the detected variations were confirmed by direct sequencing and potential pathogenicity was assessed by functional predictions and frequency in controls. For validation purposes 4 positive controls for variants consisting of previously identified changes were hybridized on the array. As a result of the screening, we detected 44 variants, of which 15 are very likely pathogenic detected in 14 arRP families (14\%). Finally, the design of this array can easily be transformed in an equivalent diagnostic system based on targeted enrichment followed by next generation sequencing.

}, keywords = {Alleles, DNA Mutational Analysis, Exons, Genetic Variation, Genome, Hispanic or Latino, Humans, Introns, Language, mutation, Mutation, Missense, Oligonucleotide Array Sequence Analysis, Polymerase Chain Reaction, Reproducibility of Results, Retinitis pigmentosa, United States}, issn = {1932-6203}, doi = {10.1371/journal.pone.0027894}, author = {Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Borrego, Salud and Barrag{\'a}n, Isabel and Pieras, Juan I and Santoyo, Javier and Matamala, Nerea and Naranjo, Bel{\'e}n and Dopazo, Joaquin and Anti{\v n}olo, Guillermo} } @article {537, title = {Natural selection on functional modules, a genome-wide analysis.}, journal = {PLoS Comput Biol}, volume = {7}, year = {2011}, month = {2011 Mar}, pages = {e1001093}, abstract = {

Classically, the functional consequences of natural selection over genomes have been analyzed as the compound effects of individual genes. The current paradigm for large-scale analysis of adaptation is based on the observed significant deviations of rates of individual genes from neutral evolutionary expectation. This approach, which assumed independence among genes, has not been able to identify biological functions significantly enriched in positively selected genes in individual species. Alternatively, pooling related species has enhanced the search for signatures of selection. However, grouping signatures does not allow testing for adaptive differences between species. Here we introduce the Gene-Set Selection Analysis (GSSA), a new genome-wide approach to test for evidences of natural selection on functional modules. GSSA is able to detect lineage specific evolutionary rate changes in a notable number of functional modules. For example, in nine mammal and Drosophilae genomes GSSA identifies hundreds of functional modules with significant associations to high and low rates of evolution. Many of the detected functional modules with high evolutionary rates have been previously identified as biological functions under positive selection. Notably, GSSA identifies conserved functional modules with many positively selected genes, which questions whether they are exclusively selected for fitting genomes to environmental changes. Our results agree with previous studies suggesting that adaptation requires positive selection, but not every mutation under positive selection contributes to the adaptive dynamical process of the evolution of species.

}, keywords = {Animals, Databases, Genetic, Drosophila, Genome, Insect, Genome-Wide Association Study, Genomics, Mammals, Phylogeny, Selection, Genetic, Sequence Analysis, DNA}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1001093}, author = {Serra, Fran{\c c}ois and Arbiza, Leonardo and Dopazo, Joaquin and Dopazo, Hern{\'a}n} } @article {21605378, title = {Profiling the venom gland transcriptomes of Costa Rican snakes by 454 pyrosequencing.}, journal = {BMC genomics}, volume = {12}, year = {2011}, month = {2011}, pages = {259}, abstract = {

A long term research goal of venomics, of applied importance for improving current antivenom therapy, but also for drug discovery, is to understand the pharmacological potential of venoms. Individually or combined, proteomic and transcriptomic studies have demonstrated their feasibility to explore in depth the molecular diversity of venoms. In the absence of genome sequence, transcriptomes represent also valuable searchable databases for proteomic projects.

}, author = {Durban, Jordi and Ju{\'a}rez, Paula and Angulo, Yamileth and Lomonte, Bruno and Flores-Diaz, Marietta and Alape-Gir{\'o}n, Alberto and Sasa, Mahmood and Sanz, Libia and Guti{\'e}rrez, Jos{\'e} M and Joaqu{\'\i}n Dopazo and Ana Conesa and Calvete, Juan J} } @article {20028698, title = {Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus.}, journal = {Genome research}, volume = {20}, year = {2010}, month = {2010 Feb}, pages = {170-9}, abstract = {

Monozygotic (MZ) twins are partially concordant for most complex diseases, including autoimmune disorders. Whereas phenotypic concordance can be used to study heritability, discordance suggests the role of non-genetic factors. In autoimmune diseases, environmentally driven epigenetic changes are thought to contribute to their etiology. Here we report the first high-throughput and candidate sequence analyses of DNA methylation to investigate discordance for autoimmune disease in twins. We used a cohort of MZ twins discordant for three diseases whose clinical signs often overlap: systemic lupus erythematosus (SLE), rheumatoid arthritis, and dermatomyositis. Only MZ twins discordant for SLE featured widespread changes in the DNA methylation status of a significant number of genes. Gene ontology analysis revealed enrichment in categories associated with immune function. Individual analysis confirmed the existence of DNA methylation and expression changes in genes relevant to SLE pathogenesis. These changes occurred in parallel with a global decrease in the 5-methylcytosine content that was concomitantly accompanied with changes in DNA methylation and expression levels of ribosomal RNA genes, although no changes in repetitive sequences were found. Our findings not only identify potentially relevant DNA methylation markers for the clinical characterization of SLE patients but also support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease.

}, author = {Javierre, Biola M and Fernandez, Agustin F and Richter, Julia and Fatima Al-Shahrour and Martin-Subero, J Ignacio and Rodriguez-Ubreva, Javier and Berdasco, Maria and Fraga, Mario F and O{\textquoteright}Hanlon, Terrance P and Rider, Lisa G and Jacinto, Filipe V and Lopez-Longo, F Javier and Dopazo, Joaquin and Forn, Marta and Peinado, Miguel A and Carre{\~n}o, Luis and Sawalha, Amr H and Harley, John B and Siebert, Reiner and Esteller, Manel and Miller, Frederick W and Ballestar, Esteban} } @article {547, title = {DNA methylation epigenotypes in breast cancer molecular subtypes.}, journal = {Breast Cancer Res}, volume = {12}, year = {2010}, month = {2010}, pages = {R77}, abstract = {

INTRODUCTION: Identification of gene expression based breast cancer subtypes is considered as a critical means of prognostication. Genetic mutations along with epigenetic alterations contribute to gene expression changes occurring in breast cancer. So far, these epigenetic contributions to sporadic breast cancer subtypes have not been well characterized, and there is only a limited understanding of the epigenetic mechanisms affected in those particular breast cancer subtypes. The present study was undertaken to dissect the breast cancer methylome and deliver specific epigenotypes associated with particular breast cancer subtypes.

METHODS: Using a microarray approach we analyzed DNA methylation in regulatory regions of 806 cancer related genes in 28 breast cancer paired samples. We subsequently performed substantial technical and biological validation by Pyrosequencing, investigating the top qualifying 19 CpG regions in independent cohorts encompassing 47 basal-like, 44 ERBB2+ overexpressing, 48 luminal A and 48 luminal B paired breast cancer/adjacent tissues. Using all-subset selection method, we identified the most subtype predictive methylation profiles in multivariable logistic regression analysis.

RESULTS: The approach efficiently recognized 15 individual CpG loci differentially methylated in breast cancer tumor subtypes. We further identify novel subtype specific epigenotypes which clearly demonstrate the differences in the methylation profiles of basal-like and human epidermal growth factor 2 (HER2)-overexpressing tumors.

CONCLUSIONS: Our results provide evidence that well defined DNA methylation profiles enables breast cancer subtype prediction and support the utilization of this biomarker for prognostication and therapeutic stratification of patients with breast cancer.

}, keywords = {Aged, Breast Neoplasms, CpG Islands, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Profiling, Genes, p53, Genotype, Humans, Ki-67 Antigen, Middle Aged, mutation, Neoplasm Grading, Oligonucleotide Array Sequence Analysis, Receptor, ErbB-2, Tumor Suppressor Protein p53}, issn = {1465-542X}, doi = {10.1186/bcr2721}, author = {Bediaga, Naiara G and Acha-Sagredo, Amelia and Guerra, Isabel and Viguri, Amparo and Albaina, Carmen and Ruiz Diaz, Irune and Rezola, Ricardo and Alberdi, Maria Jesus and Dopazo, Joaquin and Montaner, David and Renobales, Mertxe and Fernandez, Agustin F and Field, John K and Fraga, Mario F and Liloglou, Triantafillos and de Pancorbo, Marian M} } @article {20164864, title = {Fine-scale evolution: genomic, phenotypic and ecological differentiation in two coexisting Salinibacter ruber strains.}, journal = {The ISME journal}, year = {2010}, month = {2010 Feb 18}, abstract = {

Genomic and metagenomic data indicate a high degree of genomic variation within microbial populations, although the ecological and evolutive meaning of this microdiversity remains unknown. Microevolution analyses, including genomic and experimental approaches, are so far very scarce for non-pathogenic bacteria. In this study, we compare the genomes, metabolomes and selected ecological traits of the strains M8 and M31 of the hyperhalophilic bacterium Salinibacter ruber that contain ribosomal RNA (rRNA) gene and intergenic regions that are identical in sequence and were simultaneously isolated from a Mediterranean solar saltern. Comparative analyses indicate that S. ruber genomes present a mosaic structure with conserved and hypervariable regions (HVRs). The HVRs or genomic islands, are enriched in transposases, genes related to surface properties, strain-specific genes and highly divergent orthologous. However, the many indels outside the HVRs indicate that genome plasticity extends beyond them. Overall, 10\% of the genes encoded in the M8 genome are absent from M31 and could stem from recent acquisitions. S. ruber genomes also harbor 34 genes located outside HVRs that are transcribed during standard growth and probably derive from lateral gene transfers with Archaea preceding the M8/M31 divergence. Metabolomic analyses, phage susceptibility and competition experiments indicate that these genomic differences cannot be considered neutral from an ecological perspective. The results point to the avoidance of competition by micro-niche adaptation and response to viral predation as putative major forces that drive microevolution within these Salinibacter strains. In addition, this work highlights the extent of bacterial functional diversity and environmental adaptation, beyond the resolution of the 16S rRNA and internal transcribed spacers regions.The ISME Journal advance online publication, 18 February 2010; doi:10.1038/ismej.2010.6.

}, author = {Pe{\~n}a, Arantxa and Teeling, Hanno and Huerta-Cepas, Jaime and Santos, Fernando and Yarza, Pablo and Brito-Echeverr{\'\i}a, Jocelyn and Lucio, Marianna and Schmitt-Kopplin, Philippe and Meseguer, Inmaculada and Schenowitz, Chantal and Dossat, Carole and Barbe, Valerie and Joaqu{\'\i}n Dopazo and Rossell{\'o}-Mora, Ramon and Sch{\"u}ler, Margarete and Gl{\"o}ckner, Frank Oliver and Amann, Rudolf and Gabald{\'o}n, Toni and Ant{\'o}n, Josefa} } @article {19897487, title = {FM19G11, a new hypoxia-inducible factor (HIF) modulator, affects stem cell differentiation status.}, journal = {The Journal of biological chemistry}, volume = {285}, year = {2010}, month = {2010 Jan 8}, pages = {1333-42}, abstract = {

The biology of the alpha subunits of hypoxia-inducible factors (HIFalpha) has expanded from their role in angiogenesis to their current position in the self-renewal and differentiation of stem cells. The results reported in this article show the discovery of FM19G11, a novel chemical entity that inhibits HIFalpha proteins that repress target genes of the two alpha subunits, in various tumor cell lines as well as in adult and embryonic stem cell models from rodents and humans, respectively. FM19G11 inhibits at nanomolar range the transcriptional and protein expression of Oct4, Sox2, Nanog, and Tgf-alpha undifferentiating factors, in adult rat and human embryonic stem cells, FM19G11 activity occurs in ependymal progenitor stem cells from rats (epSPC), a cell model reported for spinal cord regeneration, which allows the progression of oligodendrocyte cell differentiation in a hypoxic environment, has created interest in its characterization for pharmacological research. Experiments using small interfering RNA showed a significant depletion in Sox2 protein only in the case of HIF2alpha silencing, but not in HIF1alpha-mediated ablation. Moreover, chromatin immunoprecipitation data, together with the significant presence of functional hypoxia response element consensus sequences in the promoter region of Sox2, strongly validated that this factor behaves as a target gene of HIF2alpha in epSPCs. FM19G11 causes a reduction of overall histone acetylation with significant repression of p300, a histone acetyltransferase required as a co-factor for HIF-transcription activation. Arrays carried out in the presence and absence of the inhibitor showed the predominant involvement of epigenetic-associated events mediated by the drug.

}, author = {Moreno-Manzano, Victoria and Rodr{\'\i}guez-Jim{\'e}nez, Francisco J and Ace{\~n}a-Bonilla, Jose L and Fustero-Lard{\'\i}es, Santos and Erceg, Slaven and Dopazo, Joaquin and Montaner, David and Stojkovic, Miodrag and S{\'a}nchez-Puelles, Jose M} } @article {553, title = {Functional genomics of 5- to 8-cell stage human embryos by blastomere single-cell cDNA analysis.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010 Oct 26}, pages = {e13615}, abstract = {

Blastomere fate and embryonic genome activation (EGA) during human embryonic development are unsolved areas of high scientific and clinical interest. Forty-nine blastomeres from 5- to 8-cell human embryos have been investigated following an efficient single-cell cDNA amplification protocol to provide a template for high-density microarray analysis. The previously described markers, characteristic of Inner Cell Mass (ICM) (n = 120), stemness (n = 190) and Trophectoderm (TE) (n = 45), were analyzed, and a housekeeping pattern of 46 genes was established. All the human blastomeres from the 5- to 8-cell stage embryo displayed a common gene expression pattern corresponding to ICM markers (e.g., DDX3, FOXD3, LEFTY1, MYC, NANOG, POU5F1), stemness (e.g., POU5F1, DNMT3B, GABRB3, SOX2, ZFP42, TERT), and TE markers (e.g., GATA6, EOMES, CDX2, LHCGR). The EGA profile was also investigated between the 5-6- and 8-cell stage embryos, and compared to the blastocyst stage. Known genes (n = 92) such as depleted maternal transcripts (e.g., CCNA1, CCNB1, DPPA2) and embryo-specific activation (e.g., POU5F1, CDH1, DPPA4), as well as novel genes, were confirmed. In summary, the global single-cell cDNA amplification microarray analysis of the 5- to 8-cell stage human embryos reveals that blastomere fate is not committed to ICM or TE. Finally, new EGA features in human embryogenesis are presented.

}, keywords = {Blastomeres, DNA, Complementary, Gene Expression Profiling, Genomics, Humans, Oligonucleotide Array Sequence Analysis}, issn = {1932-6203}, doi = {10.1371/journal.pone.0013615}, author = {Galan, Amparo and Montaner, David and P{\'o}o, M Eugenia and Valbuena, Diana and Ruiz, Veronica and Aguilar, Crist{\'o}bal and Dopazo, Joaquin and Simon, Carlos} } @article {572, title = {Hypoxia promotes efficient differentiation of human embryonic stem cells to functional endothelium.}, journal = {Stem Cells}, volume = {28}, year = {2010}, month = {2010 Mar 31}, pages = {407-18}, abstract = {

Early development of mammalian embryos occurs in an environment of relative hypoxia. Nevertheless, human embryonic stem cells (hESC), which are derived from the inner cell mass of blastocyst, are routinely cultured under the same atmospheric conditions (21\% O(2)) as somatic cells. We hypothesized that O(2) levels modulate gene expression and differentiation potential of hESC, and thus, we performed gene profiling of hESC maintained under normoxic or hypoxic (1\% or 5\% O(2)) conditions. Our analysis revealed that hypoxia downregulates expression of pluripotency markers in hESC but increases significantly the expression of genes associated with angio- and vasculogenesis including vascular endothelial growth factor and angiopoitein-like proteins. Consequently, we were able to efficiently differentiate hESC to functional endothelial cells (EC) by varying O(2) levels; after 24 hours at 5\% O(2), more than 50\% of cells were CD34+. Transplantation of resulting endothelial-like cells improved both systolic function and fractional shortening in a rodent model of myocardial infarction. Moreover, analysis of the infarcted zone revealed that transplanted EC reduced the area of fibrous scar tissue by 50\%. Thus, use of hypoxic conditions to specify the endothelial lineage suggests a novel strategy for cellular therapies aimed at repair of damaged vasculature in pathologies such as cerebral ischemia and myocardial infarction.

}, keywords = {Angiopoietin-1, Animals, biomarkers, Cell Culture Techniques, Cell Differentiation, Cell Hypoxia, Cell Transplantation, Cells, Cultured, Down-Regulation, Embryonic Stem Cells, Endothelial Cells, Gene Expression Profiling, Gene Expression Regulation, Humans, Male, Myocardial Infarction, Neovascularization, Physiologic, Oxygen, Pluripotent Stem Cells, Rats, Rats, Nude, Vascular Endothelial Growth Factor A}, issn = {1549-4918}, doi = {10.1002/stem.295}, author = {Prado-Lopez, Sonia and Conesa, Ana and Armi{\~n}{\'a}n, Ana and Mart{\'\i}nez-Losa, Magdalena and Escobedo-Lucea, Carmen and Gandia, Carolina and Tarazona, Sonia and Melguizo, Dario and Blesa, David and Montaner, David and Sanz-Gonz{\'a}lez, Silvia and Sep{\'u}lveda, Pilar and G{\"o}tz, Stefan and O{\textquoteright}Connor, Jos{\'e} Enrique and Moreno, Ruben and Dopazo, Joaquin and Burks, Deborah J and Stojkovic, Miodrag} } @article {20676074, title = {The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models.}, journal = {Nature biotechnology}, volume = {28}, year = {2010}, month = {2010 Aug}, pages = {827-38}, abstract = {

Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, \>30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.

}, url = {http://www.nature.com/nbt/journal/v28/n8/full/nbt.1665.html}, author = {Shi, Leming and Campbell, Gregory and Jones, Wendell D and Campagne, Fabien and Wen, Zhining and Walker, Stephen J and Su, Zhenqiang and Chu, Tzu-Ming and Goodsaid, Federico M and Pusztai, Lajos and Shaughnessy, John D and Oberthuer, Andr{\'e} and Thomas, Russell S and Paules, Richard S and Fielden, Mark and Barlogie, Bart and Chen, Weijie and Du, Pan and Fischer, Matthias and Furlanello, Cesare and Gallas, Brandon D and Ge, Xijin and Megherbi, Dalila B and Symmans, W Fraser and Wang, May D and Zhang, John and Bitter, Hans and Brors, Benedikt and Bushel, Pierre R and Bylesjo, Max and Chen, Minjun and Cheng, Jie and Cheng, Jing and Chou, Jeff and Davison, Timothy S and Delorenzi, Mauro and Deng, Youping and Devanarayan, Viswanath and Dix, David J and Dopazo, Joaquin and Dorff, Kevin C and Elloumi, Fathi and Fan, Jianqing and Fan, Shicai and Fan, Xiaohui and Fang, Hong and Gonzaludo, Nina and Hess, Kenneth R and Hong, Huixiao and Huan, Jun and Irizarry, Rafael A and Judson, Richard and Juraeva, Dilafruz and Lababidi, Samir and Lambert, Christophe G and Li, Li and Li, Yanen and Li, Zhen and Lin, Simon M and Liu, Guozhen and Lobenhofer, Edward K and Luo, Jun and Luo, Wen and McCall, Matthew N and Nikolsky, Yuri and Pennello, Gene A and Perkins, Roger G and Philip, Reena and Popovici, Vlad and Price, Nathan D and Qian, Feng and Scherer, Andreas and Shi, Tieliu and Shi, Weiwei and Sung, Jaeyun and Thierry-Mieg, Danielle and Thierry-Mieg, Jean and Thodima, Venkata and Trygg, Johan and Vishnuvajjala, Lakshmi and Wang, Sue Jane and Wu, Jianping and Wu, Yichao and Xie, Qian and Yousef, Waleed A and Zhang, Liang and Zhang, Xuegong and Zhong, Sheng and Zhou, Yiming and Zhu, Sheng and Arasappan, Dhivya and Bao, Wenjun and Lucas, Anne Bergstrom and Berthold, Frank and Brennan, Richard J and Buness, Andreas and Catalano, Jennifer G and Chang, Chang and Chen, Rong and Cheng, Yiyu and Cui, Jian and Czika, Wendy and Demichelis, Francesca and Deng, Xutao and Dosymbekov, Damir and Eils, Roland and Feng, Yang and Fostel, Jennifer and Fulmer-Smentek, Stephanie and Fuscoe, James C and Gatto, Laurent and Ge, Weigong and Goldstein, Darlene R and Guo, Li and Halbert, Donald N and Han, Jing and Harris, Stephen C and Hatzis, Christos and Herman, Damir and Huang, Jianping and Jensen, Roderick V and Jiang, Rui and Johnson, Charles D and Jurman, Giuseppe and Kahlert, Yvonne and Khuder, Sadik A and Kohl, Matthias and Li, Jianying and Li, Li and Li, Menglong and Li, Quan-Zhen and Li, Shao and Li, Zhiguang and Liu, Jie and Liu, Ying and Liu, Zhichao and Meng, Lu and Madera, Manuel and Martinez-Murillo, Francisco and Medina, Ignacio and Meehan, Joseph and Miclaus, Kelci and Moffitt, Richard A and Montaner, David and Mukherjee, Piali and Mulligan, George J and Neville, Padraic and Nikolskaya, Tatiana and Ning, Baitang and Page, Grier P and Parker, Joel and Parry, R Mitchell and Peng, Xuejun and Peterson, Ron L and Phan, John H and Quanz, Brian and Ren, Yi and Riccadonna, Samantha and Roter, Alan H and Samuelson, Frank W and Schumacher, Martin M and Shambaugh, Joseph D and Shi, Qiang and Shippy, Richard and Si, Shengzhu and Smalter, Aaron and Sotiriou, Christos and Soukup, Mat and Staedtler, Frank and Steiner, Guido and Stokes, Todd H and Sun, Qinglan and Tan, Pei-Yi and Tang, Rong and Tezak, Zivana and Thorn, Brett and Tsyganova, Marina and Turpaz, Yaron and Vega, Silvia C and Visintainer, Roberto and von Frese, Juergen and Wang, Charles and Wang, Eric and Wang, Junwei and Wang, Wei and Westermann, Frank and Willey, James C and Woods, Matthew and Wu, Shujian and Xiao, Nianqing and Xu, Joshua and Xu, Lei and Yang, Lun and Zeng, Xiao and Zhang, Jialu and Zhang, Li and Zhang, Min and Zhao, Chen and Puri, Raj K and Scherf, Uwe and Tong, Weida and Wolfinger, Russell D} } @article {575, title = {Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa.}, journal = {Hum Mutat}, volume = {31}, year = {2010}, month = {2010 Nov}, pages = {E1772-800}, abstract = {

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene(EYS) encoding an ortholog of Drosophila space maker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9\% (12/28) are very likely pathogenic, 17.9\% (5/28)are possibly pathogenic, whereas 39.3\% (11/28) are SNPs. In addition, we have detected 3 pathogenic changes previously reported in other populations. We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain.Majority of the mutations in the arRP patients have been found within the domain structures of EYS. The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9\% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population. Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study.

}, keywords = {Amino Acid Sequence, Animals, Case-Control Studies, DNA Mutational Analysis, Drosophila Proteins, Evolution, Molecular, Eye Proteins, Female, Genes, Recessive, Genetic Variation, Humans, Male, Molecular Sequence Data, mutation, Pedigree, Polymorphism, Single Nucleotide, Protein Structure, Tertiary, Retinitis pigmentosa, Spain, Structural Homology, Protein}, issn = {1098-1004}, doi = {10.1002/humu.21334}, author = {Barrag{\'a}n, Isabel and Borrego, Salud and Pieras, Juan Ignacio and Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Santoyo, Javier and Ayuso, Carmen and Baiget, Montserrat and Mill{\'a}n, Jos{\'e} M and Mena, Marcela and Abd El-Aziz, Mai M and Audo, Isabelle and Zeitz, Christina and Littink, Karin W and Dopazo, Joaquin and Bhattacharya, Shomi S and Anti{\v n}olo, Guillermo} } @article {808, title = {Selection upon Genome Architecture: Conservation of Functional Neighborhoods with Changing Genes}, journal = {PLoS Comput. Biol.}, volume = {6}, number = {10}, year = {2010}, pages = {e1000953}, doi = {doi:10.1371/journal.pcbi.1000953}, url = {http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000953}, author = {Al-Shahrour, F{\'a}tima and Minguez, Pablo and Marqu{\'e}s-Bonet, Tom{\'a}s and Gazave, Elodie and Navarro, Arcadi and Dopazo, Joaquin} } @article {19906725, title = {SIMAP{\textendash}a comprehensive database of pre-calculated protein sequence similarities, domains, annotations and clusters.}, journal = {Nucleic acids research}, volume = {38}, year = {2010}, month = {2010 Jan}, pages = {D223-6}, abstract = {

The prediction of protein function as well as the reconstruction of evolutionary genesis employing sequence comparison at large is still the most powerful tool in sequence analysis. Due to the exponential growth of the number of known protein sequences and the subsequent quadratic growth of the similarity matrix, the computation of the Similarity Matrix of Proteins (SIMAP) becomes a computational intensive task. The SIMAP database provides a comprehensive and up-to-date pre-calculation of the protein sequence similarity matrix, sequence-based features and sequence clusters. As of September 2009, SIMAP covers 48 million proteins and more than 23 million non-redundant sequences. Novel features of SIMAP include the expansion of the sequence space by including databases such as ENSEMBL as well as the integration of metagenomes based on their consistent processing and annotation. Furthermore, protein function predictions by Blast2GO are pre-calculated for all sequences in SIMAP and the data access and query functions have been improved. SIMAP assists biologists to query the up-to-date sequence space systematically and facilitates large-scale downstream projects in computational biology. Access to SIMAP is freely provided through the web portal for individuals (http://mips.gsf.de/simap/) and for programmatic access through DAS (http://webclu.bio.wzw.tum.de/das/) and Web-Service (http://mips.gsf.de/webservices/services/SimapService2.0?wsdl).

}, author = {Rattei, Thomas and Tischler, Patrick and G{\"o}tz, Stefan and Jehl, Marc-Andr{\'e} and Hoser, Jonathan and Arnold, Roland and Ana Conesa and Mewes, Hans-Werner} } @article {19246752, title = {Exploring the antimicrobial action of a carbon monoxide-releasing compound through whole-genome transcription profiling of Escherichia coli}, journal = {Microbiology}, volume = {155}, number = {Pt 3}, year = {2009}, note = {

Nobre, Ligia S Al-Shahrour, Fatima Dopazo, Joaquin Saraiva, Ligia M Research Support, Non-U.S. Gov{\textquoteright}t England Microbiology (Reading, England) Microbiology. 2009 Mar;155(Pt 3):813-24.

}, pages = {813-24}, abstract = {

We recently reported that carbon monoxide (CO) has bactericidal activity. To understand its mode of action we analysed the gene expression changes occurring when Escherichia coli, grown aerobically and anaerobically, is treated with the CO-releasing molecule CORM-2 (tricarbonyldichlororuthenium(II) dimer). Microarray analysis shows that the E. coli CORM-2 response is multifaceted, with a high number of differentially regulated genes spread through several functional categories, namely genes involved in inorganic ion transport and metabolism, regulators, and genes implicated in post-translational modification, such as chaperones. CORM-2 has a higher impact in E. coli cells grown anaerobically, as judged by the repression of genes belonging to eight functional classes which are not seen in the response of aerobically CORM-2-treated cells. The biological relevance of the variations caused by CORM-2 was substantiated by studying the CORM-2 sensitivity of selected E. coli mutants. The results show that the deletion of redox-sensing regulators SoxS and OxyR increased the sensitivity to CORM-2 and suggest that while SoxS plays an important role in protection against CORM-2 under both growth conditions, OxyR seems to participate only in the aerobic CORM-2 response. Under anaerobic conditions, we found that the heat-shock proteins IbpA and IbpB contribute to CORM-2 defence since the deletion of these genes increases the sensitivity of the strain. The induction of several met genes and the hypersensitivity to CORM-2 of the DeltametR, DeltametI and DeltametN mutant strains suggest that CO has effects on the methionine metabolism of E. coli. CORM-2 also affects the transcription of several E. coli biofilm-related genes and increases biofilm formation in E. coli. In particular, the absence of tqsA or bhsA increases the resistance of E. coli to CORM-2, and deletion of tsqA leads to a strain that has lost its capacity to form biofilm upon treatment with CORM-2. In spite of the relatively stable nature of the CO molecule, our results show that CO is able to trigger a significant alteration in the transcriptome of E. coli which necessarily has effects in several key metabolic pathways.

}, keywords = {Bacterial Genes, Bacterial/genetics, Biofilms Carbon Monoxide/*metabolism Escherichia coli/*genetics/metabolism Escherichia coli Proteins/genetics/metabolism *Gene Expression Profiling Gene Expression Regulation, Regulator Genetic Complementation Test Methionine/metabolism Microbial Viability Mutation Oligonucleotide Array Sequence Analysis Organometallic Compounds/*pharmacology Phenotype RNA}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=19246752}, author = {Nobre, L. S. and Fatima Al-Shahrour and Dopazo, J. and Saraiva, L. M.} } @article {578, title = {Exploring the antimicrobial action of a carbon monoxide-releasing compound through whole-genome transcription profiling of Escherichia coli.}, journal = {Microbiology (Reading)}, volume = {155}, year = {2009}, month = {2009 Mar}, pages = {813-824}, abstract = {

We recently reported that carbon monoxide (CO) has bactericidal activity. To understand its mode of action we analysed the gene expression changes occurring when Escherichia coli, grown aerobically and anaerobically, is treated with the CO-releasing molecule CORM-2 (tricarbonyldichlororuthenium(II) dimer). Microarray analysis shows that the E. coli CORM-2 response is multifaceted, with a high number of differentially regulated genes spread through several functional categories, namely genes involved in inorganic ion transport and metabolism, regulators, and genes implicated in post-translational modification, such as chaperones. CORM-2 has a higher impact in E. coli cells grown anaerobically, as judged by the repression of genes belonging to eight functional classes which are not seen in the response of aerobically CORM-2-treated cells. The biological relevance of the variations caused by CORM-2 was substantiated by studying the CORM-2 sensitivity of selected E. coli mutants. The results show that the deletion of redox-sensing regulators SoxS and OxyR increased the sensitivity to CORM-2 and suggest that while SoxS plays an important role in protection against CORM-2 under both growth conditions, OxyR seems to participate only in the aerobic CORM-2 response. Under anaerobic conditions, we found that the heat-shock proteins IbpA and IbpB contribute to CORM-2 defence since the deletion of these genes increases the sensitivity of the strain. The induction of several met genes and the hypersensitivity to CORM-2 of the DeltametR, DeltametI and DeltametN mutant strains suggest that CO has effects on the methionine metabolism of E. coli. CORM-2 also affects the transcription of several E. coli biofilm-related genes and increases biofilm formation in E. coli. In particular, the absence of tqsA or bhsA increases the resistance of E. coli to CORM-2, and deletion of tsqA leads to a strain that has lost its capacity to form biofilm upon treatment with CORM-2. In spite of the relatively stable nature of the CO molecule, our results show that CO is able to trigger a significant alteration in the transcriptome of E. coli which necessarily has effects in several key metabolic pathways.

}, keywords = {Biofilms, Carbon Monoxide, Escherichia coli, Escherichia coli Proteins, Gene Expression Profiling, Gene Expression Regulation, Bacterial, Genes, Bacterial, Genes, Regulator, Genetic Complementation Test, Methionine, Microbial Viability, mutation, Oligonucleotide Array Sequence Analysis, Organometallic Compounds, Phenotype, RNA, Bacterial}, issn = {1350-0872}, doi = {10.1099/mic.0.023911-0}, author = {Nobre, L{\'\i}gia S and Al-Shahrour, F{\'a}tima and Dopazo, Joaquin and Saraiva, L{\'\i}gia M} } @article {581, title = {Functional signatures identified in B-cell non-Hodgkin lymphoma profiles.}, journal = {Leuk Lymphoma}, volume = {50}, year = {2009}, month = {2009 Oct}, pages = {1699-708}, abstract = {

Gene-expression profiling in B-cell lymphomas has provided crucial data on specific lymphoma types, which can contribute to the identification of essential lymphoma survival genes and pathways. In this study, the gene-expression profiling data of all major B-cell lymphoma types were analyzed by unsupervised clustering. The transcriptome classification so obtained, was explored using gene set enrichment analysis generating a heatmap for B-cell lymphoma that identifies common lymphoma survival mechanisms and potential therapeutic targets, recognizing sets of coregulated genes and functional pathways expressed in different lymphoma types. Some of the most relevant signatures (stroma, cell cycle, B-cell receptor (BCR)) are shared by multiple lymphoma types or subclasses. A specific attention was paid to the analysis of BCR and coregulated pathways, defining molecular heterogeneity within multiple B-cell lymphoma types.

}, keywords = {Adult, Cluster Analysis, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Genetic Heterogeneity, Humans, Lymphoma, B-Cell, Neoplasm Proteins, Oligonucleotide Array Sequence Analysis, RNA, Messenger, RNA, Neoplasm, Transcription, Genetic}, issn = {1029-2403}, doi = {10.1080/10428190903189035}, author = {Aggarwal, Mohit and S{\'a}nchez-Beato, Margarita and G{\'o}mez-L{\'o}pez, Gonzalo and Al-Shahrour, F{\'a}tima and Mart{\'\i}nez, Nerea and Rodr{\'\i}guez, Antonia and Ruiz-Ballesteros, Elena and Camacho, Francisca I and P{\'e}rez-Rosado, Alberto and de la Cueva, Paloma and Artiga, Mar{\'\i}a J and Pisano, David G and Kimby, Eva and Dopazo, Joaquin and Villuendas, Raquel and Piris, Miguel A} } @article {582, title = {Gene set internal coherence in the context of functional profiling.}, journal = {BMC Genomics}, volume = {10}, year = {2009}, month = {2009 Apr 27}, pages = {197}, abstract = {

BACKGROUND: Functional profiling methods have been extensively used in the context of high-throughput experiments and, in particular, in microarray data analysis. Such methods use available biological information to define different types of functional gene modules (e.g. gene ontology -GO-, KEGG pathways, etc.) whose representation in a pre-defined list of genes is further studied. In the most popular type of microarray experimental designs (e.g. up- or down-regulated genes, clusters of co-expressing genes, etc.) or in other genomic experiments (e.g. Chip-on-chip, epigenomics, etc.) these lists are composed by genes with a high degree of co-expression. Therefore, an implicit assumption in the application of functional profiling methods within this context is that the genes corresponding to the modules tested are effectively defining sets of co-expressing genes. Nevertheless not all the functional modules are biologically coherent entities in terms of co-expression, which will eventually hinder its detection with conventional methods of functional enrichment.

RESULTS: Using a large collection of microarray data we have carried out a detailed survey of internal correlation in GO terms and KEGG pathways, providing a coherence index to be used for measuring functional module co-regulation. An unexpected low level of internal correlation was found among the modules studied. Only around 30\% of the modules defined by GO terms and 57\% of the modules defined by KEGG pathways display an internal correlation higher than the expected by chance.This information on the internal correlation of the genes within the functional modules can be used in the context of a logistic regression model in a simple way to improve their detection in gene expression experiments.

CONCLUSION: For the first time, an exhaustive study on the internal co-expression of the most popular functional categories has been carried out. Interestingly, the real level of coexpression within many of them is lower than expected (or even inexistent), which will preclude its detection by means of most conventional functional profiling methods. If the gene-to-function correlation information is used in functional profiling methods, the results obtained improve the ones obtained by conventional enrichment methods.

}, keywords = {Algorithms, Breast Neoplasms, Carcinoma, Intraductal, Noninfiltrating, Computational Biology, Databases, Nucleic Acid, Female, Gene Expression Profiling, Genomics, Humans, Oligonucleotide Array Sequence Analysis, Papillomavirus Infections, Reproducibility of Results}, issn = {1471-2164}, doi = {10.1186/1471-2164-10-197}, author = {Montaner, David and Minguez, Pablo and Al-Shahrour, F{\'a}tima and Dopazo, Joaquin} } @article {583, title = {Gene set-based analysis of polymorphisms: finding pathways or biological processes associated to traits in genome-wide association studies.}, journal = {Nucleic Acids Res}, volume = {37}, year = {2009}, month = {2009 Jul}, pages = {W340-4}, abstract = {

Genome-wide association studies have become a popular strategy to find associations of genes to traits of interest. Despite the high-resolution available today to carry out genotyping studies, the success of its application in real studies has been limited by the testing strategy used. As an alternative to brute force solutions involving the use of very large cohorts, we propose the use of the Gene Set Analysis (GSA), a different analysis strategy based on testing the association of modules of functionally related genes. We show here how the Gene Set-based Analysis of Polymorphisms (GeSBAP), which is a simple implementation of the GSA strategy for the analysis of genome-wide association studies, provides a significant increase in the power testing for this type of studies. GeSBAP is freely available at http://bioinfo.cipf.es/gesbap/.

}, keywords = {Biological Phenomena, Breast Neoplasms, Female, Genes, Genetic Variation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Software, User-Computer Interface}, issn = {1362-4962}, doi = {10.1093/nar/gkp481}, author = {Medina, Ignacio and Montaner, David and Bonifaci, N{\'u}ria and Pujana, Miguel Angel and Carbonell, Jos{\'e} and T{\'a}rraga, Joaqu{\'\i}n and Al-Shahrour, F{\'a}tima and Dopazo, Joaquin} } @article {IgnacioMedina07012009, title = {Gene set-based analysis of polymorphisms: finding pathways or biological processes associated to traits in genome-wide association studies}, journal = {Nucl. Acids Res.}, volume = {37}, number = {suppl_2}, year = {2009}, pages = {W340-344}, abstract = {

Genome-wide association studies have become a popular strategy to find associations of genes to traits of interest. Despite the high-resolution available today to carry out genotyping studies, the success of its application in real studies has been limited by the testing strategy used. As an alternative to brute force solutions involving the use of very large cohorts, we propose the use of the Gene Set Analysis (GSA), a different analysis strategy based on testing the association of modules of functionally related genes. We show here how the Gene Set-based Analysis of Polymorphisms (GeSBAP), which is a simple implementation of the GSA strategy for the analysis of genome-wide association studies, provides a significant increase in the power testing for this type of studies. GeSBAP is freely available at http://bioinfo.cipf.es/gesbap/

}, keywords = {babelomics, gene set, GESBAP, pathway-based analysis, SNP}, doi = {10.1093/nar/gkp481}, url = {http://nar.oxfordjournals.org/cgi/content/abstract/37/suppl_2/W340}, author = {Medina, Ignacio and Montaner, David and Bonifaci, N{\'u}ria and Pujana, Miguel Angel and Carbonell, Jos{\'e} and T{\'a}rraga, Joaqu{\'\i}n and Fatima Al-Shahrour and Dopazo, Joaquin} } @inbook {761, title = {Gen{\'o}mica Comparativa y Selecci{\'o}n Natural. Aplicaciones en el Genoma Humano. Cap{\'\i}tulo 1.6}, booktitle = {Evoluci{\'o}n y Adaptac{\'o}n. 150 a{\~n}os despu{\'e}s del Origen de las Especies}, year = {2009}, pages = {51-59}, publisher = {Obrapropia.}, organization = {Obrapropia.}, chapter = {19}, address = {Valencia}, abstract = {

La b\úsqueda de los eventos adaptativos a nivel molecular que ha diferenciado el genoma humano del de nuestro pariente vivo m\ás cercano, el chimpanc\é, ha sido una de las \áreas de mayor investigaci\ón en gen\ómica comparativa. Paralelamente, la predicci\ón funcional de variantes gen\éticas en nuestra especie ha sido un \área de intenso desarrollo en bioinform\ática. En este trabajo discutiremos resultados previos y otros m\ás recientes que dan cuenta de estos desarrollos. Veremos que en todos los casos la estimaci\ón de las presiones selectivas a nivel de los genes individuales o de los residuos de las prote\ínas son el denominador com\ún para discutir ambos aspectos. Finalmente mostraremos c\ómo el an\álisis de estas presiones selectivas por grupos funcionales de genes resulta una alternativa viable y con suficiente poder estad\ístico para el an\álisis de la adaptaci\ón y de las restricciones evolutivas a nivel gen\ómico.\ 

}, issn = {978-84-92910-06-9}, author = {Serra, Fran{\c c}ois and Arbiza, L. and H. Dopazo}, editor = {H. Dopazo and Navarro, A.} } @article {19357100, title = {ModLink+: Improving fold recognition by using protein-protein interactions}, journal = {Bioinformatics}, year = {2009}, note = {

Journal article Bioinformatics (Oxford, England) Bioinformatics. 2009 Apr 8.

}, abstract = {

MOTIVATION: Several strategies have been developed to predict the fold of a target protein sequence, most of which are based on aligning the target sequence to other sequences of known structure. Previously, we demonstrated that the consideration of protein-protein interactions significantly increases the accuracy of fold assignment compared to PSI-BLAST sequence comparisons. A drawback of our method was the low number of proteins to which a fold could be assigned. Here, we present an improved version of the method that addresses this limitation. We also compare our method to other state-of-the-art fold assignment methodologies. RESULTS: Our approach (ModLink+) has been tested on 3,716 proteins with domain folds classified in the Structural Classification Of Proteins (SCOP) as well as known interacting partners in the Database of Interacting Proteins (DIP). For this test set, the ratio of success (PPV) on fold assignment increases from 75\% for PSI-BLAST, 83\% for HHSearch and 81\% for PRC to more than 90\% for ModLink+ at the e-value cutoff of 10(-3). Under this e-value, ModLink+ can assign a fold to 30-45\% of the proteins in the test set, while our previous method could cover less than 25\%. When applied to 6,384 proteins with unknown fold in the yeast proteome, ModLink+ combined with PSI-BLAST assigns a fold for domains in 3,738 proteins, while PSI-BLAST alone only covers 2,122 proteins, HHSearch 2,969 and PRC 2,826 proteins, using a threshold e-value that would represent a PPV higher than 82\% for each method in the test set. AVAILABILITY: The ModLink+ server is freely accessible in the World Wide Web at http://sbi.imim.es/modlink/. CONTACT: boliva@imim.es.

}, keywords = {protein folding}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=19357100}, author = {Fornes, O. and Aragues, R. and Espadaler, J. and M. A. Marti-Renom and Sali, A. and Oliva, B.} } @article {763, title = {Pere Alberch: Originator of EvoDevo}, journal = {Biological Theory}, volume = {3}, number = {4}, year = {2009}, pages = {351-353}, author = {Reiss, JO and Burke, A C and Archer, C and De Renzi, M and H. Dopazo and Etxeberria, A and Gale, E A and Hinchliffe, J R and Nu{\~n}o de la Rosa, L and Rose, C S and Rasskin-Gutman, D and M{\"u}ller, G} } @conference {585, title = {Peripheral blood cells transcriptome to study new biomarkers for myocardial infarction follow up}, year = {2009}, month = {06}, author = {Silbiger, Vivian and Luchessi, Andr{\'e} and Hirata, Rosario and Carracedo, {\'A}ngel and Bri{\'o}n, Maria and Lima Neto, Lidio and P. Pastorelli, C and Dopazo, Joaquin and Montaner, David and Garcia, F and P. Sampaio, M and P. Pereira, M and S. Santos, E and Armaganijan, Dikran and Hirata, Mario} } @article {19364735, title = {Sexual selection drives weak positive selection in protamine genes and high promoter divergence, enhancing sperm competitiveness}, journal = {Proc Biol Sci}, year = {2009}, note = {

Journal article Proceedings. Biological sciences / The Royal Society Proc Biol Sci. 2009 Apr 8.

}, abstract = {

Phenotypic adaptations may be the result of changes in gene structure or gene regulation, but little is known about the evolution of gene expression. In addition, it is unclear whether the same selective forces may operate at both levels simultaneously. Reproductive proteins evolve rapidly, but the underlying selective forces promoting such rapid changes are still a matter of debate. In particular, the role of sexual selection in driving positive selection among reproductive proteins remains controversial, whereas its potential influence on changes in promoter regions has not been explored. Protamines are responsible for maintaining DNA in a compacted form in chromosomes in sperm and the available evidence suggests that they evolve rapidly. Because protamines condense DNA within the sperm nucleus, they influence sperm head shape. Here, we examine the influence of sperm competition upon protamine 1 and protamine 2 genes and their promoters, by comparing closely related species of Mus that differ in relative testes size, a reliable indicator of levels of sperm competition. We find evidence of positive selection in the protamine 2 gene in the species with the highest inferred levels of sperm competition. In addition, sperm competition levels across all species are strongly associated with high divergence in protamine 2 promoters that, in turn, are associated with sperm swimming speed. We suggest that changes in protamine 2 promoters are likely to enhance sperm swimming speed by making sperm heads more hydrodynamic. Such phenotypic changes are adaptive because sperm swimming speed may be a major determinant of fertilization success under sperm competition. Thus, when species have diverged recently, few changes in gene-coding sequences are found, while high divergence in promoters seems to be associated with the intensity of sexual selection.

}, keywords = {Adaptation, positive selection, sperm competition}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=19364735}, author = {Martin-Coello, J. and H. Dopazo and Arbiza, L. and Ausio, J. and Roldan, E. R. and Gomendio, M.} } @article {PabloMinguez05192009, title = {SNOW, a web-based tool for the statistical analysis of protein-protein interaction networks}, journal = {Nucl. Acids Res.}, volume = {37}, year = {2009}, pages = {W109-114}, abstract = {

Understanding the structure and the dynamics of the complex intercellular network of interactions that contributes to the structure and function of a living cell is one of the main challenges of today{\textquoteright}s biology. SNOW inputs a collection of protein (or gene) identifiers and, by using the interactome as scaffold, draws the connections among them, calculates several relevant network parameters and, as a novelty among the rest of tools of its class, it estimates their statistical significance. The parameters calculated for each node are: connectivity, betweenness and clustering coefficient. It also calculates the number of components, number of bicomponents and articulation points. An interactive network viewer is also available to explore the resulting network. SNOW is available at http://snow.bioinfo.cipf.es.

}, keywords = {interactome, network, snow}, doi = {10.1093/nar/gkp402}, url = {http://nar.oxfordjournals.org/content/early/2009/05/19/nar.gkp402.full}, author = {Minguez, Pablo and Gotz, S. and Montaner, David and Fatima Al-Shahrour and Dopazo, Joaquin} } @article {586, title = {SNOW, a web-based tool for the statistical analysis of protein-protein interaction networks.}, journal = {Nucleic Acids Res}, volume = {37}, year = {2009}, month = {2009 Jul}, pages = {W109-14}, abstract = {

Understanding the structure and the dynamics of the complex intercellular network of interactions that contributes to the structure and function of a living cell is one of the main challenges of today{\textquoteright}s biology. SNOW inputs a collection of protein (or gene) identifiers and, by using the interactome as scaffold, draws the connections among them, calculates several relevant network parameters and, as a novelty among the rest of tools of its class, it estimates their statistical significance. The parameters calculated for each node are: connectivity, betweenness and clustering coefficient. It also calculates the number of components, number of bicomponents and articulation points. An interactive network viewer is also available to explore the resulting network. SNOW is available at http://snow.bioinfo.cipf.es.

}, keywords = {Computer Graphics, Data Interpretation, Statistical, Databases, Protein, Humans, Internet, Protein Interaction Mapping, Software}, issn = {1362-4962}, doi = {10.1093/nar/gkp402}, author = {Minguez, Pablo and G{\"o}tz, Stefan and Montaner, David and Al-Shahrour, F{\'a}tima and Dopazo, Joaquin} } @article {18515841, title = {Babelomics: advanced functional profiling of transcriptomics, proteomics and genomics experiments}, journal = {Nucleic Acids Res}, volume = {36}, year = {2008}, note = {

Al-Shahrour, Fatima Carbonell, Jose Minguez, Pablo Goetz, Stefan Conesa, Ana Tarraga, Joaquin Medina, Ignacio Alloza, Eva Montaner, David Dopazo, Joaquin Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W341-6. Epub 2008 May 31.

}, pages = {W341-6}, abstract = {

We present a new version of Babelomics, a complete suite of web tools for the functional profiling of genome scale experiments, with new and improved methods as well as more types of functional definitions. Babelomics includes different flavours of conventional functional enrichment methods as well as more advanced gene set analysis methods that makes it a unique tool among the similar resources available. In addition to the well-known functional definitions (GO, KEGG), Babelomics includes new ones such as Biocarta pathways or text mining-derived functional terms. Regulatory modules implemented include transcriptional control (Transfac, CisRed) and other levels of regulation such as miRNA-mediated interference. Moreover, Babelomics allows for sub-selection of terms in order to test more focused hypothesis. Also gene annotation correspondence tables can be imported, which allows testing with user-defined functional modules. Finally, a tool for the {\textquoteright}de novo{\textquoteright} functional annotation of sequences has been included in the system. This allows using yet unannotated organisms in the program. Babelomics has been extensively re-engineered and now it includes the use of web services and Web 2.0 technology features, a new user interface with persistent sessions and a new extended database of gene identifiers. Babelomics is available at http://www.babelomics.org.

}, keywords = {babelomics, funtional profiling}, url = {http://nar.oxfordjournals.org/content/36/suppl_2/W341.long}, author = {Fatima Al-Shahrour and Carbonell, J. and Minguez, P. and Goetz, S. and A. Conesa and Tarraga, J. and Medina, Ignacio and Alloza, E. and Montaner, D. and Dopazo, J.} } @article {591, title = {Expression and microarrays.}, journal = {Methods Mol Biol}, volume = {453}, year = {2008}, month = {2008}, pages = {245-55}, abstract = {

High throughput methodologies have increased by several orders of magnitude the amount of experimental microarray data available. Nevertheless, translating these data into useful biological knowledge remains a challenge. There is a risk of perceiving these methodologies as mere factories that produce never-ending quantities of data if a proper biological interpretation is not provided. Methods of interpreting these data are continuously evolving. Typically, a simple two-step approach has been used, in which genes of interest are first selected based on thresholds for the experimental values, and then enrichment in biologically relevant terms in the annotations of these genes is analyzed in a second step. For various reasons, such methods are quite poor in terms of performance and new procedures inspired by systems biology that directly address sets of functionally related genes are currently under development.

}, keywords = {Animals, Computational Biology, gene expression, Gene Expression Profiling, Humans, Oligonucleotide Array Sequence Analysis}, issn = {1064-3745}, doi = {10.1007/978-1-60327-429-6_12}, author = {Dopazo, Joaquin and Al-Shahrour, F{\'a}tima} } @article {593, title = {GEPAS, a web-based tool for microarray data analysis and interpretation.}, journal = {Nucleic Acids Res}, volume = {36}, year = {2008}, month = {2008 Jul 01}, pages = {W308-14}, abstract = {

Gene Expression Profile Analysis Suite (GEPAS) is one of the most complete and extensively used web-based packages for microarray data analysis. During its more than 5 years of activity it has continuously been updated to keep pace with the state-of-the-art in the changing microarray data analysis arena. GEPAS offers diverse analysis options that include well established as well as novel algorithms for normalization, gene selection, class prediction, clustering and functional profiling of the experiment. New options for time-course (or dose-response) experiments, microarray-based class prediction, new clustering methods and new tests for differential expression have been included. The new pipeliner module allows automating the execution of sequential analysis steps by means of a simple but powerful graphic interface. An extensive re-engineering of GEPAS has been carried out which includes the use of web services and Web 2.0 technology features, a new user interface with persistent sessions and a new extended database of gene identifiers. GEPAS is nowadays the most quoted web tool in its field and it is extensively used by researchers of many countries and its records indicate an average usage rate of 500 experiments per day. GEPAS, is available at http://www.gepas.org.

}, keywords = {Computer Graphics, Dose-Response Relationship, Drug, Gene Expression Profiling, Internet, Kinetics, Oligonucleotide Array Sequence Analysis, Software}, issn = {1362-4962}, doi = {10.1093/nar/gkn303}, author = {T{\'a}rraga, Joaqu{\'\i}n and Medina, Ignacio and Carbonell, Jos{\'e} and Huerta-Cepas, Jaime and Minguez, Pablo and Alloza, Eva and Al-Shahrour, F{\'a}tima and Vegas-Azc{\'a}rate, Susana and Goetz, Stefan and Escobar, Pablo and Garcia-Garcia, Francisco and Conesa, Ana and Montaner, David and Dopazo, Joaquin} } @article {18508806, title = {GEPAS, a web-based tool for microarray data analysis and interpretation}, journal = {Nucleic Acids Res}, volume = {36}, year = {2008}, note = {

Tarraga, Joaquin Medina, Ignacio Carbonell, Jose Huerta-Cepas, Jaime Minguez, Pablo Alloza, Eva Al-Shahrour, Fatima Vegas-Azcarate, Susana Goetz, Stefan Escobar, Pablo Garcia-Garcia, Francisco Conesa, Ana Montaner, David Dopazo, Joaquin Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W308-14. Epub 2008 May 28.

}, pages = {W308-14}, abstract = {

Gene Expression Profile Analysis Suite (GEPAS) is one of the most complete and extensively used web-based packages for microarray data analysis. During its more than 5 years of activity it has continuously been updated to keep pace with the state-of-the-art in the changing microarray data analysis arena. GEPAS offers diverse analysis options that include well established as well as novel algorithms for normalization, gene selection, class prediction, clustering and functional profiling of the experiment. New options for time-course (or dose-response) experiments, microarray-based class prediction, new clustering methods and new tests for differential expression have been included. The new pipeliner module allows automating the execution of sequential analysis steps by means of a simple but powerful graphic interface. An extensive re-engineering of GEPAS has been carried out which includes the use of web services and Web 2.0 technology features, a new user interface with persistent sessions and a new extended database of gene identifiers. GEPAS is nowadays the most quoted web tool in its field and it is extensively used by researchers of many countries and its records indicate an average usage rate of 500 experiments per day. GEPAS, is available at http://www.gepas.org.

}, keywords = {gepas, microarray data analysis}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=18508806}, author = {Tarraga, J. and Medina, Ignacio and Carbonell, J. and Huerta-Cepas, J. and Minguez, P. and Alloza, E. and Fatima Al-Shahrour and Vegas-Azcarate, S. and Goetz, S. and Escobar, P. and Garcia-Garcia, F. and A. Conesa and Montaner, D. and Dopazo, J.} } @article {595, title = {Interoperability with Moby 1.0--it{\textquoteright}s better than sharing your toothbrush!}, journal = {Brief Bioinform}, volume = {9}, year = {2008}, month = {2008 May}, pages = {220-31}, abstract = {

The BioMoby project was initiated in 2001 from within the model organism database community. It aimed to standardize methodologies to facilitate information exchange and access to analytical resources, using a consensus driven approach. Six years later, the BioMoby development community is pleased to announce the release of the 1.0 version of the interoperability framework, registry Application Programming Interface and supporting Perl and Java code-bases. Together, these provide interoperable access to over 1400 bioinformatics resources worldwide through the BioMoby platform, and this number continues to grow. Here we highlight and discuss the features of BioMoby that make it distinct from other Semantic Web Service and interoperability initiatives, and that have been instrumental to its deployment and use by a wide community of bioinformatics service providers. The standard, client software, and supporting code libraries are all freely available at http://www.biomoby.org/.

}, keywords = {Computational Biology, Database Management Systems, Databases, Factual, Information Storage and Retrieval, Internet, Programming Languages, Systems Integration}, issn = {1477-4054}, doi = {10.1093/bib/bbn003}, author = {Wilkinson, Mark D and Senger, Martin and Kawas, Edward and Bruskiewich, Richard and Gouzy, Jerome and Noirot, Celine and Bardou, Philippe and Ng, Ambrose and Haase, Dirk and Saiz, Enrique de Andres and Wang, Dennis and Gibbons, Frank and Gordon, Paul M K and Sensen, Christoph W and Carrasco, Jose Manuel Rodriguez and Fern{\'a}ndez, Jos{\'e} M and Shen, Lixin and Links, Matthew and Ng, Michael and Opushneva, Nina and Neerincx, Pieter B T and Leunissen, Jack A M and Ernst, Rebecca and Twigger, Simon and Usadel, Bjorn and Good, Benjamin and Wong, Yan and Stein, Lincoln and Crosby, William and Karlsson, Johan and Royo, Romina and P{\'a}rraga, Iv{\'a}n and Ram{\'\i}rez, Sergio and Gelpi, Josep Lluis and Trelles, Oswaldo and Pisano, David G and Jimenez, Natalia and Kerhornou, Arnaud and Rosset, Roman and Zamacola, Leire and T{\'a}rraga, Joaqu{\'\i}n and Huerta-Cepas, Jaime and Carazo, Jose Mar{\'\i}a and Dopazo, Joaquin and Guig{\'o}, Roderic and Navarro, Arcadi and Orozco, Modesto and Valencia, Alfonso and Claros, M Gonzalo and P{\'e}rez, Antonio J and Aldana, Jose and Rojano, M Mar and Fernandez-Santa Cruz, Raul and Navas, Ismael and Schiltz, Gary and Farmer, Andrew and Gessler, Damian and Schoof, Heiko and Groscurth, Andreas} } @article {18238804, title = {Interoperability with Moby 1.0{\textendash}it{\textquoteright}s better than sharing your toothbrush!}, journal = {Brief Bioinform}, volume = {9}, number = {3}, year = {2008}, note = {

BioMoby Consortium Wilkinson, Mark D Senger, Martin Kawas, Edward Bruskiewich, Richard Gouzy, Jerome Noirot, Celine Bardou, Philippe Ng, Ambrose Haase, Dirk Saiz, Enrique de Andres Wang, Dennis Gibbons, Frank Gordon, Paul M K Sensen, Christoph W Carrasco, Jose Manuel Rodriguez Fernandez, Jose M Shen, Lixin Links, Matthew Ng, Michael Opushneva, Nina Neerincx, Pieter B T Leunissen, Jack A M Ernst, Rebecca Twigger, Simon Usadel, Bjorn Good, Benjamin Wong, Yan Stein, Lincoln Crosby, William Karlsson, Johan Royo, Romina Parraga, Ivan Ramirez, Sergio Gelpi, Josep Lluis Trelles, Oswaldo Pisano, David G Jimenez, Natalia Kerhornou, Arnaud Rosset, Roman Zamacola, Leire Tarraga, Joaquin Huerta-Cepas, Jaime Carazo, Jose Maria Dopazo, Joaquin Guigo, Roderic Navarro, Arcadi Orozco, Modesto Valencia, Alfonso Claros, M Gonzalo Perez, Antonio J Aldana, Jose Rojano, M Mar Fernandez-Santa Cruz, Raul Navas, Ismael Schiltz, Gary Farmer, Andrew Gessler, Damian Schoof, Heiko Groscurth, Andreas Research Support, Non-U.S. Gov{\textquoteright}t Review England Briefings in bioinformatics Brief Bioinform. 2008 May;9(3):220-31. Epub 2008 Jan 31.

}, pages = {220-31}, abstract = {

The BioMoby project was initiated in 2001 from within the model organism database community. It aimed to standardize methodologies to facilitate information exchange and access to analytical resources, using a consensus driven approach. Six years later, the BioMoby development community is pleased to announce the release of the 1.0 version of the interoperability framework, registry Application Programming Interface and supporting Perl and Java code-bases. Together, these provide interoperable access to over 1400 bioinformatics resources worldwide through the BioMoby platform, and this number continues to grow. Here we highlight and discuss the features of BioMoby that make it distinct from other Semantic Web Service and interoperability initiatives, and that have been instrumental to its deployment and use by a wide community of bioinformatics service providers. The standard, client software, and supporting code libraries are all freely available at http://www.biomoby.org/.

}, keywords = {Computational Biology/*methods *Database Management Systems *Databases, Factual Information Storage and Retrieval/*methods *Internet *Programming Languages Systems Integration}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=18238804}, author = {Wilkinson, M. D. and Senger, M. and Kawas, E. and Bruskiewich, R. and Gouzy, J. and Noirot, C. and Bardou, P. and Ng, A. and Haase, D. and Saiz Ede, A. and Wang, D. and Gibbons, F. and Gordon, P. M. and Sensen, C. W. and Carrasco, J. M. and Fernandez, J. M. and Shen, L. and Links, M. and Ng, M. and Opushneva, N. and Neerincx, P. B. and Leunissen, J. A. and Ernst, R. and Twigger, S. and Usadel, B. and Good, B. and Wong, Y. and Stein, L. and Crosby, W. and Karlsson, J. and Royo, R. and Parraga, I. and Ramirez, S. and Gelpi, J. L. and Trelles, O. and Pisano, D. G. and Jimenez, N. and Kerhornou, A. and Rosset, R. and Zamacola, L. and Tarraga, J. and Huerta-Cepas, J. and Carazo, J. M. and Dopazo, J. and R. Guigo and Navarro, A. and Orozco, M. and Valencia, A. and Claros, M. G. and Perez, A. J. and Aldana, J. and Rojano, M. M. and Fernandez-Santa Cruz, R. and Navas, I. and Schiltz, G. and Farmer, A. and Gessler, D. and Schoof, H. and Groscurth, A.} } @article {18505562, title = {Prediction of enzyme function by combining sequence similarity and protein interactions}, journal = {BMC Bioinformatics}, volume = {9}, year = {2008}, note = {Espadaler, Jordi Eswar, Narayanan Querol, Enrique Aviles, Francesc X Sali, Andrej Marti-Renom, Marc A Oliva, Baldomero GM54762/GM/NIGMS NIH HHS/United States GM71790/GM/NIGMS NIH HHS/United States GM74929/GM/NIGMS NIH HHS/United States GM74945/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov{\textquoteright}t England BMC bioinformatics BMC Bioinformatics. 2008 May 27;9:249.}, pages = {249}, abstract = {BACKGROUND: A number of studies have used protein interaction data alone for protein function prediction. Here, we introduce a computational approach for annotation of enzymes, based on the observation that similar protein sequences are more likely to perform the same function if they share similar interacting partners. RESULTS: The method has been tested against the PSI-BLAST program using a set of 3,890 protein sequences from which interaction data was available. For protein sequences that align with at least 40\% sequence identity to a known enzyme, the specificity of our method in predicting the first three EC digits increased from 80\% to 90\% at 80\% coverage when compared to PSI-BLAST. CONCLUSION: Our method can also be used in proteins for which homologous sequences with known interacting partners can be detected. Thus, our method could increase 10\% the specificity of genome-wide enzyme predictions based on sequence matching by PSI-BLAST alone.}, keywords = {Amino Acid *Software Structure-Activity Relationship Substrate Specificity/genetics, Amino Acid Sequence/physiology Databases, Automated Predictive Value of Tests Protein Interaction Mapping Proteins/analysis/metabolism Sequence Alignment Sequence Analysis, Protein *Sequence Homology, Protein Enzymes/analysis/*metabolism Fuzzy Logic Pattern Recognition}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=18505562}, author = {Espadaler, J. and Eswar, N. and Querol, E. and Aviles, F. X. and Sali, A. and M. A. Marti-Renom and Oliva, B.} } @article {18552980, title = {Time course profiling of the retinal transcriptome after optic nerve transection and optic nerve crush}, journal = {Mol Vis}, volume = {14}, year = {2008}, note = {Agudo, Marta Perez-Marin, Maria Cruz Lonngren, Ulrika Sobrado, Paloma Conesa, Ana Canovas, Isabel Salinas-Navarro, Manuel Miralles-Imperial, Jaime Hallbook, Finn Vidal-Sanz, Manuel Research Support, Non-U.S. Gov{\textquoteright}t United States Molecular vision Mol Vis. 2008 Jun 3;14:1050-63.}, pages = {1050-63}, abstract = {PURPOSE: A time-course analysis of gene regulation in the adult rat retina after intraorbital nerve crush (IONC) and intraorbital nerve transection (IONT). METHODS: RNA was extracted from adult rat retinas undergoing either IONT or IONC at increasing times post-lesion. Affymetrix RAE230.2 arrays were hybridized and analyzed. Statistically regulated genes were annotated and functionally clustered. Arrays were validated by means of quantative reverse transcription polymerase chain reaction (qRT-PCR) on ten regulated genes at two times post-lesion. Western blotting and immunohistofluorescence for four pro-apoptotic proteins were performed on naive and injured retinas. Finally, custom signaling maps for IONT- and IONC-induced death response were generated (MetaCore, Genego Inc.). RESULTS: Here we show that over time, 3,219 sequences were regulated after IONT and 1,996 after IONC. Out of the total of regulated sequences, 1,078 were commonly regulated by both injuries. Interestingly, while IONT mainly triggers a gene upregulation-sustained over time, IONC causes a transitory downregulation. Functional clustering identified the regulation of high interest biologic processes, most importantly cell death wherein apoptosis was the most significant cluster. Ten death-related genes upregulated by both injuries were used for array validation by means of qRT-PCR. In addition, western blotting and immunohistofluorescence of total and active Caspase 3 (Casp3), tumor necrosis factor receptor type 1 associated death domain (TRADD), tumor necrosis factor receptor superfamily member 1a (TNFR1a), and c-fos were performed to confirm their protein regulation and expression pattern in naive and injured retinas. These analyses demonstrated that for these genes, protein regulation followed transcriptional regulation and that these pro-apoptotic proteins were expressed by retinal ganglion cells (RGCs). MetaCore-based death-signaling maps show that several apoptotic cascades were regulated in the retina following optic nerve injury and highlight the similarities and differences between IONT and IONC in cell death profiling. CONCLUSIONS: This comprehensive time course retinal transcriptome study comparing IONT and IONC lesions provides a unique valuable tool to understand the molecular mechanisms underlying optic nerve injury and to design neuroprotective protocols.}, keywords = {Animals Cell Death Cluster Analysis Female *Gene Expression Profiling Gene Expression Regulation *Nerve Crush Optic Nerve/*metabolism/*pathology Optic Nerve Injuries/*genetics Rats Rats, Sprague-Dawley Reproducibility of Results Retina/*metabolism/*pathology Time Factors}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=18552980}, author = {Agudo, M. and Perez-Marin, M. C. and Lonngren, U. and Sobrado, P. and A. Conesa and Canovas, I. and Salinas-Navarro, M. and Miralles-Imperial, J. and Hallbook, F. and Vidal-Sanz, M.} } @article {600, title = {Use of estimated evolutionary strength at the codon level improves the prediction of disease-related protein mutations in humans.}, journal = {Hum Mutat}, volume = {29}, year = {2008}, month = {2008 Jan}, pages = {198-204}, abstract = {

Predicting the functional impact of protein variation is one of the most challenging problems in bioinformatics. A rapidly growing number of genome-scale studies provide large amounts of experimental data, allowing the application of rigorous statistical approaches for predicting whether a given single point mutation has an impact on human health. Up until now, existing methods have limited their source data to either protein or gene information. Novel in this work, we take advantage of both and focus on protein evolutionary information by using estimated selective pressures at the codon level. Here we introduce a new method (SeqProfCod) to predict the likelihood that a given protein variant is associated with human disease or not. Our method relies on a support vector machine (SVM) classifier trained using three sources of information: protein sequence, multiple protein sequence alignments, and the estimation of selective pressure at the codon level. SeqProfCod has been benchmarked with a large dataset of 8,987 single point mutations from 1,434 human proteins from SWISS-PROT. It achieves 82\% overall accuracy and a correlation coefficient of 0.59, indicating that the estimation of the selective pressure helps in predicting the functional impact of single-point mutations. Moreover, this study demonstrates the synergic effect of combining two sources of information for predicting the functional effects of protein variants: protein sequence/profile-based information and the evolutionary estimation of the selective pressures at the codon level. The results of large-scale application of SeqProfCod over all annotated point mutations in SWISS-PROT (available for download at http://sgu.bioinfo.cipf.es/services/Omidios/; last accessed: 24 August 2007), could be used to support clinical studies.

}, keywords = {Algorithms, Codon, Computational Biology, Databases, Protein, DNA Mutational Analysis, Evolution, Molecular, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Humans, Iduronic Acid, Point Mutation, Polymorphism, Single Nucleotide, Proteins, Tumor Suppressor Protein p53}, issn = {1098-1004}, doi = {10.1002/humu.20628}, author = {Capriotti, Emidio and Arbiza, Leonardo and Casadio, Rita and Dopazo, Joaquin and Dopazo, Hern{\'a}n and Marti-Renom, Marc A} } @article {17935148, title = {Use of estimated evolutionary strength at the codon level improves the prediction of disease-related protein mutations in humans}, journal = {Hum Mutat}, volume = {29}, number = {1}, year = {2008}, note = {Capriotti, Emidio Arbiza, Leonardo Casadio, Rita Dopazo, Joaquin Dopazo, Hernan Marti-Renom, Marc A Evaluation Studies Research Support, Non-U.S. Gov{\textquoteright}t United States Human mutation Hum Mutat. 2008 Jan;29(1):198-204.}, pages = {198-204}, abstract = {Predicting the functional impact of protein variation is one of the most challenging problems in bioinformatics. A rapidly growing number of genome-scale studies provide large amounts of experimental data, allowing the application of rigorous statistical approaches for predicting whether a given single point mutation has an impact on human health. Up until now, existing methods have limited their source data to either protein or gene information. Novel in this work, we take advantage of both and focus on protein evolutionary information by using estimated selective pressures at the codon level. Here we introduce a new method (SeqProfCod) to predict the likelihood that a given protein variant is associated with human disease or not. Our method relies on a support vector machine (SVM) classifier trained using three sources of information: protein sequence, multiple protein sequence alignments, and the estimation of selective pressure at the codon level. SeqProfCod has been benchmarked with a large dataset of 8,987 single point mutations from 1,434 human proteins from SWISS-PROT. It achieves 82\% overall accuracy and a correlation coefficient of 0.59, indicating that the estimation of the selective pressure helps in predicting the functional impact of single-point mutations. Moreover, this study demonstrates the synergic effect of combining two sources of information for predicting the functional effects of protein variants: protein sequence/profile-based information and the evolutionary estimation of the selective pressures at the codon level. The results of large-scale application of SeqProfCod over all annotated point mutations in SWISS-PROT (available for download at http://sgu.bioinfo.cipf.es/services/Omidios/; last accessed: 24 August 2007), could be used to support clinical studies.}, keywords = {Algorithms Codon/genetics Computational Biology/*methods *DNA Mutational Analysis Databases, Human Humans Iduronic Acid/analogs \& derivatives/metabolism *Point Mutation Polymorphism, Molecular *Genetic Predisposition to Disease Genetic Variation Genome, Protein *Evolution, Single Nucleotide Proteins/chemistry/*genetics Tumor Suppressor Protein p53/genetics}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17935148}, author = {E. Capriotti and Arbiza, L. and Casadio, R. and Dopazo, J. and H. Dopazo and M. A. Marti-Renom} } @article {17254327, title = {Analysis of 13000 unique Citrus clusters associated with fruit quality, production and salinity tolerance}, journal = {BMC Genomics}, volume = {8}, year = {2007}, note = {Terol, Javier Conesa, Ana Colmenero, Jose M Cercos, Manuel Tadeo, Francisco Agusti, Javier Alos, Enriqueta Andres, Fernando Soler, Guillermo Brumos, Javier Iglesias, Domingo J Gotz, Stefan Legaz, Francisco Argout, Xavier Courtois, Brigitte Ollitrault, Patrick Dossat, Carole Wincker, Patrick Morillon, Raphael Talon, Manuel Comparative Study Research Support, Non-U.S. Gov{\textquoteright}t England BMC genomics BMC Genomics. 2007 Jan 25;8:31.}, pages = {31}, abstract = {BACKGROUND: Improvement of Citrus, the most economically important fruit crop in the world, is extremely slow and inherently costly because of the long-term nature of tree breeding and an unusual combination of reproductive characteristics. Aside from disease resistance, major commercial traits in Citrus are improved fruit quality, higher yield and tolerance to environmental stresses, especially salinity. RESULTS: A normalized full length and 9 standard cDNA libraries were generated, representing particular treatments and tissues from selected varieties (Citrus clementina and C. sinensis) and rootstocks (C. reshni, and C. sinenis x Poncirus trifoliata) differing in fruit quality, resistance to abscission, and tolerance to salinity. The goal of this work was to provide a large expressed sequence tag (EST) collection enriched with transcripts related to these well appreciated agronomical traits. Towards this end, more than 54000 ESTs derived from these libraries were analyzed and annotated. Assembly of 52626 useful sequences generated 15664 putative transcription units distributed in 7120 contigs, and 8544 singletons. BLAST annotation produced significant hits for more than 80\% of the hypothetical transcription units and suggested that 647 of these might be Citrus specific unigenes. The unigene set, composed of 13000 putative different transcripts, including more than 5000 novel Citrus genes, was assigned with putative functions based on similarity, GO annotations and protein domains CONCLUSION: Comparative genomics with Arabidopsis revealed the presence of putative conserved orthologs and single copy genes in Citrus and also the occurrence of both gene duplication events and increased number of genes for specific pathways. In addition, phylogenetic analysis performed on the ammonium transporter family and glycosyl transferase family 20 suggested the existence of Citrus paralogs. Analysis of the Citrus gene space showed that the most important metabolic pathways known to affect fruit quality were represented in the unigene set. Overall, the similarity analyses indicated that the sequences of the genes belonging to these varieties and rootstocks were essentially identical, suggesting that the differential behaviour of these species cannot be attributed to major sequence divergences. This Citrus EST assembly contributes both crucial information to discover genes of agronomical interest and tools for genetic and genomic analyses, such as the development of new markers and microarrays.}, keywords = {Acclimatization/*genetics Amino Acid Motifs Citrus/*genetics Cluster Analysis Expressed Sequence Tags Fruit/genetics Gene Duplication *Gene Expression Regulation, Plant Gene Library Genes, Plant Genomics Molecular Sequence Data Multigene Family Phylogeny *Salts/adverse effects}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17254327}, author = {Terol, J. and A. Conesa and Colmenero, J. M. and Cercos, M. and Tadeo, F. and Agusti, J. and Alos, E. and Andres, F. and Soler, G. and Brumos, J. and Iglesias, D. J. and Gotz, S. and Legaz, F. and Argout, X. and Courtois, B. and Ollitrault, P. and Dossat, C. and Wincker, P. and Morillon, R. and Talon, M.} } @article {17570147, title = {The AnnoLite and AnnoLyze programs for comparative annotation of protein structures}, journal = {BMC Bioinformatics}, volume = {8 Suppl 4}, year = {2007}, note = {Marti-Renom, Marc A Rossi, Andrea Al-Shahrour, Fatima Davis, Fred P Pieper, Ursula Dopazo, Joaquin Sali, Andrej Research Support, Non-U.S. Gov{\textquoteright}t England BMC bioinformatics BMC Bioinformatics. 2007 May 22;8 Suppl 4:S4.}, pages = {S4}, abstract = {BACKGROUND: Advances in structural biology, including structural genomics, have resulted in a rapid increase in the number of experimentally determined protein structures. However, about half of the structures deposited by the structural genomics consortia have little or no information about their biological function. Therefore, there is a need for tools for automatically and comprehensively annotating the function of protein structures. We aim to provide such tools by applying comparative protein structure annotation that relies on detectable relationships between protein structures to transfer functional annotations. Here we introduce two programs, AnnoLite and AnnoLyze, which use the structural alignments deposited in the DBAli database. DESCRIPTION: AnnoLite predicts the SCOP, CATH, EC, InterPro, PfamA, and GO terms with an average sensitivity of 90\% and average precision of 80\%. AnnoLyze predicts ligand binding site and domain interaction patches with an average sensitivity of 70\% and average precision of 30\%, correctly localizing binding sites for small molecules in 95\% of its predictions. CONCLUSION: The AnnoLite and AnnoLyze programs for comparative annotation of protein structures can reliably and automatically annotate new protein structures. The programs are fully accessible via the Internet as part of the DBAli suite of tools at http://salilab.org/DBAli/.}, keywords = {*Algorithms Amino Acid Sequence Confidence Intervals Data Interpretation, Amino Acid *Software Structure-Activity Relationship, Protein Information Storage and Retrieval/methods Molecular Sequence Data Proteins/*chemistry/classification/*metabolism Sensitivity and Specificity Sequence Alignment/*methods Sequence Analysis, Protein/*methods Sequence Homology, Statistical *Databases}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17570147}, author = {M. A. Marti-Renom and Rossi, A. and Fatima Al-Shahrour and Davis, F. P. and Pieper, U. and Dopazo, J. and Sali, A.} } @article {17909067, title = {Association study of 69 genes in the ret pathway identifies low-penetrance loci in sporadic medullary thyroid carcinoma}, journal = {Cancer Res}, volume = {67}, number = {19}, year = {2007}, note = {Ruiz-Llorente, Sergio Montero-Conde, Cristina Milne, Roger L Moya, Christian M Cebrian, Arancha Leton, Rocio Cascon, Alberto Mercadillo, Fatima Landa, Inigo Borrego, Salud Perez de Nanclares, Guiomar Alvarez-Escola, Cristina Diaz-Perez, Jose Angel Carracedo, Angel Urioste, Miguel Gonzalez-Neira, Anna Benitez, Javier Santisteban, Pilar Dopazo, Joaquin Ponder, Bruce A Robledo, Mercedes Medullary Thyroid Carcinoma Clinical Group Research Support, Non-U.S. Gov{\textquoteright}t United States Cancer research Cancer Res. 2007 Oct 1;67(19):9561-7.}, pages = {9561-7}, abstract = {To date, few association studies have been done to better understand the genetic basis for the development of sporadic medullary thyroid carcinoma (sMTC). To identify additional low-penetrance genes, we have done a two-stage case-control study in two European populations using high-throughput genotyping. We selected 417 single nucleotide polymorphisms (SNP) belonging to 69 genes either related to RET signaling pathway/functions or involved in key processes for cancer development. TagSNPs and functional variants were included where possible. These SNPs were initially studied in the largest known series of sMTC cases (n = 266) and controls (n = 422), all of Spanish origin. In stage II, an independent British series of 155 sMTC patients and 531 controls was included to validate the previous results. Associations were assessed by an exhaustive analysis of individual SNPs but also considering gene- and linkage disequilibrium-based haplotypes. This strategy allowed us to identify seven low-penetrance genes, six of them (STAT1, AURKA, BCL2, CDKN2B, CDK6, and COMT) consistently associated with sMTC risk in the two case-control series and a seventh (HRAS) with individual SNPs and haplotypes associated with sMTC in the Spanish data set. The potential role of CDKN2B was confirmed by a functional assay showing a role of a SNP (rs7044859) in the promoter region in altering the binding of the transcription factor HNF1. These results highlight the utility of association studies using homogeneous series of cases for better understanding complex diseases.}, keywords = {80 and over Carcinoma, Adolescent Adult Aged Aged, Genetic, Genetic Proto-Oncogene Proteins c-ret/*genetics/metabolism Signal Transduction Thyroid Neoplasms/*genetics/metabolism Transcription, Medullary/*genetics/metabolism Case-Control Studies Cyclin-Dependent Kinase Inhibitor p15/biosynthesis/genetics Female Genetic Predisposition to Disease Germ-Line Mutation Haplotypes Humans Male Middle Aged Penetrance Polymorphism, Single Nucleotide Promoter Regions}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17909067}, author = {Ruiz-Llorente, S. and Montero-Conde, C. and Milne, R. L. and Moya, C. M. and Cebrian, A. and Leton, R. and Cascon, A. and Mercadillo, F. and Landa, I. and Borrego, S. and Perez de Nanclares, G. and Alvarez-Escola, C. and Diaz-Perez, J. A. and Carracedo, A. and Urioste, M. and Gonzalez-Neira, A. and Benitez, J. and Santisteban, P. and Dopazo, J. and Ponder, B. A. and M. Robledo} } @article {17941705, title = {Characterization of protein hubs by inferring interacting motifs from protein interactions}, journal = {PLoS Comput Biol}, volume = {3}, number = {9}, year = {2007}, note = {Aragues, Ramon Sali, Andrej Bonet, Jaume Marti-Renom, Marc A Oliva, Baldo PN2 EY016525,/EY/NEI NIH HHS/United States U54 RR022220/RR/NCRR NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov{\textquoteright}t United States PLoS computational biology PLoS Comput Biol. 2007 Sep;3(9):1761-71. Epub 2007 Jul 30.}, pages = {1761-71}, abstract = {The characterization of protein interactions is essential for understanding biological systems. While genome-scale methods are available for identifying interacting proteins, they do not pinpoint the interacting motifs (e.g., a domain, sequence segments, a binding site, or a set of residues). Here, we develop and apply a method for delineating the interacting motifs of hub proteins (i.e., highly connected proteins). The method relies on the observation that proteins with common interaction partners tend to interact with these partners through a common interacting motif. The sole input for the method are binary protein interactions; neither sequence nor structure information is needed. The approach is evaluated by comparing the inferred interacting motifs with domain families defined for 368 proteins in the Structural Classification of Proteins (SCOP). The positive predictive value of the method for detecting proteins with common SCOP families is 75\% at sensitivity of 10\%. Most of the inferred interacting motifs were significantly associated with sequence patterns, which could be responsible for the common interactions. We find that yeast hubs with multiple interacting motifs are more likely to be essential than hubs with one or two interacting motifs, thus rationalizing the previously observed correlation between essentiality and the number of interacting partners of a protein. We also find that yeast hubs with multiple interacting motifs evolve slower than the average protein, contrary to the hubs with one or two interacting motifs. The proposed method will help us discover unknown interacting motifs and provide biological insights about protein hubs and their roles in interaction networks.}, keywords = {Amino Acid Motifs Amino Acid Sequence Binding Sites Computer Simulation *Models, Chemical *Models, Molecular Molecular Sequence Data Protein Binding Protein Interaction Mapping/*methods Proteins/*chemistry Sequence Analysis, Protein/*methods}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17941705}, author = {Aragues, R. and Sali, A. and Bonet, J. and M. A. Marti-Renom and Oliva, B.} } @article {603, title = {DBAli tools: mining the protein structure space.}, journal = {Nucleic Acids Res}, volume = {35}, year = {2007}, month = {2007 Jul}, pages = {W393-7}, abstract = {

The DBAli tools use a comprehensive set of structural alignments in the DBAli database to leverage the structural information deposited in the Protein Data Bank (PDB). These tools include (i) the DBAlit program that allows users to input the 3D coordinates of a protein structure for comparison by MAMMOTH against all chains in the PDB; (ii) the AnnoLite and AnnoLyze programs that annotate a target structure based on its stored relationships to other structures; (iii) the ModClus program that clusters structures by sequence and structure similarities; (iv) the ModDom program that identifies domains as recurrent structural fragments and (v) an implementation of the COMPARER method in the SALIGN command in MODELLER that creates a multiple structure alignment for a set of related protein structures. Thus, the DBAli tools, which are freely accessible via the World Wide Web at http://salilab.org/DBAli/, allow users to mine the protein structure space by establishing relationships between protein structures and their functions.

}, keywords = {Algorithms, Amino Acid Sequence, Computational Biology, Data Interpretation, Statistical, Databases, Protein, Internet, Molecular Sequence Data, Protein Conformation, Proteins, Pseudomonas aeruginosa, Sequence Alignment, Sequence Analysis, Protein, Sequence Homology, Amino Acid, Software, Structure-Activity Relationship}, issn = {1362-4962}, doi = {10.1093/nar/gkm236}, author = {Marti-Renom, Marc A and Pieper, Ursula and Madhusudhan, M S and Rossi, Andrea and Eswar, Narayanan and Davis, Fred P and Al-Shahrour, F{\'a}tima and Dopazo, Joaquin and Sali, Andrej} } @article {17478513, title = {DBAli tools: mining the protein structure space}, journal = {Nucleic Acids Res}, volume = {35}, number = {Web Server issue}, year = {2007}, note = {Marti-Renom, Marc A Pieper, Ursula Madhusudhan, M S Rossi, Andrea Eswar, Narayanan Davis, Fred P Al-Shahrour, Fatima Dopazo, Joaquin Sali, Andrej GM 62529/GM/NIGMS NIH HHS/United States GM074929/GM/NIGMS NIH HHS/United States GM54762/GM/NIGMS NIH HHS/United States GM71790/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2007 Jul;35(Web Server issue):W393-7. Epub 2007 May 3.}, pages = {W393-7}, abstract = {The DBAli tools use a comprehensive set of structural alignments in the DBAli database to leverage the structural information deposited in the Protein Data Bank (PDB). These tools include (i) the DBAlit program that allows users to input the 3D coordinates of a protein structure for comparison by MAMMOTH against all chains in the PDB; (ii) the AnnoLite and AnnoLyze programs that annotate a target structure based on its stored relationships to other structures; (iii) the ModClus program that clusters structures by sequence and structure similarities; (iv) the ModDom program that identifies domains as recurrent structural fragments and (v) an implementation of the COMPARER method in the SALIGN command in MODELLER that creates a multiple structure alignment for a set of related protein structures. Thus, the DBAli tools, which are freely accessible via the World Wide Web at http://salilab.org/DBAli/, allow users to mine the protein structure space by establishing relationships between protein structures and their functions.}, keywords = {*Algorithms Amino Acid Sequence Computational Biology/*methods Data Interpretation, Amino Acid *Software Structure-Activity Relationship, Protein Internet Molecular Sequence Data Protein Conformation Proteins/*chemistry/classification/*metabolism Pseudomonas aeruginosa/*metabolism Sequence Alignment/*methods Sequence Analysis, Protein/*methods Sequence Homology, Statistical *Databases}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17478513}, author = {M. A. Marti-Renom and Pieper, U. and Madhusudhan, M. S. and Rossi, A. and Eswar, N. and Davis, F. P. and Fatima Al-Shahrour and Dopazo, J. and Sali, A.} } @article {604, title = {Evidence for systems-level molecular mechanisms of tumorigenesis.}, journal = {BMC Genomics}, volume = {8}, year = {2007}, month = {2007 Jun 20}, pages = {185}, abstract = {

BACKGROUND: Cancer arises from the consecutive acquisition of genetic alterations. Increasing evidence suggests that as a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. Coordinated reprogramming would allow the cell to acquire the capabilities for malignant growth.

RESULTS: Here, we determine the coordinated function of cancer gene products (i.e., proteins encoded by differentially expressed genes in tumors relative to healthy tissue counterparts, hereafter referred to as "CGPs") defined as their topological properties and organization in the interactome network. We show that CGPs are central to information exchange and propagation and that they are specifically organized to promote tumorigenesis. Centrality is identified by both local (degree) and global (betweenness and closeness) measures, and systematically appears in down-regulated CGPs. Up-regulated CGPs do not consistently exhibit centrality, but both types of cancer products determine the overall integrity of the network structure. In addition to centrality, down-regulated CGPs show topological association that correlates with common biological processes and pathways involved in tumorigenesis.

CONCLUSION: Given the current limited coverage of the human interactome, this study proposes that tumorigenesis takes place in a specific and organized way at the molecular systems-level and suggests a model that comprises the precise down-regulation of groups of topologically-associated proteins involved in particular functions, orchestrated with the up-regulation of specific proteins.

}, keywords = {Cell Transformation, Neoplastic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Male, Models, Biological, Models, Genetic, Models, Statistical, Neoplasm Proteins, Neoplasms, Prostatic Neoplasms, Protein Interaction Mapping, RNA, Messenger, Signal Transduction, Systems biology}, issn = {1471-2164}, doi = {10.1186/1471-2164-8-185}, author = {Hern{\'a}ndez, Pilar and Huerta-Cepas, Jaime and Montaner, David and Al-Shahrour, F{\'a}tima and Valls, Joan and G{\'o}mez, Laia and Capell{\`a}, Gabriel and Dopazo, Joaquin and Pujana, Miguel Angel} } @article {17584915, title = {Evidence for systems-level molecular mechanisms of tumorigenesis}, journal = {BMC Genomics}, volume = {8}, year = {2007}, note = {Hernandez, Pilar Huerta-Cepas, Jaime Montaner, David Al-Shahrour, Fatima Valls, Joan Gomez, Laia Capella, Gabriel Dopazo, Joaquin Pujana, Miguel Angel Research Support, Non-U.S. Gov{\textquoteright}t England BMC genomics BMC Genomics. 2007 Jun 20;8:185.}, pages = {185}, abstract = {BACKGROUND: Cancer arises from the consecutive acquisition of genetic alterations. Increasing evidence suggests that as a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. Coordinated reprogramming would allow the cell to acquire the capabilities for malignant growth. RESULTS: Here, we determine the coordinated function of cancer gene products (i.e., proteins encoded by differentially expressed genes in tumors relative to healthy tissue counterparts, hereafter referred to as "CGPs") defined as their topological properties and organization in the interactome network. We show that CGPs are central to information exchange and propagation and that they are specifically organized to promote tumorigenesis. Centrality is identified by both local (degree) and global (betweenness and closeness) measures, and systematically appears in down-regulated CGPs. Up-regulated CGPs do not consistently exhibit centrality, but both types of cancer products determine the overall integrity of the network structure. In addition to centrality, down-regulated CGPs show topological association that correlates with common biological processes and pathways involved in tumorigenesis. CONCLUSION: Given the current limited coverage of the human interactome, this study proposes that tumorigenesis takes place in a specific and organized way at the molecular systems-level and suggests a model that comprises the precise down-regulation of groups of topologically-associated proteins involved in particular functions, orchestrated with the up-regulation of specific proteins.}, keywords = {*Cell Transformation, Biological Models, Genetic Models, Messenger/metabolism Signal Transduction Systems Biology, Neoplastic *Gene Expression Profiling *Gene Expression Regulation, Neoplastic Humans Male Models, Statistical Neoplasm Proteins/*physiology Neoplasms/etiology/*genetics Prostatic Neoplasms/genetics Protein Interaction Mapping RNA}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17584915}, author = {Hernandez, P. and Huerta-Cepas, J. and Montaner, D. and Fatima Al-Shahrour and Valls, J. and Gomez, L. and Capella, G. and Dopazo, J. and Pujana, M. A.} } @article {17478504, title = {FatiGO +: a functional profiling tool for genomic data. Integration of functional annotation, regulatory motifs and interaction data with microarray experiments}, journal = {Nucleic Acids Res}, volume = {35}, number = {Web Server issue}, year = {2007}, note = {

Al-Shahrour, Fatima Minguez, Pablo Tarraga, Joaquin Medina, Ignacio Alloza, Eva Montaner, David Dopazo, Joaquin Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2007 Jul;35(Web Server issue):W91-6. Epub 2007 May 3.

}, pages = {W91-6}, abstract = {

The ultimate goal of any genome-scale experiment is to provide a functional interpretation of the data, relating the available information with the hypotheses that originated the experiment. Thus, functional profiling methods have become essential in diverse scenarios such as microarray experiments, proteomics, etc. We present the FatiGO+, a web-based tool for the functional profiling of genome-scale experiments, specially oriented to the interpretation of microarray experiments. In addition to different functional annotations (gene ontology, KEGG pathways, Interpro motifs, Swissprot keywords and text-mining based bioentities related to diseases and chemical compounds) FatiGO+ includes, as a novelty, regulatory and structural information. The regulatory information used includes predictions of targets for distinct regulatory elements (obtained from the Transfac and CisRed databases). Additionally FatiGO+ uses predictions of target motifs of miRNA to infer which of these can be activated or deactivated in the sample of genes studied. Finally, properties of gene products related to their relative location and connections in the interactome have also been used. Also, enrichment of any of these functional terms can be directly analysed on chromosomal coordinates. FatiGO+ can be found at: http://www.fatigoplus.org and within the Babelomics environment http://www.babelomics.org.

}, keywords = {babelomics, functional enrichment analysys}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17478504}, author = {Fatima Al-Shahrour and Minguez, P. and Tarraga, J. and Medina, Ignacio and Alloza, E. and Montaner, D. and Dopazo, J.} } @article {605, title = {FatiGO +: a functional profiling tool for genomic data. Integration of functional annotation, regulatory motifs and interaction data with microarray experiments.}, journal = {Nucleic Acids Res}, volume = {35}, year = {2007}, month = {2007 Jul}, pages = {W91-6}, abstract = {

The ultimate goal of any genome-scale experiment is to provide a functional interpretation of the data, relating the available information with the hypotheses that originated the experiment. Thus, functional profiling methods have become essential in diverse scenarios such as microarray experiments, proteomics, etc. We present the FatiGO+, a web-based tool for the functional profiling of genome-scale experiments, specially oriented to the interpretation of microarray experiments. In addition to different functional annotations (gene ontology, KEGG pathways, Interpro motifs, Swissprot keywords and text-mining based bioentities related to diseases and chemical compounds) FatiGO+ includes, as a novelty, regulatory and structural information. The regulatory information used includes predictions of targets for distinct regulatory elements (obtained from the Transfac and CisRed databases). Additionally FatiGO+ uses predictions of target motifs of miRNA to infer which of these can be activated or deactivated in the sample of genes studied. Finally, properties of gene products related to their relative location and connections in the interactome have also been used. Also, enrichment of any of these functional terms can be directly analysed on chromosomal coordinates. FatiGO+ can be found at: http://www.fatigoplus.org and within the Babelomics environment http://www.babelomics.org.

}, keywords = {Amino Acid Motifs, Animals, Binding Sites, Computational Biology, Gene Expression Profiling, Genes, Genomics, Humans, Internet, Oligonucleotide Array Sequence Analysis, Programming Languages, Software, Systems Integration, Transcription Factors}, issn = {1362-4962}, doi = {10.1093/nar/gkm260}, author = {Al-Shahrour, F{\'a}tima and Minguez, Pablo and T{\'a}rraga, Joaqu{\'\i}n and Medina, Ignacio and Alloza, Eva and Montaner, David and Dopazo, Joaquin} } @article {17407596, title = {From genes to functional classes in the study of biological systems}, journal = {BMC Bioinformatics}, volume = {8}, year = {2007}, note = {

Al-Shahrour, Fatima Arbiza, Leonardo Dopazo, Hernan Huerta-Cepas, Jaime Minguez, Pablo Montaner, David Dopazo, Joaquin Research Support, Non-U.S. Gov{\textquoteright}t England BMC bioinformatics BMC Bioinformatics. 2007 Apr 3;8:114.

}, pages = {114}, abstract = {

BACKGROUND: With the popularization of high-throughput techniques, the need for procedures that help in the biological interpretation of results has increased enormously. Recently, new procedures inspired in systems biology criteria have started to be developed. RESULTS: Here we present FatiScan, a web-based program which implements a threshold-independent test for the functional interpretation of large-scale experiments that does not depend on the pre-selection of genes based on the multiple application of independent tests to each gene. The test implemented aims to directly test the behaviour of blocks of functionally related genes, instead of focusing on single genes. In addition, the test does not depend on the type of the data used for obtaining significance values, and consequently different types of biologically informative terms (gene ontology, pathways, functional motifs, transcription factor binding sites or regulatory sites from CisRed) can be applied to different classes of genome-scale studies. We exemplify its application in microarray gene expression, evolution and interactomics. CONCLUSION: Methods for gene set enrichment which, in addition, are independent from the original data and experimental design constitute a promising alternative for the functional profiling of genome-scale experiments. A web server that performs the test described and other similar ones can be found at: http://www.babelomics.org.

}, keywords = {Algorithms Chromosome Mapping/*methods Computer Simulation Gene Expression Profiling/methods *Models, babelomics, Biological Multigene Family/*physiology Signal Transduction/*physiology *Software Systems Biology/*methods *User-Computer Interface}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17407596}, author = {Fatima Al-Shahrour and Arbiza, L. and H. Dopazo and Huerta-Cepas, J. and Minguez, P. and Montaner, D. and Dopazo, J.} } @article {606, title = {From genes to functional classes in the study of biological systems.}, journal = {BMC Bioinformatics}, volume = {8}, year = {2007}, month = {2007 Apr 03}, pages = {114}, abstract = {

BACKGROUND: With the popularization of high-throughput techniques, the need for procedures that help in the biological interpretation of results has increased enormously. Recently, new procedures inspired in systems biology criteria have started to be developed.

RESULTS: Here we present FatiScan, a web-based program which implements a threshold-independent test for the functional interpretation of large-scale experiments that does not depend on the pre-selection of genes based on the multiple application of independent tests to each gene. The test implemented aims to directly test the behaviour of blocks of functionally related genes, instead of focusing on single genes. In addition, the test does not depend on the type of the data used for obtaining significance values, and consequently different types of biologically informative terms (gene ontology, pathways, functional motifs, transcription factor binding sites or regulatory sites from CisRed) can be applied to different classes of genome-scale studies. We exemplify its application in microarray gene expression, evolution and interactomics.

CONCLUSION: Methods for gene set enrichment which, in addition, are independent from the original data and experimental design constitute a promising alternative for the functional profiling of genome-scale experiments. A web server that performs the test described and other similar ones can be found at: http://www.babelomics.org.

}, keywords = {Algorithms, Chromosome Mapping, Computer Simulation, Gene Expression Profiling, Models, Biological, Multigene Family, Signal Transduction, Software, Systems biology, User-Computer Interface}, issn = {1471-2105}, doi = {10.1186/1471-2105-8-114}, author = {Al-Shahrour, F{\'a}tima and Arbiza, Leonardo and Dopazo, Hern{\'a}n and Huerta-Cepas, Jaime and Minguez, Pablo and Montaner, David and Dopazo, Joaquin} } @inbook {478, title = {Functional annotation of microarray experiments}, booktitle = {Microarray Technology Through Applications}, year = {2007}, publisher = {Taylor \& Francis, F. Falciani}, organization = {Taylor \& Francis, F. Falciani}, address = {New York, USA}, author = {Dopazo, J. and Fatima Al-Shahrour} } @article {17597935, title = {Functional profiling and gene expression analysis of chromosomal copy number alterations}, journal = {Bioinformation}, volume = {1}, number = {10}, year = {2007}, note = {

Conde, Lucia Montaner, David Burguet-Castell, Jordi Tarraga, Joaquin Al-Shahrour, Fatima Dopazo, Joaquin Singapore Bioinformation Bioinformation. 2007 Apr 10;1(10):432-5.

}, pages = {432-5}, abstract = {

Contrarily to the traditional view in which only one or a few key genes were supposed to be the causative factors of diseases, we discuss the importance of considering groups of functionally related genes in the study of pathologies characterised by chromosomal copy number alterations. Recent observations have reported the existence of regions in higher eukaryotic chromosomes (including humans) containing genes of related function that show a high degree of coregulation. Copy number alterations will consequently affect to clusters of functionally related genes, which will be the final causative agents of the diseased phenotype, in many cases. Therefore, we propose that the functional profiling of the regions affected by copy number alterations must be an important aspect to take into account in the understanding of this type of pathologies. To illustrate this, we present an integrated study of DNA copy number variations, gene expression along with the functional profiling of chromosomal regions in a case of multiple myeloma.

}, keywords = {babelomics}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17597935}, author = {L. Conde and Montaner, D. and Burguet-Castell, J. and Tarraga, J. and Fatima Al-Shahrour and Dopazo, J.} } @article {607, title = {Functional profiling and gene expression analysis of chromosomal copy number alterations.}, journal = {Bioinformation}, volume = {1}, year = {2007}, month = {2007 Apr 10}, pages = {432-5}, abstract = {

Contrarily to the traditional view in which only one or a few key genes were supposed to be the causative factors of diseases, we discuss the importance of considering groups of functionally related genes in the study of pathologies characterised by chromosomal copy number alterations. Recent observations have reported the existence of regions in higher eukaryotic chromosomes (including humans) containing genes of related function that show a high degree of coregulation. Copy number alterations will consequently affect to clusters of functionally related genes, which will be the final causative agents of the diseased phenotype, in many cases. Therefore, we propose that the functional profiling of the regions affected by copy number alterations must be an important aspect to take into account in the understanding of this type of pathologies. To illustrate this, we present an integrated study of DNA copy number variations, gene expression along with the functional profiling of chromosomal regions in a case of multiple myeloma.

}, issn = {0973-2063}, doi = {10.6026/97320630001432}, author = {Conde, Lucia and Montaner, David and Burguet-Castell, Jordi and T{\'a}rraga, Joaqu{\'\i}n and Al-Shahrour, F{\'a}tima and Dopazo, Joaquin} } @article {17855415, title = {Functional profiling of microarray experiments using text-mining derived bioentities}, journal = {Bioinformatics}, volume = {23}, number = {22}, year = {2007}, note = {

Minguez, Pablo Al-Shahrour, Fatima Montaner, David Dopazo, Joaquin Research Support, Non-U.S. Gov{\textquoteright}t England Bioinformatics (Oxford, England) Bioinformatics. 2007 Nov 15;23(22):3098-9. Epub 2007 Sep 13.

}, pages = {3098-9}, abstract = {

MOTIVATION: The increasing use of microarray technologies brought about a parallel demand in methods for the functional interpretation of the results. Beyond the conventional functional annotations for genes, such as gene ontology, pathways, etc. other sources of information are still to be exploited. Text-mining methods allow extracting informative terms (bioentities) with different functional, chemical, clinical, etc. meanings, that can be associated to genes. We show how to use these associations within an appropriate statistical framework and how to apply them through easy-to-use, web-based environments to the functional interpretation of microarray experiments. Functional enrichment and gene set enrichment tests using bioentities are presented.

}, keywords = {Artificial Intelligence *Databases, babelomics, Protein Gene Expression Profiling/*methods Information Storage and Retrieval/*methods *Natural Language Processing Proteins/*classification/*metabolism Research/*methods Systems Integration}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17855415}, author = {Minguez, P. and Fatima Al-Shahrour and Montaner, D. and Dopazo, J.} } @article {592, title = {Functional profiling of microarray experiments using text-mining derived bioentities.}, journal = {Bioinformatics}, volume = {23}, year = {2007}, month = {2007 Nov 15}, pages = {3098-9}, abstract = {

MOTIVATION: The increasing use of microarray technologies brought about a parallel demand in methods for the functional interpretation of the results. Beyond the conventional functional annotations for genes, such as gene ontology, pathways, etc. other sources of information are still to be exploited. Text-mining methods allow extracting informative terms (bioentities) with different functional, chemical, clinical, etc. meanings, that can be associated to genes. We show how to use these associations within an appropriate statistical framework and how to apply them through easy-to-use, web-based environments to the functional interpretation of microarray experiments. Functional enrichment and gene set enrichment tests using bioentities are presented.

}, keywords = {Artificial Intelligence, Databases, Protein, Gene Expression Profiling, Information Storage and Retrieval, Natural Language Processing, Proteins, Research Design, Systems Integration}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btm445}, author = {Minguez, Pablo and Al-Shahrour, F{\'a}tima and Montaner, David and Dopazo, Joaquin} } @article {608, title = {ISACGH: a web-based environment for the analysis of Array CGH and gene expression which includes functional profiling.}, journal = {Nucleic Acids Res}, volume = {35}, year = {2007}, month = {2007 Jul}, pages = {W81-5}, abstract = {

We present the ISACGH, a web-based system that allows for the combination of genomic data with gene expression values and provides different options for functional profiling of the regions found. Several visualization options offer a convenient representation of the results. Different efficient methods for accurate estimation of genomic copy number from array-CGH hybridization data have been included in the program. Moreover, the connection to the gene expression analysis package GEPAS allows the use of different facilities for data pre-processing and analysis. A DAS server allows exporting the results to the Ensembl viewer where contextual genomic information can be obtained. The program is freely available at: http://isacgh.bioinfo.cipf.es or within http://www.gepas.org.

}, keywords = {Animals, Cluster Analysis, Computational Biology, Computer Graphics, Gene Expression Profiling, Humans, Internet, Models, Genetic, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, Programming Languages, Software, Systems Integration, User-Computer Interface}, issn = {1362-4962}, doi = {10.1093/nar/gkm257}, author = {Conde, Lucia and Montaner, David and Burguet-Castell, Jordi and T{\'a}rraga, Joaqu{\'\i}n and Medina, Ignacio and Al-Shahrour, F{\'a}tima and Dopazo, Joaquin} } @article {17468499, title = {ISACGH: a web-based environment for the analysis of Array CGH and gene expression which includes functional profiling}, journal = {Nucleic Acids Res}, volume = {35}, number = {Web Server issue}, year = {2007}, note = {Conde, Lucia Montaner, David Burguet-Castell, Jordi Tarraga, Joaquin Medina, Ignacio Al-Shahrour, Fatima Dopazo, Joaquin Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2007 Jul;35(Web Server issue):W81-5. Epub 2007 Apr 27.}, pages = {W81-5}, abstract = {We present the ISACGH, a web-based system that allows for the combination of genomic data with gene expression values and provides different options for functional profiling of the regions found. Several visualization options offer a convenient representation of the results. Different efficient methods for accurate estimation of genomic copy number from array-CGH hybridization data have been included in the program. Moreover, the connection to the gene expression analysis package GEPAS allows the use of different facilities for data pre-processing and analysis. A DAS server allows exporting the results to the Ensembl viewer where contextual genomic information can be obtained. The program is freely available at: http://isacgh.bioinfo.cipf.es or within http://www.gepas.org.}, keywords = {Animals Cluster Analysis Computational Biology/*methods Computer Graphics Gene Expression Profiling/*methods Humans Internet Models, Genetic *Nucleic Acid Hybridization Oligonucleotide Array Sequence Analysis/*methods Programming Languages *Software Systems Integration User-Computer Interface}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17468499}, author = {L. Conde and Montaner, D. and Burguet-Castell, J. and Tarraga, J. and Medina, Ignacio and Fatima Al-Shahrour and Dopazo, J.} } @inbook {680, title = {New Trends in the Analysis of Functional Genomic Data}, booktitle = {Progress in Industrial Mathematics at ECMI 2006}, volume = {12}, year = {2007}, pages = {576-580}, publisher = {Springer}, organization = {Springer}, address = {Berlin}, issn = {978-3-540-71991-5}, doi = {10.1007/978-3-540-71992-2_94}, url = {http://www.springerlink.com/content/m62p07r8111004vr/}, author = {Montaner, D. and Fatima Al-Shahrour and Dopazo, J.} } @article {17452346, title = {Phylemon: a suite of web tools for molecular evolution, phylogenetics and phylogenomics}, journal = {Nucleic Acids Res}, volume = {35}, number = {Web Server issue}, year = {2007}, note = {Tarraga, Joaquin Medina, Ignacio Arbiza, Leonardo Huerta-Cepas, Jaime Gabaldon, Toni Dopazo, Joaquin Dopazo, Hernan Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2007 Jul;35(Web Server issue):W38-42. Epub 2007 Apr 22.}, pages = {W38-42}, abstract = {Phylemon is an online platform for phylogenetic and evolutionary analyses of molecular sequence data. It has been developed as a web server that integrates a suite of different tools selected among the most popular stand-alone programs in phylogenetic and evolutionary analysis. It has been conceived as a natural response to the increasing demand of data analysis of many experimental scientists wishing to add a molecular evolution and phylogenetics insight into their research. Tools included in Phylemon cover a wide yet selected range of programs: from the most basic for multiple sequence alignment to elaborate statistical methods of phylogenetic reconstruction including methods for evolutionary rates analyses and molecular adaptation. Phylemon has several features that differentiates it from other resources: (i) It offers an integrated environment that enables the direct concatenation of evolutionary analyses, the storage of results and handles required data format conversions, (ii) Once an outfile is produced, Phylemon suggests the next possible analyses, thus guiding the user and facilitating the integration of multi-step analyses, and (iii) users can define and save complete pipelines for specific phylogenetic analysis to be automatically used on many genes in subsequent sessions or multiple genes in a single session (phylogenomics). The Phylemon web server is available at http://phylemon.bioinfo.cipf.es.}, keywords = {Animals Computational Biology/*methods Databases, DNA Sequence Analysis, Genetic Evolution, Molecular Genetic Techniques Humans *Internet Models, Protein Software User-Computer Interface, Statistical *Phylogeny Programming Languages Sequence Alignment Sequence Analysis}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17452346}, author = {Tarraga, J. and Medina, Ignacio and Arbiza, L. and Huerta-Cepas, J. and Gabald{\'o}n, T. and Dopazo, J. and H. Dopazo} } @article {17617431, title = {Transcriptional response of Citrus aurantifolia to infection by Citrus tristeza virus}, journal = {Virology}, volume = {367}, number = {2}, year = {2007}, note = {Gandia, Monica Conesa, Ana Ancillo, Gema Gadea, Jose Forment, Javier Pallas, Vicente Flores, Ricardo Duran-Vila, Nuria Moreno, Pedro Guerri, Jose Research Support, Non-U.S. Gov{\textquoteright}t United States Virology Virology. 2007 Oct 25;367(2):298-306. Epub 2007 Jul 9.}, pages = {298-306}, abstract = {Changes in gene expression of Mexican lime plants in response to infection with a severe (T305) or a mild (T385) isolate of Citrus tristeza virus (CTV) were analyzed using a cDNA microarray containing 12,672 probes to 6875 different citrus genes. Statistically significant (P<0.01) expression changes of 334 genes were detected in response to infection with isolate T305, whereas infection with T385 induced no significant change. Induced genes included 145 without significant similarity with known sequences and 189 that were classified in seven functional categories. Genes related with response to stress and defense were the main category and included 28\% of the genes induced. Selected transcription changes detected by microarray analysis were confirmed by quantitative real-time RT-PCR. Changes detected in the transcriptome upon infecting lime with T305 may be associated either with symptom expression, with a strain-specific defense mechanism, or with a general response to stress.}, keywords = {Citrus/*genetics/physiology/virology Closterovirus/genetics/*physiology Genes, Genetic, Plant Oligonucleotide Array Sequence Analysis Reverse Transcriptase Polymerase Chain Reaction *Transcription}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17617431}, author = {Gandia, M. and A. Conesa and Ancillo, G. and J. Gadea and J. Forment and Pallas, V. and Flores, R. and Duran-Vila, N. and Moreno, P. and Guerri, J.} } @article {16845052, title = {BABELOMICS: a systems biology perspective in the functional annotation of genome-scale experiments}, journal = {Nucleic Acids Res}, volume = {34}, year = {2006}, note = {

Al-Shahrour, Fatima Minguez, Pablo Tarraga, Joaquin Montaner, David Alloza, Eva Vaquerizas, Juan M Conde, Lucia Blaschke, Christian Vera, Javier Dopazo, Joaquin Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W472-6.

}, pages = {W472-6}, abstract = {

We present a new version of Babelomics, a complete suite of web tools for functional analysis of genome-scale experiments, with new and improved tools. New functionally relevant terms have been included such as CisRed motifs or bioentities obtained by text-mining procedures. An improved indexing has considerably speeded up several of the modules. An improved version of the FatiScan method for studying the coordinate behaviour of groups of functionally related genes is presented, along with a similar tool, the Gene Set Enrichment Analysis. Babelomics is now more oriented to test systems biology inspired hypotheses. Babelomics can be found at http://www.babelomics.org.

}, keywords = {babelomics, functional profiling}, url = {http://nar.oxfordjournals.org/content/34/suppl_2/W472.long}, author = {Fatima Al-Shahrour and Minguez, P. and Tarraga, J. and Montaner, D. and Alloza, E. and Vaquerizas, J. M. and L. Conde and Blaschke, C. and Vera, J. and Dopazo, J.} } @article {16823138, title = {Blast2GO goes grid: developing a grid-enabled prototype for functional genomics analysis}, journal = {Stud Health Technol Inform}, volume = {120}, year = {2006}, note = {

Aparicio, G Gotz, S Conesa, A Segrelles, D Blanquer, I Garcia, J M Hernandez, V Robles, M Talon, M Netherlands Studies in health technology and informatics Stud Health Technol Inform. 2006;120:194-204.

}, pages = {194-204}, abstract = {

The vast amount in complexity of data generated in Genomic Research implies that new dedicated and powerful computational tools need to be developed to meet their analysis requirements. Blast2GO (B2G) is a bioinformatics tool for Gene Ontology-based DNA or protein sequence annotation and function-based data mining. The application has been developed with the aim of affering an easy-to-use tool for functional genomics research. Typical B2G users are middle size genomics labs carrying out sequencing, ETS and microarray projects, handling datasets up to several thousand sequences. In the current version of B2G. The power and analytical potential of both annotation and function data-mining is somehow restricted to the computational power behind each particular installation. In order to be able to offer the possibility of an enhanced computational capacity within this bioinformatics application, a Grid component is being developed. A prototype has been conceived for the particular problem of speeding up the Blast searches to obtain fast results for large datasets. Many efforts have been done in the literature concerning the speeding up of Blast searches, but few of them deal with the use of large heterogeneous production Grid Infrastructures. These are the infrastructures that could reach the largest number of resources and the best load balancing for data access. The Grid Service under development will analyse requests based on the number of sequences, splitting them accordingly to the available resources. Lower-level computation will be performed through MPIBLAST. The software architecture is based on the WSRF standard.

}, keywords = {babelomics}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16823138}, author = {Aparicio, G. and Gotz, S. and A. Conesa and Segrelles, D. and Blanquer, I. and Garcia, J. M. and Hernandez, V. and Robles, M. and Talon, M.} } @article {16522224, title = {Discovery and hypothesis generation through bioinformatics}, journal = {Genome Biol}, volume = {7}, number = {2}, year = {2006}, note = {Dopazo, Joaquin Aloy, Patrick Congresses England Genome biology Genome Biol. 2006;7(2):307. Epub 2006 Feb 27.}, pages = {307}, abstract = {A report on the 4th European Conference on Computational Biology and the 6th Spanish Annual Meeting on Bioinformatics, Madrid, Spain, 28 September-1 October 2005.}, keywords = {*Computational Biology Genome, Genetic Phylogeny, Human *Genomics Humans *Models}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16522224}, author = {Dopazo, J. and Aloy, P.} } @article {17503379, title = {A function-centric approach to the biological interpretation of microarray time-series}, journal = {Genome Inform}, volume = {17}, number = {2}, year = {2006}, note = {

Minguez, Pablo Al-Shahrour, Fatima Dopazo, Joaquin Research Support, Non-U.S. Gov{\textquoteright}t Japan Genome informatics. International Conference on Genome Informatics Genome Inform. 2006;17(2):57-66.

}, pages = {57-66}, abstract = {

The interpretation of microarray experiments is commonly addressed by means a two-step approach in which the relevant genes are firstly selected uniquely on the basis of their experimental values (ignoring their coordinate behaviors) and in a second step their functional properties are studied to hypothesize about the biological roles they are fulfilling in the cell. Recently, different methods (e.g. GSEA or FatiScan) have been proposed to study the coordinate behavior of blocks of functionally-related genes. These methods study the distribution of functional information across lists of genes ranked according their different experimental values in a static situation, such as the comparison between two classes (e.g. healthy controls versus diseased cases). Nevertheless there is no an equivalent way of studying a dynamic situation from a functional point of view. We present a method for the functional analysis of microarrays series in which the experiments display autocorrelation between successive points (e.g. time series, dose-response experiments, etc.) The method allows to recover the dynamics of the molecular roles fulfilled by the genes along the series which provides a novel approach to functional interpretation of such experiments. The method finds blocks of functionally-related genes which are significantly and coordinately over-expressed at different points of the series. This method draws inspiration from systems biology given that the analysis does not focus on individual properties of genes but on collective behaving blocks of functionally-related genes. The FatiScan algorithm used in the method proposed is available at: http://fatiscan.bioinfo.cipf.es, or within the Babelomics suite: http://www.babelomics.org. Additional material is available at: http://bioinfo.cipf.es/data/plasmodium.

}, keywords = {babelomics}, author = {Minguez, P. and Fatima Al-Shahrour and Dopazo, J.} } @article {16461302, title = {Identification of overexpressed genes in frequently gained/amplified chromosome regions in multiple myeloma}, journal = {Haematologica}, volume = {91}, number = {2}, year = {2006}, note = {Largo, Cristina Alvarez, Sara Saez, Borja Blesa, David Martin-Subero, Jose I Gonzalez-Garcia, Ines Brieva, Jose A Dopazo, Joaquin Siebert, Reiner Calasanz, Maria J Cigudosa, Juan C Research Support, Non-U.S. Gov{\textquoteright}t Italy Haematologica Haematologica. 2006 Feb;91(2):184-91.}, pages = {184-91}, abstract = {BACKGROUND AND OBJECTIVES: Multiple myeloma (MM) is a malignancy characterized by clonal expansion of plasma cells. In 50\% of the cases, the neoplastic transformation begins with a chromosomal translocation that juxtaposes the IGH gene locus to an oncogene. Gene copy number changes are also frequent in MM but less characterized than in other neoplasias. We aimed to characterize genes that are amplified and overexpressed in human myeloma cell lines (HMCL) to provide putative molecular targets for MM therapy. DESIGN AND METHODS: Nine HMCL were characterized by fluorescent in situ hybridization, comparative genomic hybridization (CGH) and cDNA microarrays for gene expression profiling and copy number changes. RESULTS: After defining the IGH-translocations present in the cell lines, we conducted expression-profiling analysis. Supervised analysis identified 166 genes with significantly different expression among the cell lines harboring MMSET/FGFR3 (4p16), MAF (16q) and CCND1 (11q13) rearrangements. Array-CGH was then performed. Five chromosomes recurrently affected by gains/amplifications in primary samples and cell lines were analyzed in detail. Sixty amplified and overexpressed genes were found and 25 (42\%) of them were only overexpressed when amplified; moreover, six showed a significant association between overexpression and gain/amplification. We also found co-amplification and overexpression for genes located within the same amplicons, such as MALT1 and BCL2. INTERPRETATION AND CONCLUSIONS: Parallel analysis of gene copy numbers and expression levels by cDNA microarray in MM allowed efficient identification of genes whose expression levels are elevated because of increased copy number. This is the first time that MALT1 and BCL2 have been shown to be overexpressed and amplified in MM.}, keywords = {B-Cell, Caspases Cell Line, Human *Gene Amplification Gene Dosage Gene Expression Profiling *Gene Expression Regulation, Marginal Zone/genetics Multiple Myeloma/*genetics Neoplasm Proteins/genetics Proto-Oncogene Proteins c-bcl-2/genetics, Neoplasm Humans Immunoglobulin Heavy Chains/genetics Lymphoma, Neoplastic Gene Rearrangement *Genes, Tumor *Chromosomes}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16461302}, author = {Largo, C. and Alvarez, S. and Saez, B. and Blesa, D. and Martin-Subero, J. I. and Gonzalez-Garcia, I. and Brieva, J. A. and Dopazo, J. and Siebert, R. and Calasanz, M. J. and Cigudosa, J. C.} } @article {16845056, title = {Next station in microarray data analysis: GEPAS}, journal = {Nucleic Acids Res}, volume = {34}, year = {2006}, note = {

Montaner, David Tarraga, Joaquin Huerta-Cepas, Jaime Burguet, Jordi Vaquerizas, Juan M Conde, Lucia Minguez, Pablo Vera, Javier Mukherjee, Sach Valls, Joan Pujana, Miguel A G Alloza, Eva Herrero, Javier Al-Shahrour, Fatima Dopazo, Joaquin Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W486-91.

}, pages = {W486-91}, abstract = {

The Gene Expression Profile Analysis Suite (GEPAS) has been running for more than four years. During this time it has evolved to keep pace with the new interests and trends in the still changing world of microarray data analysis. GEPAS has been designed to provide an intuitive although powerful web-based interface that offers diverse analysis options from the early step of preprocessing (normalization of Affymetrix and two-colour microarray experiments and other preprocessing options), to the final step of the functional annotation of the experiment (using Gene Ontology, pathways, PubMed abstracts etc.), and include different possibilities for clustering, gene selection, class prediction and array-comparative genomic hybridization management. GEPAS is extensively used by researchers of many countries and its records indicate an average usage rate of 400 experiments per day. The web-based pipeline for microarray gene expression data, GEPAS, is available at http://www.gepas.org.

}, keywords = {gepas, microarray data analysis}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16845056}, author = {Montaner, D. and Tarraga, J. and Huerta-Cepas, J. and Burguet, J. and Vaquerizas, J. M. and L. Conde and Minguez, P. and Vera, J. and Mukherjee, S. and Valls, J. and Pujana, M. A. and Alloza, E. and Herrero, J. and Fatima Al-Shahrour and Dopazo, J.} } @article {16671401, title = {Ontology-driven approaches to analyzing data in functional genomics}, journal = {Methods Mol Biol}, volume = {316}, year = {2006}, note = {

Azuaje, Francisco Al-Shahrour, Fatima Dopazo, Joaquin Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov{\textquoteright}t Review United States Methods in molecular biology (Clifton, N.J.) Methods Mol Biol. 2006;316:67-86.

}, pages = {67-86}, abstract = {

Ontologies are fundamental knowledge representations that provide not only standards for annotating and indexing biological information, but also the basis for implementing functional classification and interpretation models. This chapter discusses the application of gene ontology (GO) for predictive tasks in functional genomics. It focuses on the problem of analyzing functional patterns associated with gene products. This chapter is divided into two main parts. The first part overviews GO and its applications for the development of functional classification models. The second part presents two methods for the characterization of genomic information using GO. It discusses methods for measuring functional similarity of gene products, and a tool for supporting gene expression clustering analysis and validation.

}, keywords = {babelomics, Cluster Analysis, Cluster Analysis Computational Biology/*methods *Data Interpretation, Computational Biology, Statistical Gene Expression Profiling, Statistical Gene Expression Profiling *Genomics Humans}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16671401}, author = {F. Azuaje and Fatima Al-Shahrour and Dopazo, J.} } @article {16683019, title = {Positive selection, relaxation, and acceleration in the evolution of the human and chimp genome}, journal = {PLoS Comput Biol}, volume = {2}, number = {4}, year = {2006}, note = {Arbiza, Leonardo Dopazo, Joaquin Dopazo, Hernan Research Support, Non-U.S. Gov{\textquoteright}t United States PLoS computational biology PLoS Comput Biol. 2006 Apr;2(4):e38. Epub 2006 Apr 28.}, pages = {e38}, abstract = {For years evolutionary biologists have been interested in searching for the genetic bases underlying humanness. Recent efforts at a large or a complete genomic scale have been conducted to search for positively selected genes in human and in chimp. However, recently developed methods allowing for a more sensitive and controlled approach in the detection of positive selection can be employed. Here, using 13,198 genes, we have deduced the sets of genes involved in rate acceleration, positive selection, and relaxation of selective constraints in human, in chimp, and in their ancestral lineage since the divergence from murids. Significant deviations from the strict molecular clock were observed in 469 human and in 651 chimp genes. The more stringent branch-site test of positive selection detected 108 human and 577 chimp positively selected genes. An important proportion of the positively selected genes did not show a significant acceleration in rates, and similarly, many of the accelerated genes did not show significant signals of positive selection. Functional differentiation of genes under rate acceleration, positive selection, and relaxation was not statistically significant between human and chimp with the exception of terms related to G-protein coupled receptors and sensory perception. Both of these were over-represented under relaxation in human in relation to chimp. Comparing differences between derived and ancestral lineages, a more conspicuous change in trends seems to have favored positive selection in the human lineage. Since most of the positively selected genes are different under the same functional categories between these species, we suggest that the individual roles of the alternative positively selected genes may be an important factor underlying biological differences between these species.}, keywords = {Adaptation, Biological/genetics Animals *Evolution, Molecular Genome/*genetics Humans Pan troglodytes/*genetics *Selection (Genetics)}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16683019}, author = {Arbiza, L. and Dopazo, J. and H. Dopazo} } @article {16845085, title = {PupaSuite: finding functional single nucleotide polymorphisms for large-scale genotyping purposes}, journal = {Nucleic Acids Res}, volume = {34}, number = {Web Server issue}, year = {2006}, note = {

Conde, Lucia Vaquerizas, Juan M Dopazo, Hernan Arbiza, Leonardo Reumers, Joke Rousseau, Frederic Schymkowitz, Joost Dopazo, Joaquin Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W621-5.

}, pages = {W621-5}, abstract = {

We have developed a web tool, PupaSuite, for the selection of single nucleotide polymorphisms (SNPs) with potential phenotypic effect, specifically oriented to help in the design of large-scale genotyping projects. PupaSuite uses a collection of data on SNPs from heterogeneous sources and a large number of pre-calculated predictions to offer a flexible and intuitive interface for selecting an optimal set of SNPs. It improves the functionality of PupaSNP and PupasView programs and implements new facilities such as the analysis of user{\textquoteright}s data to derive haplotypes with functional information. A new estimator of putative effect of polymorphisms has been included that uses evolutionary information. Also SNPeffect database predictions have been included. The PupaSuite web interface is accessible through http://pupasuite.bioinfo.cipf.es and through http://www.pupasnp.org.

}, keywords = {Algorithms Computer Graphics Databases, Molecular Genotype Haplotypes Internet Linkage Disequilibrium *Polymorphism, Nucleic Acid Evolution, Single Nucleotide *Software User-Computer Interface}, url = {http://nar.oxfordjournals.org/cgi/content/full/34/suppl_2/W621}, author = {L. Conde and Vaquerizas, J. M. and H. Dopazo and Arbiza, L. and Reumers, J. and Rousseau, F. and Schymkowitz, J. and Dopazo, J.} } @article {16584746, title = {Selective pressures at a codon-level predict deleterious mutations in human disease genes}, journal = {J Mol Biol}, volume = {358}, number = {5}, year = {2006}, note = {Arbiza, Leonardo Duchi, Serena Montaner, David Burguet, Jordi Pantoja-Uceda, David Pineda-Lucena, Antonio Dopazo, Joaquin Dopazo, Hernan Research Support, Non-U.S. Gov{\textquoteright}t England Journal of molecular biology J Mol Biol. 2006 May 19;358(5):1390-404. Epub 2006 Mar 15.}, pages = {1390-404}, abstract = {Deleterious mutations affecting biological function of proteins are constantly being rejected by purifying selection from the gene pool. The non-synonymous/synonymous substitution rate ratio (omega) is a measure of selective pressure on amino acid replacement mutations for protein-coding genes. Different methods have been developed in order to predict non-synonymous changes affecting gene function. However, none has considered the estimation of selective constraints acting on protein residues. Here, we have used codon-based maximum likelihood models in order to estimate the selective pressures on the individual amino acid residues of a well-known model protein: p53. We demonstrate that the number of residues under strong purifying selection in p53 is much higher than those that are strictly conserved during the evolution of the species. In agreement with theoretical expectations, residues that have been noted to be of structural relevance, or in direct association with DNA, were among those showing the highest signals of purifying selection. Conversely, those changing according to a neutral, or nearly neutral mode of evolution, were observed to be irrelevant for protein function. Finally, using more than 40 human disease genes, we demonstrate that residues evolving under strong selective pressures (omega<0.1) are significantly associated (p<0.01) with human disease. We hypothesize that non-synonymous change on amino acids showing omega<0.1 will most likely affect protein function. The application of this evolutionary prediction at a genomic scale will provide an a priori hypothesis of the phenotypic effect of non-synonymous coding single nucleotide polymorphisms (SNPs) in the human genome.}, keywords = {Amino Acid Sequence Amino Acid Substitution Codon/*genetics Databases, Genetic Evolution, Genetic Models, Human Humans Models, Inborn/*genetics Genome, Molecular Genes, Molecular Molecular Sequence Data *Mutation Neoplasms/genetics Proteins/genetics *Selection (Genetics) Tumor Suppressor Protein p53/chemistry/genetics, p53 Genetic Diseases}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16584746}, author = {Arbiza, L. and Duchi, S. and Montaner, D. and Burguet, J. and Pantoja-Uceda, D. and Pineda-Lucena, A. and Dopazo, J. and H. Dopazo} } @article {15980512, title = {BABELOMICS: a suite of web tools for functional annotation and analysis of groups of genes in high-throughput experiments}, journal = {Nucleic Acids Res}, volume = {33}, year = {2005}, note = {

Al-Shahrour, Fatima Minguez, Pablo Vaquerizas, Juan M Conde, Lucia Dopazo, Joaquin Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W460-4.

}, pages = {W460-4}, abstract = {

We present Babelomics, a complete suite of web tools for the functional analysis of groups of genes in high-throughput experiments, which includes the use of information on Gene Ontology terms, interpro motifs, KEGG pathways, Swiss-Prot keywords, analysis of predicted transcription factor binding sites, chromosomal positions and presence in tissues with determined histological characteristics, through five integrated modules: FatiGO (fast assignment and transference of information), FatiWise, transcription factor association test, GenomeGO and tissues mining tool, respectively. Additionally, another module, FatiScan, provides a new procedure that integrates biological information in combination with experimental results in order to find groups of genes with modest but coordinate significant differential behaviour. FatiScan is highly sensitive and is capable of finding significant asymmetries in the distribution of genes of common function across a list of ordered genes even if these asymmetries were not extreme. The strong multiple-testing nature of the contrasts made by the tools is taken into account. All the tools are integrated in the gene expression analysis package GEPAS. Babelomics is the natural evolution of our tool FatiGO (which analysed almost 22,000 experiments during the last year) to include more sources on information and new modes of using it. Babelomics can be found at http://www.babelomics.org.

}, keywords = {babelomics, functional profiling}, url = {http://nar.oxfordjournals.org/content/33/suppl_2/W460.long}, author = {Fatima Al-Shahrour and Minguez, P. and Vaquerizas, J. M. and L. Conde and Dopazo, J.} } @inbook {482, title = {Data analysis and visualisation in genomics and proteomics}, year = {2005}, publisher = {Wiley, F. Azuaje and J. Dopazo}, organization = {Wiley, F. Azuaje and J. Dopazo}, keywords = {babelomics}, author = {F. Azuaje and Dopazo, J.} } @inbook {489, title = {Data and Predictive Model Integration: an Overview of Key Concepts, Problems and Solutions}, booktitle = {Data analysis and visualisation in genomics and proteomics}, year = {2005}, publisher = {Wiley, F. Azuaje and J. Dopazo}, organization = {Wiley, F. Azuaje and J. Dopazo}, author = {F. Azuaje and Dopazo, J. and Wang, H} } @article {15883372, title = {Detecting remotely related proteins by their interactions and sequence similarity}, journal = {Proc Natl Acad Sci U S A}, volume = {102}, number = {20}, year = {2005}, note = {Espadaler, Jordi Aragues, Ramon Eswar, Narayanan Marti-Renom, Marc A Querol, Enrique Aviles, Francesc X Sali, Andrej Oliva, Baldomero R01 GM54762/GM/NIGMS NIH HHS/United States Comparative Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, P.H.S. United States Proceedings of the National Academy of Sciences of the United States of America Proc Natl Acad Sci U S A. 2005 May 17;102(20):7151-6. Epub 2005 May 9.}, pages = {7151-6}, abstract = {The function of an uncharacterized protein is usually inferred either from its homology to, or its interactions with, characterized proteins. Here, we use both sequence similarity and protein interactions to identify relationships between remotely related protein sequences. We rely on the fact that homologous sequences share similar interactions, and, therefore, the set of interacting partners of the partners of a given protein is enriched by its homologs. The approach was bench-marked by assigning the fold and functional family to test sequences of known structure. Specifically, we relied on 1,434 proteins with known folds, as defined in the Structural Classification of Proteins (SCOP) database, and with known interacting partners, as defined in the Database of Interacting Proteins (DIP). For this subset, the specificity of fold assignment was increased from 54\% for position-specific iterative BLAST to 75\% for our approach, with a concomitant increase in sensitivity for a few percentage points. Similarly, the specificity of family assignment at the e-value threshold of 10(-8) was increased from 70\% to 87\%. The proposed method would be a useful tool for large-scale automated discovery of remote relationships between protein sequences, given its unique reliance on sequence similarity and protein-protein interactions.}, keywords = {Amino Acid, Computational Biology Databases, Molecular Protein Conformation Protein Folding Proteins/*genetics/*metabolism Proteomics/*methods *Sequence Homology, Protein *Evolution}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15883372}, author = {Espadaler, J. and Aragues, R. and Eswar, N. and M. A. Marti-Renom and Querol, E. and Aviles, F. X. and Sali, A. and Oliva, B.} } @article {15830128, title = {Development of a citrus genome-wide EST collection and cDNA microarray as resources for genomic studies}, journal = {Plant Mol Biol}, volume = {57}, number = {3}, year = {2005}, note = {Forment, J Gadea, J Huerta, L Abizanda, L Agusti, J Alamar, S Alos, E Andres, F Arribas, R Beltran, J P Berbel, A Blazquez, M A Brumos, J Canas, L A Cercos, M Colmenero-Flores, J M Conesa, A Estables, B Gandia, M Garcia-Martinez, J L Gimeno, J Gisbert, A Gomez, G Gonzalez-Candelas, L Granell, A Guerri, J Lafuente, M T Madueno, F Marcos, J F Marques, M C Martinez, F Martinez-Godoy, M A Miralles, S Moreno, P Navarro, L Pallas, V Perez-Amador, M A Perez-Valle, J Pons, C Rodrigo, I Rodriguez, P L Royo, C Serrano, R Soler, G Tadeo, F Talon, M Terol, J Trenor, M Vaello, L Vicente, O Vidal, Ch Zacarias, L Conejero, V Comparative Study Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S. Netherlands Plant molecular biology Plant Mol Biol. 2005 Feb;57(3):375-91.}, pages = {375-91}, abstract = {A functional genomics project has been initiated to approach the molecular characterization of the main biological and agronomical traits of citrus. As a key part of this project, a citrus EST collection has been generated from 25 cDNA libraries covering different tissues, developmental stages and stress conditions. The collection includes a total of 22,635 high-quality ESTs, grouped in 11,836 putative unigenes, which represent at least one third of the estimated number of genes in the citrus genome. Functional annotation of unigenes which have Arabidopsis orthologues (68\% of all unigenes) revealed gene representation in every major functional category, suggesting that a genome-wide EST collection was obtained. A Citrus clementina Hort. ex Tan. cv. Clemenules genomic library, that will contribute to further characterization of relevant genes, has also been constructed. To initiate the analysis of citrus transcriptome, we have developed a cDNA microarray containing 12,672 probes corresponding to 6875 putative unigenes of the collection. Technical characterization of the microarray showed high intra- and inter-array reproducibility, as well as a good range of sensitivity. We have also validated gene expression data achieved with this microarray through an independent technique such as RNA gel blot analysis.}, keywords = {Citrus/*genetics DNA, Complementary/chemistry/genetics *Expressed Sequence Tags Gene Expression Profiling Gene Library *Genome, DNA, Plant Genomics/*methods Molecular Sequence Data Oligonucleotide Array Sequence Analysis/*methods RNA, Plant/genetics/metabolism Reproducibility of Results Sequence Analysis}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15830128}, author = {J. Forment and J. Gadea and Huerta, L. and Abizanda, L. and Agusti, J. and Alamar, S. and Alos, E. and Andres, F. and Arribas, R. and Beltran, J. P. and Berbel, A. and Blazquez, M. A. and Brumos, J. and Canas, L. A. and Cercos, M. and Colmenero-Flores, J. M. and A. Conesa and Estables, B. and Gandia, M. and Garcia-Martinez, J. L. and Gimeno, J. and Gisbert, A. and Gomez, G. and Gonzalez-Candelas, L. and Granell, A. and Guerri, J. and Lafuente, M. T. and Madueno, F. and Marcos, J. F. and Marques, M. C. and Martinez, F. and Martinez-Godoy, M. A. and Miralles, S. and Moreno, P. and Navarro, L. and Pallas, V. and Perez-Amador, M. A. and Perez-Valle, J. and Pons, C. and Rodrigo, I. and Rodriguez, P. L. and Royo, C. and Serrano, R. and Soler, G. and Tadeo, F. and Talon, M. and Terol, J. and Trenor, M. and Vaello, L. and Vicente, O. and Vidal, Ch and Zacarias, L. and Conejero, V.} } @article {15840702, title = {Discovering molecular functions significantly related to phenotypes by combining gene expression data and biological information}, journal = {Bioinformatics}, volume = {21}, number = {13}, year = {2005}, note = {

Al-Shahrour, Fatima Diaz-Uriarte, Ramon Dopazo, Joaquin Evaluation Studies Research Support, Non-U.S. Gov{\textquoteright}t England Bioinformatics (Oxford, England) Bioinformatics. 2005 Jul 1;21(13):2988-93. Epub 2005 Apr 19.

}, pages = {2988-93}, abstract = {

MOTIVATION: The analysis of genome-scale data from different high throughput techniques can be used to obtain lists of genes ordered according to their different behaviours under distinct experimental conditions corresponding to different phenotypes (e.g. differential gene expression between diseased samples and controls, different response to a drug, etc.). The order in which the genes appear in the list is a consequence of the biological roles that the genes play within the cell, which account, at molecular scale, for the macroscopic differences observed between the phenotypes studied. Typically, two steps are followed for understanding the biological processes that differentiate phenotypes at molecular level: first, genes with significant differential expression are selected on the basis of their experimental values and subsequently, the functional properties of these genes are analysed. Instead, we present a simple procedure which combines experimental measurements with available biological information in a way that genes are simultaneously tested in groups related by common functional properties. The method proposed constitutes a very sensitive tool for selecting genes with significant differential behaviour in the experimental conditions tested. RESULTS: We propose the use of a method to scan ordered lists of genes. The method allows the understanding of the biological processes operating at molecular level behind the macroscopic experiment from which the list was generated. This procedure can be useful in situations where it is not possible to obtain statistically significant differences based on the experimental measurements (e.g. low prevalence diseases, etc.). Two examples demonstrate its application in two microarray experiments and the type of information that can be extracted.

}, keywords = {babelomics, Biological Neoplasm Proteins/genetics/*metabolism Phenotype Software Structure-Activity Relationship Systems Integration Tumor Markers, Biological/genetics/*metabolism, Breast Neoplasms/genetics/*metabolism Computer Simulation *Database Management Systems *Databases, Protein Documentation/methods Gene Expression Profiling/*methods Humans *Models}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15840702}, author = {Fatima Al-Shahrour and Diaz-Uriarte, R. and Dopazo, J.} } @article {15980548, title = {GEPAS, an experiment-oriented pipeline for the analysis of microarray gene expression data}, journal = {Nucleic Acids Res}, volume = {33}, year = {2005}, note = {

Vaquerizas, Juan M Conde, Lucia Yankilevich, Patricio Cabezon, Amaya Minguez, Pablo Diaz-Uriarte, Ramon Al-Shahrour, Fatima Herrero, Javier Dopazo, Joaquin Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W616-20.

}, pages = {W616-20}, abstract = {

The Gene Expression Profile Analysis Suite, GEPAS, has been running for more than three years. With \>76,000 experiments analysed during the last year and a daily average of almost 300 analyses, GEPAS can be considered a well-established and widely used platform for gene expression microarray data analysis. GEPAS is oriented to the analysis of whole series of experiments. Its design and development have been driven by the demands of the biomedical community, probably the most active collective in the field of microarray users. Although clustering methods have obviously been implemented in GEPAS, our interest has focused more on methods for finding genes differentially expressed among distinct classes of experiments or correlated to diverse clinical outcomes, as well as on building predictors. There is also a great interest in CGH-arrays which fostered the development of the corresponding tool in GEPAS: InSilicoCGH. Much effort has been invested in GEPAS for developing and implementing efficient methods for functional annotation of experiments in the proper statistical framework. Thus, the popular FatiGO has expanded to a suite of programs for functional annotation of experiments, including information on transcription factor binding sites, chromosomal location and tissues. The web-based pipeline for microarray gene expression data, GEPAS, is available at http://www.gepas.org.

}, keywords = {gepas, microarray data analysis}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15980548}, author = {Vaquerizas, J. M. and L. Conde and Yankilevich, P. and Cabezon, A. and Minguez, P. and Diaz-Uriarte, R. and Fatima Al-Shahrour and Herrero, J. and Dopazo, J.} } @inbook {488, title = {Integrative Data Analysis and Visualization: Introduction to Critical Problems, Goals and Challenges}, booktitle = {Data analysis and visualisation in genomics and proteomics}, year = {2005}, pages = {3-9}, publisher = {Wiley, F. Azuaje and J. Dopazo}, organization = {Wiley, F. Azuaje and J. Dopazo}, author = {F. Azuaje and Dopazo, J.} } @inbook {485, title = {Ontologies and functional genomics}, booktitle = {Data analysis and visualisation in genomics and proteomics}, year = {2005}, pages = {99-102}, publisher = {Wiley, F. Azuaje and J. Dopazo}, organization = {Wiley, F. Azuaje and J. Dopazo}, author = {Fatima Al-Shahrour and Dopazo, J.} } @article {15770521, title = {Phenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers}, journal = {Breast Cancer Res Treat}, volume = {90}, number = {1}, year = {2005}, note = {Palacios, Jose Honrado, Emiliano Osorio, Ana Cazorla, Alicia Sarrio, David Barroso, Alicia Rodriguez, Sandra Cigudosa, Juan C Diez, Orland Alonso, Carmen Lerma, Enrique Dopazo, Joaquin Rivas, Carmen Benitez, Javier Research Support, Non-U.S. Gov{\textquoteright}t Netherlands Breast cancer research and treatment Breast Cancer Res Treat. 2005 Mar;90(1):5-14.}, pages = {5-14}, abstract = {Familial breast cancers that are associated with BRCA1 or BRCA2 germline mutations differ in both their morphological and immunohistochemical characteristics. To further characterize the molecular difference between genotypes, the authors evaluated the expression of 37 immunohistochemical markers in a tissue microarray (TMA) containing cores from 20 BRCA1, 14 BRCA2, and 59 sporadic age-matched breast carcinomas. Markers analyzed included, amog others, common markers in breast cancer, such as hormone receptors, p53 and HER2, along with 15 molecules involved in cell cycle regulation, such as cyclins, cyclin dependent kinases (CDK) and CDK inhibitors (CDKI), apoptosis markers, such as BCL2 and active caspase 3, and two basal/myoepithelial markers (CK 5/6 and P-cadherin). In addition, we analyzed the amplification of CCND1, CCNE, HER2 and MYC by FISH.Unsupervised cluster data analysis of both hereditary and sporadic cases using the complete set of immunohistochemical markers demonstrated that most BRCA1-associated carcinomas grouped in a branch of ER-, HER2-negative tumors that expressed basal cell markers and/or p53 and had higher expression of activated caspase 3. The cell cycle proteins associated with these tumors were E2F6, cyclins A, B1 and E, SKP2 and Topo IIalpha. In contrast, most BRCA2-associated carcinomas grouped in a branch composed by ER/PR/BCL2-positive tumors with a higher expression of the cell cycle proteins cyclin D1, cyclin D3, p27, p16, p21, CDK4, CDK2 and CDK1. In conclusion, our study in hereditary breast cancer tumors analyzing 37 immunohistochemical markers, define the molecular differences between BRCA1 and BRCA2 tumors with respect to hormonal receptors, cell cycle, apoptosis and basal cell markers.}, keywords = {Adult Apoptosis Breast Neoplasms/*genetics/*pathology Cell Cycle Proteins Cluster Analysis Female *Genes, Biological/genetics/metabolism, BRCA1 *Genes, BRCA2 Humans Immunohistochemistry In Situ Hybridization, Fluorescence Phenotype Spain *Tissue Array Analysis *Tumor Markers}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15770521}, author = {Palacios, J. and Honrado, E. and Osorio, A. and Cazorla, A. and Sarrio, D. and Barroso, A. and Rodriguez, S. and Cigudosa, J. C. and Diez, O. and Alonso, C. and Lerma, E. and Dopazo, J. and Rivas, C. and Benitez, J.} } @article {15709182, title = {A predictor based on the somatic genomic changes of the BRCA1/BRCA2 breast cancer tumors identifies the non-BRCA1/BRCA2 tumors with BRCA1 promoter hypermethylation}, journal = {Clin Cancer Res}, volume = {11}, number = {3}, year = {2005}, note = {Alvarez, Sara Diaz-Uriarte, Ramon Osorio, Ana Barroso, Alicia Melchor, Lorenzo Paz, Maria Fe Honrado, Emiliano Rodriguez, Raquel Urioste, Miguel Valle, Laura Diez, Orland Cigudosa, Juan Cruz Dopazo, Joaquin Esteller, Manel Benitez, Javier Comparative Study Research Support, Non-U.S. Gov{\textquoteright}t United States Clinical cancer research : an official journal of the American Association for Cancer Research Clin Cancer Res. 2005 Feb 1;11(3):1146-53.}, pages = {1146-53}, abstract = {The genetic changes underlying in the development and progression of familial breast cancer are poorly understood. To identify a somatic genetic signature of tumor progression for each familial group, BRCA1, BRCA2, and non-BRCA1/BRCA2 (BRCAX) tumors, by high-resolution comparative genomic hybridization, we have analyzed 77 tumors previously characterized for BRCA1 and BRCA2 germ line mutations. Based on a combination of the somatic genetic changes observed at the six most different chromosomal regions and the status of the estrogen receptor, we developed using random forests a molecular classifier, which assigns to a given tumor a probability to belong either to the BRCA1 or to the BRCA2 class. Because 76.5\% (26 of 34) of the BRCAX cases were classified with our predictor to the BRCA1 class with a probability of >50\%, we analyzed the BRCA1 promoter region for aberrant methylation in all the BRCAX cases. We found that 15 of the 34 BRCAX analyzed tumors had hypermethylation of the BRCA1 gene. When we considered the predictor, we observed that all the cases with this epigenetic event were assigned to the BRCA1 class with a probability of >50\%. Interestingly, 84.6\% of the cases (11 of 13) assigned to the BRCA1 class with a probability >80\% had an aberrant methylation of the BRCA1 promoter. This fact suggests that somatic BRCA1 inactivation could modify the profile of tumor progression in most of the BRCAX cases.}, keywords = {BRCA1 Protein/*genetics BRCA2 Protein/*genetics Breast Neoplasms/*genetics/pathology Chromosomes, Genetic/*genetics, Human, Human Humans Male Mutation Nucleic Acid Hybridization/methods Promoter Regions, Pair 12/genetics Chromosomes, Pair 15/genetics Chromosomes, Pair 18/genetics Chromosomes, Pair 2/genetics Chromosomes, Pair 8/genetics *DNA Methylation Female Genome}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15709182}, author = {Alvarez, S. and Diaz-Uriarte, R. and Osorio, A. and Barroso, A. and Melchor, L. and Paz, M. F. and Honrado, E. and Rodriguez, R. and Urioste, M. and Valle, L. and Diez, O. and Cigudosa, J. C. and Dopazo, J. and Esteller, M. and Benitez, J.} } @inbook {486, title = {Salinibacter ruber: genomics and biogeography}, booktitle = {Adaptation to life in high salt concentrations in Archaea, Bacteria and Eukarya}, volume = {9}, year = {2005}, pages = {257-266}, publisher = {Nina Gunde-Cimerman, Ana Plemenitas, and Aharon Oren. Kluwer Academic Publishers}, organization = {Nina Gunde-Cimerman, Ana Plemenitas, and Aharon Oren. Kluwer Academic Publishers}, address = {Dordrecht, Netherlands}, author = {Ant{\'o}n, J and Pe{\~n}a, A and Valens, M and Santos, F and Gl{\"o}ckner, F.O and Bauer, M and Dopazo, J. and Herrero, J. and Rossell{\'o}-Mora, R and Amann, R} } @article {15297397, title = {Expression profiling of T-cell lymphomas differentiates peripheral and lymphoblastic lymphomas and defines survival related genes.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {10}, year = {2004}, month = {2004 Aug 1}, pages = {4971-82}, abstract = {

PURPOSE: T-Cell lymphomas constitute heterogeneous and aggressive tumors in which pathogenic alterations remain largely unknown. Expression profiling has demonstrated to be a useful tool for molecular classification of tumors. EXPERIMENTAL DESIGN: Using DNA microarrays (CNIO-OncoChip) containing 6386 cancer-related genes, we established the expression profiling of T-cell lymphomas and compared them to normal lymphocytes and lymph nodes. RESULTS: We found significant differences between the peripheral and lymphoblastic T-cell lymphomas, which include a deregulation of nuclear factor-kappaB signaling pathway. We also identify differentially expressed genes between peripheral T-cell lymphoma tumors and normal T lymphocytes or reactive lymph nodes, which could represent candidate tumor markers of these lymphomas. Additionally, a close relationship between genes associated to survival and those that differentiate among the stages of disease and responses to therapy was found. CONCLUSIONS: Our results reflect the value of gene expression profiling to gain insight about the molecular alterations involved in the pathogenesis of T-cell lymphomas.

}, url = {http://clincancerres.aacrjournals.org/content/10/15/4971.long}, author = {Martinez-Delgado, Beatriz and Mel{\'e}ndez, Barbara and Cuadros, Marta and Alvarez, Javier and Castrillo, Jose Maria and Ruiz De La Parte, Ana and Mollejo, Manuela and Bellas, Carmen and Diaz, Ramon and Lombard{\'\i}a, Luis and Fatima Al-Shahrour and Dom{\'\i}nguez, Orlando and Cascon, Alberto and Robledo, Mercedes and Rivas, Carmen and Benitez, Javier} } @article {14990455, title = {FatiGO: a web tool for finding significant associations of Gene Ontology terms with groups of genes}, journal = {Bioinformatics}, volume = {20}, number = {4}, year = {2004}, note = {

Al-Shahrour, Fatima Diaz-Uriarte, Ramon Dopazo, Joaquin England Bioinformatics (Oxford, England) Bioinformatics. 2004 Mar 1;20(4):578-80. Epub 2004 Jan 22.

}, pages = {578-80}, abstract = {

We present a simple but powerful procedure to extract Gene Ontology (GO) terms that are significantly over- or under-represented in sets of genes within the context of a genome-scale experiment (DNA microarray, proteomics, etc.). Said procedure has been implemented as a web application, FatiGO, allowing for easy and interactive querying. FatiGO, which takes the multiple-testing nature of statistical contrast into account, currently includes GO associations for diverse organisms (human, mouse, fly, worm and yeast) and the TrEMBL/Swissprot GOAnnotations@EBI correspondences from the European Bioinformatics Institute.

}, keywords = {*Algorithms Artificial Intelligence Databases, babelomics, DNA/*methods *Software, Genetic Gene Expression Profiling/*methods *Hypermedia Information Storage and Retrieval/*methods *Internet *Phylogeny Sequence Alignment/methods Sequence Analysis}, url = {http://bioinformatics.oxfordjournals.org/content/20/4/578.abstract}, author = {Fatima Al-Shahrour and Diaz-Uriarte, R. and Dopazo, J.} } @inbook {490, title = {Gene expression Correlation and Gene Ontology-Based Similarity: An Assessment of Quantitative Relationship}, booktitle = {IEEE Symposium on Computational Intelligence in Bioinformatics and Computational Biology}, year = {2004}, pages = {25-31}, author = {Wang, H and F. Azuaje and Bodenreider, O and Dopazo, J.} } @article {15215434, title = {New challenges in gene expression data analysis and the extended GEPAS}, journal = {Nucleic Acids Res}, volume = {32}, year = {2004}, note = {

Herrero, Javier Vaquerizas, Juan M Al-Shahrour, Fatima Conde, Lucia Mateos, Alvaro Diaz-Uriarte, Javier Santoyo Ramon Dopazo, Joaquin England Nucleic acids research Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W485-91.

}, pages = {W485-91}, abstract = {

Since the first papers published in the late nineties, including, for the first time, a comprehensive analysis of microarray data, the number of questions that have been addressed through this technique have both increased and diversified. Initially, interest focussed on genes coexpressing across sets of experimental conditions, implying, essentially, the use of clustering techniques. Recently, however, interest has focussed more on finding genes differentially expressed among distinct classes of experiments, or correlated to diverse clinical outcomes, as well as in building predictors. In addition to this, the availability of accurate genomic data and the recent implementation of CGH arrays has made mapping expression and genomic data on the chromosomes possible. There is also a clear demand for methods that allow the automatic transfer of biological information to the results of microarray experiments. Different initiatives, such as the Gene Ontology (GO) consortium, pathways databases, protein functional motifs, etc., provide curated annotations for genes. Whereas many resources on the web focus mainly on clustering methods, GEPAS has evolved to cope with the aforementioned new challenges that have recently arisen in the field of microarray data analysis. The web-based pipeline for microarray gene expression data, GEPAS, is available at http://gepas.bioinfo.cnio.es.

}, keywords = {gepas, microarray data analysis}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15215434}, author = {Herrero, J. and Vaquerizas, J. M. and Fatima Al-Shahrour and L. Conde and A. Mateos and Diaz-Uriarte, J. S. and Dopazo, J.} } @article {15215388, title = {PupaSNP Finder: a web tool for finding SNPs with putative effect at transcriptional level}, journal = {Nucleic Acids Res}, volume = {32}, number = {Web Server issue}, year = {2004}, note = {Conde, Lucia Vaquerizas, Juan M Santoyo, Javier Al-Shahrour, Fatima Ruiz-Llorente, Sergio Robledo, Mercedes Dopazo, Joaquin England Nucleic acids research Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W242-8.}, pages = {W242-8}, abstract = {We have developed a web tool, PupaSNP Finder (PupaSNP for short), for high-throughput searching for single nucleotide polymorphisms (SNPs) with potential phenotypic effect. PupaSNP takes as its input lists of genes (or generates them from chromosomal coordinates) and retrieves SNPs that could affect the conserved regions that the cellular machinery uses for the correct processing of genes (intron/exon boundaries or exonic splicing enhancers), predicted transcription factor binding sites (TFBS) and changes in amino acids in the proteins. The program uses the mapping of SNPs in the genome provided by Ensembl. Additionally, user-defined SNPs (not yet mapped in the genome) can be easily provided to the program. Also, additional functional information from Gene Ontology, OMIM and homologies in other model organisms is provided. In contrast to other programs already available, which focus only on SNPs with possible effect in the protein, PupaSNP includes SNPs with possible transcriptional effect. PupaSNP will be of significant help in studies of multifactorial disorders, where the use of functional SNPs will increase the sensitivity of identification of the genes responsible for the disease. The PupaSNP web interface is accessible through http://pupasnp.bioinfo.cnio.es.}, keywords = {Amino Acid Substitution Binding Sites Humans Internet Phenotype *Polymorphism, Genetic, Single Nucleotide RNA Splicing *Software Transcription Factors/metabolism *Transcription}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15215388}, author = {L. Conde and Vaquerizas, J. M. and J. Santoyo and Fatima Al-Shahrour and Ruiz-Llorente, S. and M. Robledo and Dopazo, J.} } @article {12824345, title = {GEPAS: A web-based resource for microarray gene expression data analysis}, journal = {Nucleic Acids Res}, volume = {31}, number = {13}, year = {2003}, note = {

Herrero, Javier Al-Shahrour, Fatima Diaz-Uriarte, Ramon Mateos, Alvaro Vaquerizas, Juan M Santoyo, Javier Dopazo, Joaquin Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2003 Jul 1;31(13):3461-7.

}, pages = {3461-7}, abstract = {

We present a web-based pipeline for microarray gene expression profile analysis, GEPAS, which stands for Gene Expression Profile Analysis Suite (http://gepas.bioinfo.cnio.es). GEPAS is composed of different interconnected modules which include tools for data pre-processing, two-conditions comparison, unsupervised and supervised clustering (which include some of the most popular methods as well as home made algorithms) and several tests for differential gene expression among different classes, continuous variables or survival analysis. A multiple purpose tool for data mining, based on Gene Ontology, is also linked to the tools, which constitutes a very convenient way of analysing clustering results. On-line tutorials are available from our main web server (http://bioinfo.cnio.es).

}, keywords = {gepas, microarray data analysis}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=12824345}, author = {Herrero, J. and Fatima Al-Shahrour and Diaz-Uriarte, R. and A. Mateos and Vaquerizas, J. M. and J. Santoyo and Dopazo, J.} } @inbook {491, title = {Use of GO Terms to Understand the Biological Significance of Microarray Differential Gene Expression Data}, booktitle = {Microarray data analysis III}, year = {2003}, pages = {233-247}, publisher = {Kluwer Academic, K. F. Johnson and S. M. Lin}, organization = {Kluwer Academic, K. F. Johnson and S. M. Lin}, author = {D{\'\i}az-Uriarte, R and Fatima Al-Shahrour and Dopazo, J.} } @inbook {492, title = {Using Gene Ontology on genome-scale studies to find significant associations of biologically relevant terms to group of genes}, booktitle = {Neural Networks for Signal Processing XIII}, year = {2003}, pages = {43-52}, publisher = {IEEE Press}, organization = {IEEE Press}, address = {New York, USA}, keywords = {babelomics}, author = {Fatima Al-Shahrour and Herrero, J. and A. Mateos and J. Santoyo and D{\'\i}az-Uriarte, R and Dopazo, J.} } @article {11823227, title = {Calnexin overexpression increases manganese peroxidase production in Aspergillus niger}, journal = {Appl Environ Microbiol}, volume = {68}, number = {2}, year = {2002}, note = {Conesa, Ana Jeenes, David Archer, David B van den Hondel, Cees A M J J Punt, Peter J United States Applied and environmental microbiology Appl Environ Microbiol. 2002 Feb;68(2):846-51.}, pages = {846-51}, abstract = {Heme-containing peroxidases from white rot basidiomycetes, in contrast to most proteins of fungal origin, are poorly produced in industrial filamentous fungal strains. Factors limiting peroxidase production are believed to operate at the posttranslational level. In particular, insufficient availability of the prosthetic group which is required for peroxidase biosynthesis has been proposed to be an important bottleneck. In this work, we analyzed the role of two components of the secretion pathway, the chaperones calnexin and binding protein (BiP), in the production of a fungal peroxidase. Expression of the Phanerochaete chrysosporium manganese peroxidase (MnP) in Aspergillus niger resulted in an increase in the expression level of the clxA and bipA genes. In a heme-supplemented medium, where MnP was shown to be overproduced to higher levels, induction of clxA and bipA was also higher. Overexpression of these two chaperones in an MnP-producing strain was analyzed for its effect on MnP production. Whereas bipA overexpression seriously reduced MnP production, overexpression of calnexin resulted in a four- to fivefold increase in the extracellular MnP levels. However, when additional heme was provided in the culture medium, calnexin overexpression had no synergistic effect on MnP production. The possible function of these two chaperones in MnP maturation and production is discussed.}, keywords = {Aspergillus niger/*enzymology/genetics Calcium-Binding Proteins/*metabolism Calnexin Culture Media *Fungal Proteins HSP70 Heat-Shock Proteins/metabolism Heme/metabolism Peroxidases/*biosynthesis/genetics Phanerochaete/enzymology/genetics Transformation, Genetic}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=11823227}, author = {A. Conesa and Jeenes, D. and Archer, D. B. and van den Hondel, C. A. and Punt, P. J.} } @article {11943375, title = {Filamentous fungi as cell factories for heterologous protein production}, journal = {Trends Biotechnol}, volume = {20}, number = {5}, year = {2002}, note = {Punt, Peter J van Biezen, Nick Conesa, Ana Albers, Alwin Mangnus, Jeroen van den Hondel, Cees Review England Trends in biotechnology Trends Biotechnol. 2002 May;20(5):200-6.}, pages = {200-6}, abstract = {Filamentous fungi have been used as sources of metabolites and enzymes for centuries. For about two decades, molecular genetic tools have enabled us to use these organisms to express extra copies of both endogenous and exogenous genes. This review of current practice reveals that molecular tools have enabled several new developments. But it has been process development that has driven the final breakthrough to achieving commercially relevant quantities of protein. Recent research into gene expression in filamentous fungi has explored their wealth of genetic diversity with a view to exploiting them as expression hosts and as a source of new genes. Inevitably, the progress in the {\textquoteright}genomics{\textquoteright} technology will further develop high-throughput technologies for these organisms.}, keywords = {Fermentation/genetics/physiology Fungi/*genetics/*metabolism Humans Interleukin-6/analysis/*biosynthesis/genetics Peroxidases/analysis/*biosynthesis/genetics Protein Conformation Recombinant Proteins/analysis/*biosynthesis/genetics}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=11943375}, author = {Punt, P. J. and van Biezen, N. and A. Conesa and Albers, A. and Mangnus, J. and van den Hondel, C.} } @article {12414529, title = {Identification of genes involved in resistance to interferon-alpha in cutaneous T-cell lymphoma}, journal = {Am J Pathol}, volume = {161}, number = {5}, year = {2002}, note = {Tracey, Lorraine Villuendas, Raquel Ortiz, Pablo Dopazo, Ana Spiteri, Inmaculada Lombardia, Luis Rodriguez-Peralto, Jose L Fernandez-Herrera, Jesus Hernandez, Almudena Fraga, Javier Dominguez, Orlando Herrero, Javier Alonso, Miguel A Dopazo, Joaquin Piris, Miguel A Research Support, Non-U.S. Gov{\textquoteright}t United States The American journal of pathology Am J Pathol. 2002 Nov;161(5):1825-37.}, pages = {1825-37}, abstract = {Interferon-alpha therapy has been shown to be active in the treatment of mycosis fungoides although the individual response to this therapy is unpredictable and dependent on essentially unknown factors. In an effort to better understand the molecular mechanisms of interferon-alpha resistance we have developed an interferon-alpha resistant variant from a sensitive cutaneous T-cell lymphoma cell line. We have performed expression analysis to detect genes differentially expressed between both variants using a cDNA microarray including 6386 cancer-implicated genes. The experiments showed that resistance to interferon-alpha is consistently associated with changes in the expression of a set of 39 genes, involved in signal transduction, apoptosis, transcription regulation, and cell growth. Additional studies performed confirm that STAT1 and STAT3 expression and interferon-alpha induction and activation are not altered between both variants. The gene MAL, highly overexpressed by resistant cells, was also found to be expressed by tumoral cells in a series of cutaneous T-cell lymphoma patients treated with interferon-alpha and/or photochemotherapy. MAL expression was associated with longer time to complete remission. Time-course experiments of the sensitive and resistant cells showed a differential expression of a subset of genes involved in interferon-response (1 to 4 hours), cell growth and apoptosis (24 to 48 hours.), and signal transduction.}, keywords = {Antineoplastic Agents/*pharmacology/therapeutic use Carrier Proteins/biosynthesis/genetics DNA-Binding Proteins/biosynthesis/genetics Drug Resistance, Biological Oligonucleotide Array Sequence Analysis RNA, Cultured, Cutaneous/diagnosis/drug therapy/*genetics/metabolism *Membrane Glycoproteins Models, Interleukin-1 Reproducibility of Results STAT1 Transcription Factor STAT3 Transcription Factor Trans-Activators/biosynthesis/genetics Tumor Cells, Neoplasm Gene Expression Profiling *Gene Expression Regulation, Neoplasm/biosynthesis *Receptors, Neoplastic Humans Interferon-alpha/*pharmacology/therapeutic use Kinetics Lymphoma, T-Cell}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=12414529}, author = {Tracey, L. and Villuendas, R. and Ortiz, P. and Dopazo, A. and Spiteri, I. and Lombardia, L. and Rodriguez-Peralto, J. L. and Fernandez-Herrera, J. and Hernandez, A. and Fraga, J. and Dominguez, O. and Herrero, J. and Alonso, M. A. and Dopazo, J. and Piris, M. A.} } @article {11394740, title = {Classification of protein disulphide-bridge topologies}, journal = {J Comput Aided Mol Des}, volume = {15}, number = {5}, year = {2001}, note = {Mas, J M Aloy, P Marti-Renom, M A Oliva, B de Llorens, R Aviles, F X Querol, E Comparative Study Research Support, Non-U.S. Gov{\textquoteright}t Netherlands Journal of computer-aided molecular design J Comput Aided Mol Des. 2001 May;15(5):477-87.}, pages = {477-87}, abstract = {The preferential occurrence of certain disulphide-bridge topologies in proteins has prompted us to design a method and a program, KNOT-MATCH, for their classification. The program has been applied to a database of proteins with less than 65\% homology and more than two disulphide bridges. We have investigated whether there are topological preferences that can be used to group proteins and if these can be applied to gain insight into the structural or functional relationships among them. The classification has been performed by Density Search and Hierarchical Clustering Techniques, yielding thirteen main protein classes from the superimposition and clustering process. It is noteworthy that besides the disulphide bridges, regular secondary structures and loops frequently become correctly aligned. Although the lack of significant sequence similarity among some clustered proteins precludes the easy establishment of evolutionary relationships, the program permits us to find out important structural or functional residues upon the superimposition of two protein structures apparently unrelated. The derived classification can be very useful for finding relationships among proteins which would escape detection by current sequence or topology-based analytical algorithms.}, keywords = {Algorithms Computer Simulation Databases as Topic Disulfides/*chemistry Models, Molecular Protein Structure, Secondary Protein Structure, Tertiary Proteins/*chemistry/*classification Software}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=11394740}, author = {Mas, J. M. and Aloy, P. and M. A. Marti-Renom and Oliva, B. and de Llorens, R. and Aviles, F. X. and Querol, E.} } @article {11251224, title = {Methods and approaches in the analysis of gene expression data}, journal = {J Immunol Methods}, volume = {250}, number = {1-2}, year = {2001}, note = {

Dopazo, J Zanders, E Dragoni, I Amphlett, G Falciani, F Comparative Study Review Netherlands Journal of immunological methods J Immunol Methods. 2001 Apr;250(1-2):93-112.

}, pages = {93-112}, abstract = {

The application of high-density DNA array technology to monitor gene transcription has been responsible for a real paradigm shift in biology. The majority of research groups now have the ability to measure the expression of a significant proportion of the human genome in a single experiment, resulting in an unprecedented volume of data being made available to the scientific community. As a consequence of this, the storage, analysis and interpretation of this information present a major challenge. In the field of immunology the analysis of gene expression profiles has opened new areas of investigation. The study of cellular responses has revealed that cells respond to an activation signal with waves of co-ordinated gene expression profiles and that the components of these responses are the key to understanding the specific mechanisms which lead to phenotypic differentiation. The discovery of {\textquoteright}cell type specific{\textquoteright} gene expression signatures have also helped the interpretation of the mechanisms leading to disease progression. Here we review the principles behind the most commonly used data analysis methods and discuss the approaches that have been employed in immunological research.

}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=11251224}, author = {Dopazo, J. and Zanders, E. and Dragoni, I. and Amphlett, G. and Falciani, F.} }