@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 {796, title = {Defective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis.}, journal = {Cell Rep}, volume = {42}, year = {2023}, month = {2023 Jun 13}, pages = {112640}, abstract = {

The relevance of extracellular matrix (ECM) remodeling is reported in white adipose tissue (AT) and obesity-related dysfunctions, but little is known about the importance of ECM remodeling in brown AT (BAT) function. Here, we show that a time course of high-fat diet (HFD) feeding progressively impairs diet-induced thermogenesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflammation are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at thermoneutrality, inactivated BAT features fibro-inflammation. We validate the pathophysiological relevance of BAT ECM remodeling in response to temperature challenges and HFD using a model of a primary defect in the collagen turnover mediated by partial ablation of the Pepd prolidase. Pepd-heterozygous mice display exacerbated dysfunction and BAT fibro-inflammation at thermoneutrality and in HFD. Our findings show the relevance of ECM remodeling in BAT activation and provide a mechanism for BAT dysfunction in obesity.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2023.112640}, author = {Pellegrinelli, Vanessa and Figueroa-Ju{\'a}rez, Elizabeth and Samuelson, Isabella and U-Din, Mueez and Rodriguez-Fdez, Sonia and Virtue, Samuel and Leggat, Jennifer and Cubuk, Cankut and Peirce, Vivian J and Niemi, Tarja and Campbell, Mark and Rodriguez-Cuenca, Sergio and Dopazo, Joaquin and Carobbio, Stefania and Virtanen, Kirsi A and Vidal-Puig, Antonio} } @article {767, title = {Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging.}, journal = {Commun Biol}, volume = {6}, year = {2023}, month = {2023 Mar 08}, pages = {250}, abstract = {

ATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.

}, issn = {2399-3642}, doi = {10.1038/s42003-023-04625-4}, author = {Sola-Garc{\'\i}a, Alejandro and C{\'a}liz-Molina, Mar{\'\i}a {\'A}ngeles and Espadas, Isabel and Petr, Michael and Panadero-Mor{\'o}n, Concepci{\'o}n and Gonz{\'a}lez-Mor{\'a}n, Daniel and Mart{\'\i}n-V{\'a}zquez, Mar{\'\i}a Eugenia and Narbona-P{\'e}rez, {\'A}lvaro Jes{\'u}s and L{\'o}pez-Noriega, Livia and Mart{\'\i}nez-Corrales, Guillermo and L{\'o}pez-Fern{\'a}ndez-Sobrino, Ra{\'u}l and Carmona-Marin, Lina M and Mart{\'\i}nez-Force, Enrique and Yanes, Oscar and Vinaixa, Maria and L{\'o}pez-L{\'o}pez, Daniel and Reyes, Jos{\'e} Carlos and Dopazo, Joaquin and Mart{\'\i}n, Franz and Gauthier, Benoit R and Scheibye-Knudsen, Morten and Capilla-Gonz{\'a}lez, Vivian and Mart{\'\i}n-Montalvo, Alejandro} } @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 {762, title = {Assessing the Impact of SARS-CoV-2 Lineages and Mutations on Patient Survival.}, journal = {Viruses}, volume = {14}, year = {2022}, month = {2022 Aug 27}, abstract = {

OBJECTIVES: More than two years into the COVID-19 pandemic, SARS-CoV-2 still remains a global public health problem. Successive waves of infection have produced new SARS-CoV-2 variants with new mutations for which the impact on COVID-19 severity and patient survival is uncertain.

METHODS: A total of 764 SARS-CoV-2 genomes, sequenced from COVID-19 patients, hospitalized from 19th February 2020 to 30 April 2021, along with their clinical data, were used for survival analysis.

RESULTS: A significant association of B.1.1.7, the alpha lineage, with patient mortality (log hazard ratio (LHR) = 0.51, C.I. = [0.14,0.88]) was found upon adjustment by all the covariates known to affect COVID-19 prognosis. Moreover, survival analysis of mutations in the SARS-CoV-2 genome revealed 27 of them were significantly associated with higher mortality of patients. Most of these mutations were located in the genes coding for the S, ORF8, and N proteins.

CONCLUSIONS: This study illustrates how a combination of genomic and clinical data can provide solid evidence for the impact of viral lineage on patient survival.

}, keywords = {COVID-19, Genome, Viral, Humans, mutation, Pandemics, Phylogeny, SARS-CoV-2}, issn = {1999-4915}, doi = {10.3390/v14091893}, author = {Loucera, Carlos and Perez-Florido, Javier and Casimiro-Soriguer, Carlos S and Ortuno, Francisco M and Carmona, Rosario and Bostelmann, Gerrit and Mart{\'\i}nez-Gonz{\'a}lez, L Javier and Mu{\~n}oyerro-Mu{\~n}iz, Dolores and Villegas, Rom{\'a}n and Rodr{\'\i}guez-Ba{\~n}o, Jes{\'u}s and Romero-G{\'o}mez, Manuel and Lorusso, Nicola and Garcia-Le{\'o}n, Javier and Navarro-Mar{\'\i}, Jose M and Camacho-Martinez, Pedro and Merino-Diaz, Laura and Salazar, Adolfo de and Vi{\~n}uela, Laura and Lepe, Jose A and Garc{\'\i}a, Federico and Dopazo, Joaquin} } @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 {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 {741, title = {Mutational Characterization of Cutaneous Melanoma Supports Divergent Pathways Model for Melanoma Development.}, journal = {Cancers (Basel)}, volume = {13}, year = {2021}, month = {2021 Oct 18}, abstract = {

According to the divergent pathway model, cutaneous melanoma comprises a nevogenic group with a propensity to melanocyte proliferation and another one associated with cumulative solar damage (CSD). While characterized clinically and epidemiologically, the differences in the molecular profiles between the groups have remained primarily uninvestigated. This study has used a custom gene panel and bioinformatics tools to investigate the potential molecular differences in a thoroughly characterized cohort of 119 melanoma patients belonging to nevogenic and CSD groups. We found that the nevogenic melanomas had a restricted set of mutations, with the prominently mutated gene being . The CSD melanomas, in contrast, showed mutations in a diverse group of genes that included , , , and . We thus provide evidence that nevogenic and CSD melanomas constitute different biological entities and highlight the need to explore new targeted therapies.

}, issn = {2072-6694}, doi = {10.3390/cancers13205219}, author = {Mill{\'a}n-Esteban, David and Pe{\~n}a-Chilet, Maria and Garc{\'\i}a-Casado, Zaida and Manrique-Silva, Esperanza and Requena, Celia and Ba{\~n}uls, Jos{\'e} and Lopez-Guerrero, Jose Antonio and Rodr{\'\i}guez-Hern{\'a}ndez, Aranzazu and Traves, V{\'\i}ctor and Dopazo, Joaquin and Vir{\'o}s, Amaya and Kumar, Rajiv and Nagore, Eduardo} } @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 {734, title = {Orchestrating and sharing large multimodal data for transparent and reproducible research.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 10 04}, pages = {5797}, abstract = {

Reproducibility is essential to open science, as there is limited relevance for findings that can not be reproduced by independent research groups, regardless of its validity. It is therefore crucial for scientists to describe their experiments in sufficient detail so they can be reproduced, scrutinized, challenged, and built upon. However, the intrinsic complexity and continuous growth of biomedical data makes it increasingly difficult to process, analyze, and share with the community in a FAIR (findable, accessible, interoperable, and reusable) manner. To overcome these issues, we created a cloud-based platform called ORCESTRA ( orcestra.ca ), which provides a flexible framework for the reproducible processing of multimodal biomedical data. It enables processing of clinical, genomic and perturbation profiles of cancer samples through automated processing pipelines that are user-customizable. ORCESTRA creates integrated and fully documented data objects with persistent identifiers (DOI) and manages multiple dataset versions, which can be shared for future studies.

}, issn = {2041-1723}, doi = {10.1038/s41467-021-25974-w}, author = {Mammoliti, Anthony and Smirnov, Petr and Nakano, Minoru and Safikhani, Zhaleh and Eeles, Christopher and Seo, Heewon and Nair, Sisira Kadambat and Mer, Arvind S and Smith, Ian and Ho, Chantal and Beri, Gangesh and Kusko, Rebecca and Lin, Eva and Yu, Yihong and Martin, Scott and Hafner, Marc and Haibe-Kains, Benjamin} } @article {723, title = {Phylogenetic Analysis of the 2020 West Nile Virus (WNV) Outbreak in Andalusia (Spain)}, journal = {Viruses}, volume = {13}, year = {2021}, month = {Jan-05-2021}, pages = {836}, doi = {10.3390/v13050836}, url = {https://www.mdpi.com/1999-4915/13/5/836 }, author = {Casimiro-Soriguer, Carlos S. and Perez-Florido, Javier and Fernandez-Rueda, Jose L. and Pedrosa-Corral, Irene and Guillot-Sulay, Vicente and Lorusso, Nicola and Martinez-Gonzalez, Luis Javier and Navarro-Mar{\'\i}, Jose M. and Dopazo, Joaquin and Sanbonmatsu-G{\'a}mez, Sara} } @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 {696, title = {Community Assessment of the Predictability of Cancer Protein and Phosphoprotein Levels from Genomics and Transcriptomics.}, journal = {Cell Syst}, volume = {11}, year = {2020}, month = {2020 08 26}, pages = {186-195.e9}, abstract = {

Cancer is driven by genomic alterations, but the processes causing this disease are largely performed by proteins. However, proteins are harder and more expensive to measure than genes and transcripts. To catalyze developments of methods to infer protein levels from other omics measurements, we leveraged crowdsourcing via the NCI-CPTAC DREAM proteogenomic challenge. We asked for methods to predict protein and phosphorylation levels from genomic and transcriptomic data in cancer patients. The best performance was achieved by an ensemble of models, including as predictors transcript level of the corresponding genes, interaction between genes, conservation across tumor types, and phosphosite proximity for phosphorylation prediction. Proteins from metabolic pathways and complexes were the best and worst predicted, respectively. The performance of even the best-performing model was modest, suggesting that many proteins are strongly regulated through translational control and degradation. Our results set a reference for the limitations of computational inference in proteogenomics. A record of this paper{\textquoteright}s transparent peer review process is included in the Supplemental Information.

}, keywords = {Crowdsourcing, Female, Genomics, Humans, Machine Learning, Male, Neoplasms, Phosphoproteins, Proteins, Proteomics, Transcriptome}, issn = {2405-4720}, doi = {10.1016/j.cels.2020.06.013}, author = {Yang, Mi and Petralia, Francesca and Li, Zhi and Li, Hongyang and Ma, Weiping and Song, Xiaoyu and Kim, Sunkyu and Lee, Heewon and Yu, Han and Lee, Bora and Bae, Seohui and Heo, Eunji and Kaczmarczyk, Jan and St{\k e}pniak, Piotr and Warcho{\l}, Micha{\l} and Yu, Thomas and Calinawan, Anna P and Boutros, Paul C and Payne, Samuel H and Reva, Boris and Boja, Emily and Rodriguez, Henry and Stolovitzky, Gustavo and Guan, Yuanfang and Kang, Jaewoo and Wang, Pei and Feny{\"o}, David and Saez-Rodriguez, Julio} } @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 {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 {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 {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 {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 {384, title = {Genomic expression differences between cutaneous cells from red hair color individuals and black hair color individuals based on bioinformatic analysis.}, journal = {Oncotarget}, volume = {8}, year = {2017}, month = {2017 Feb 14}, pages = {11589-11599}, abstract = {

The MC1R gene plays a crucial role in pigmentation synthesis. Loss-of-function MC1R variants, which impair protein function, are associated with red hair color (RHC) phenotype and increased skin cancer risk. Cultured cutaneous cells bearing loss-of-function MC1R variants show a distinct gene expression profile compared to wild-type MC1R cultured cutaneous cells. We analysed the gene signature associated with RHC co-cultured melanocytes and keratinocytes by Protein-Protein interaction (PPI) network analysis to identify genes related with non-functional MC1R variants. From two detected networks, we selected 23 nodes as hub genes based on topological parameters. Differential expression of hub genes was then evaluated in healthy skin biopsies from RHC and black hair color (BHC) individuals. We also compared gene expression in melanoma tumors from individuals with RHC versus BHC. Gene expression in normal skin from RHC cutaneous cells showed dysregulation in 8 out of 23 hub genes (CLN3, ATG10, WIPI2, SNX2, GABARAPL2, YWHA, PCNA and GBAS). Hub genes did not differ between melanoma tumors in RHC versus BHC individuals. The study suggests that healthy skin cells from RHC individuals present a constitutive genomic deregulation associated with the red hair phenotype and identify novel genes involved in melanocyte biology.

}, keywords = {Adult, Coculture Techniques, Computational Biology, gene expression, Genetic Predisposition to Disease, Genomics, Hair Color, Humans, Keratinocytes, Melanocytes, Middle Aged, Phenotype, Receptor, Melanocortin, Type 1}, issn = {1949-2553}, doi = {10.18632/oncotarget.14140}, url = {http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget\&page=article\&op=view\&path\%5B\%5D=14140\&path\%5B\%5D=45094}, author = {Puig-Butille, Joan Anton and Gimenez-Xavier, Pol and Visconti, Alessia and Nsengimana, J{\'e}r{\'e}mie and Garcia-Garcia, Francisco and Tell-Marti, Gemma and Escamez, Maria Jos{\'e} and Newton-Bishop, Julia and Bataille, Veronique and Del Rio, Marcela and Dopazo, Joaquin and Falchi, Mario and Puig, Susana} } @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 {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 {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 {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 {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 {1132, title = {Combining tumor genome simulation with crowdsourcing to benchmark somatic single-nucleotide-variant detection.}, journal = {Nature methods}, year = {2015}, month = {2015 May 18}, abstract = {The detection of somatic mutations from cancer genome sequences is key to understanding the genetic basis of disease progression, patient survival and response to therapy. Benchmarking is needed for tool assessment and improvement but is complicated by a lack of gold standards, by extensive resource requirements and by difficulties in sharing personal genomic information. To resolve these issues, we launched the ICGC-TCGA DREAM Somatic Mutation Calling Challenge, a crowdsourced benchmark of somatic mutation detection algorithms. Here we report the BAMSurgeon tool for simulating cancer genomes and the results of 248 analyses of three in silico tumors created with it. Different algorithms exhibit characteristic error profiles, and, intriguingly, false positives show a trinucleotide profile very similar to one found in human tumors. Although the three simulated tumors differ in sequence contamination (deviation from normal cell sequence) and in subclonality, an ensemble of pipelines outperforms the best individual pipeline in all cases. BAMSurgeon is available at https://github.com/adamewing/bamsurgeon/.}, keywords = {cancer, NGS, variant calling}, issn = {1548-7105}, doi = {10.1038/nmeth.3407}, url = {http://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth.3407.html}, author = {Ewing, Adam D and Houlahan, Kathleen E and Hu, Yin and Ellrott, Kyle and Caloian, Cristian and Yamaguchi, Takafumi N and Bare, J Christopher and P{\textquoteright}ng, Christine and Waggott, Daryl and Sabelnykova, Veronica Y and Kellen, Michael R and Norman, Thea C and Haussler, David and Friend, Stephen H and Stolovitzky, Gustavo and Margolin, Adam A and Stuart, Joshua M and Boutros, Paul C}, editor = {ICGC-TCGA DREAM Somatic Mutation Calling Challenge participants and Liu Xi and Ninad Dewal and Yu Fan and Wenyi Wang and David Wheeler and Andreas Wilm and Grace Hui Ting and Chenhao Li and Denis Bertrand and Niranjan Nagarajan and Qing-Rong Chen and Chih-Hao Hsu and Ying Hu and Chunhua Yan and Warren Kibbe and Daoud Meerzaman and Kristian Cibulskis and Mara Rosenberg and Louis Bergelson and Adam Kiezun and Amie Radenbaugh and Anne-Sophie Sertier and Anthony Ferrari and Laurie Tonton and Kunal Bhutani and Nancy F Hansen and Difei Wang and Lei Song and Zhongwu Lai and Liao, Yang and Shi, Wei and Carbonell-Caballero, Jos{\'e} and Joaqu{\'\i}n Dopazo and Cheryl C K Lau and Justin Guinney} } @article {448, title = {Differential Features Between Chronic Skin Inflammatory Diseases Revealed in Skin-Humanized Psoriasis and Atopic Dermatitis Mouse Models.}, journal = {J Invest Dermatol}, year = {2015}, month = {2015 Sep 23}, abstract = {

Psoriasis (PS) and atopic dermatitis (AD) are chronic and relapsing inflammatory diseases of the skin affecting a large number of patients worldwide. Psoriasis is characterized by a Th1/Th17 immunological response whereas acute AD lesions exhibit Th2-dominant inflammation. Current single gene and signaling pathways-based models of inflammatory skin diseases are incomplete. Previous work allowed us to model psoriasis in skin-humanized mice through proper combinations of inflammatory cell components and disruption of barrier function. Herein we describe and characterize an animal model for AD using similar bioengineered-based approaches, by intradermal injection of human Th2 lymphocytes in regenerated human skin after partial removal of stratum corneum. In the present work we have extensively compared this model with the previous and an improved version of the PS model, in which Th17/Th1 lymphocytes replace exogenous cytokines. Comparative expression analyses revealed marked differences in specific epidermal proliferation and differentiation markers and immune-related molecules including antimicrobial peptides. Likewise, the composition of the dermal inflammatory infiltrate presented important differences. Availability of accurate and reliable animal models for these diseases will contribute to the understanding of the pathogenesis and provide valuable tools for drug development and testing.Journal of Investigative Dermatology accepted article preview online, 23 September 2015. doi:10.1038/jid.2015.362.

}, issn = {1523-1747}, doi = {10.1038/jid.2015.362}, author = {Carretero, M and Guerrero-Aspizua, S and Illera, N and Galvez, V and Navarro, M and Garc{\'\i}a-Garc{\'\i}a, F and Dopazo, J and Jorcano, J L and Larcher, F and Del Rio, M} } @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 {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 {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 {491, title = {Pathway network inference from gene expression data.}, journal = {BMC Syst Biol}, volume = {8 Suppl 2}, year = {2014}, month = {2014}, pages = {S7}, abstract = {

BACKGROUND: The development of high-throughput omics technologies enabled genome-wide measurements of the activity of cellular elements and provides the analytical resources for the progress of the Systems Biology discipline. Analysis and interpretation of gene expression data has evolved from the gene to the pathway and interaction level, i.e. from the detection of differentially expressed genes, to the establishment of gene interaction networks and the identification of enriched functional categories. Still, the understanding of biological systems requires a further level of analysis that addresses the characterization of the interaction between functional modules.

RESULTS: We present a novel computational methodology to study the functional interconnections among the molecular elements of a biological system. The PANA approach uses high-throughput genomics measurements and a functional annotation scheme to extract an activity profile from each functional block -or pathway- followed by machine-learning methods to infer the relationships between these functional profiles. The result is a global, interconnected network of pathways that represents the functional cross-talk within the molecular system. We have applied this approach to describe the functional transcriptional connections during the yeast cell cycle and to identify pathways that change their connectivity in a disease condition using an Alzheimer example.

CONCLUSIONS: PANA is a useful tool to deepen in our understanding of the functional interdependences that operate within complex biological systems. We show the approach is algorithmically consistent and the inferred network is well supported by the available functional data. The method allows the dissection of the molecular basis of the functional connections and we describe the different regulatory mechanisms that explain the network{\textquoteright}s topology obtained for the yeast cell cycle data.

}, keywords = {Alzheimer Disease, Cell Cycle, DNA Replication, Gene Expression Profiling, Gene Regulatory Networks, Gluconeogenesis, Glycolysis, Oxidative Phosphorylation, Proteolysis, Purines, Saccharomyces cerevisiae, Systems biology, Ubiquitin}, issn = {1752-0509}, doi = {10.1186/1752-0509-8-S2-S7}, author = {Ponzoni, Ignacio and Nueda, Mar{\'\i}a and Tarazona, Sonia and G{\"o}tz, Stefan and Montaner, David and Dussaut, Julieta and Dopazo, Joaquin and Conesa, Ana} } @article {483, title = {Sequencing and functional analysis of the genome of a nematode egg-parasitic fungus, Pochonia chlamydosporia.}, journal = {Fungal Genet Biol}, volume = {65}, year = {2014}, month = {2014 Apr}, pages = {69-80}, abstract = {

Pochonia chlamydosporia is a worldwide-distributed soil fungus with a great capacity to infect and destroy the eggs and kill females of plant-parasitic nematodes. Additionally, it has the ability to colonize endophytically roots of economically-important crop plants, thereby promoting their growth and eliciting plant defenses. This multitrophic behavior makes P. chlamydosporia a potentially useful tool for sustainable agriculture approaches. We sequenced and assembled \~{}41 Mb of P. chlamydosporia genomic DNA and predicted 12,122 gene models, of which many were homologous to genes of fungal pathogens of invertebrates and fungal plant pathogens. Predicted genes (65\%) were functionally annotated according to Gene Ontology, and 16\% of them found to share homology with genes in the Pathogen Host Interactions (PHI) database. The genome of this fungus is highly enriched in genes encoding hydrolytic enzymes, such as proteases, glycoside hydrolases and carbohydrate esterases. We used RNA-Seq technology in order to identify the genes expressed during endophytic behavior of P. chlamydosporia when colonizing barley roots. Functional annotation of these genes showed that hydrolytic enzymes and transporters are expressed during endophytism. This structural and functional analysis of the P. chlamydosporia genome provides a starting point for understanding the molecular mechanisms involved in the multitrophic lifestyle of this fungus. The genomic information provided here should also prove useful for enhancing the capabilities of this fungus as a biocontrol agent of plant-parasitic nematodes and as a plant growth-promoting organism.

}, keywords = {Animals, Ascomycota, Female, Gene Expression Regulation, Fungal, Gene ontology, Genome, Fungal, Hordeum, Host-Pathogen Interactions, Nematoda, Ovum, Phylogeny, Plant Roots, Sequence Analysis, DNA, Signal Transduction, Transcriptome}, issn = {1096-0937}, doi = {10.1016/j.fgb.2014.02.002}, author = {Larriba, Eduardo and Jaime, Mar{\'\i}a D L A and Carbonell-Caballero, Jos{\'e} and Conesa, Ana and Dopazo, Joaquin and Nislow, Corey and Mart{\'\i}n-Nieto, Jos{\'e} and Lopez-Llorca, Luis Vicente} } @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 {566, title = {Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria.}, journal = {Mol Genet Metab}, volume = {110}, year = {2013}, month = {2013 Sep-Oct}, pages = {73-7}, abstract = {

3-Methylglutaconic aciduria (3-MGA-uria) is a heterogeneous group of syndromes characterized by an increased excretion of 3-methylglutaconic and 3-methylglutaric acids. Five types of 3-MGA-uria (I to V) with different clinical presentations have been described. Causative mutations in TAZ, OPA3, DNAJC19, ATP12, ATP5E, and TMEM70 have been identified. After excluding the known genetic causes of 3-MGA-uria we used exome sequencing to investigate a patient with Leigh syndrome and 3-MGA-uria. We identified a homozygous variant in SERAC1 (c.202C>T; p.Arg68*), that generates a premature stop codon at position 68 of SERAC1 protein. Western blot analysis in patient{\textquoteright}s fibroblasts showed a complete absence of SERAC1 that was consistent with the prediction of a truncated protein and supports the pathogenic role of the mutation. During the course of this project a parallel study identified mutations in SERAC1 as the genetic cause of the disease in 15 patients with MEGDEL syndrome, which was compatible with the clinical and biochemical phenotypes of the patient described here. In addition, our patient developed microcephaly and optic atrophy, two features not previously reported in MEGDEL syndrome. We highlight the usefulness of exome sequencing to reveal the genetic bases of human rare diseases even if only one affected individual is available.

}, keywords = {Adolescent, Adult, Carboxylic Ester Hydrolases, Child, Exome, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Male, Metabolism, Inborn Errors, mutation}, issn = {1096-7206}, doi = {10.1016/j.ymgme.2013.04.021}, author = {Tort, Frederic and Garc{\'\i}a-Silva, Mar{\'\i}a Teresa and Ferrer-Cort{\`e}s, X{\`e}nia and Navarro-Sastre, Aleix and Garcia-Villoria, Judith and Coll, Maria Josep and Vidal, Enrique and Jim{\'e}nez-Almaz{\'a}n, Jorge and Dopazo, Joaquin and Briones, Paz and Elpeleg, Orly and Ribes, Antonia} } @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 {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 {950, title = {Identification of yeast genes that confer resistance to chitosan oligosaccharide (COS) using chemogenomics.}, journal = {BMC genomics}, volume = {13}, year = {2012}, month = {2012}, pages = {267}, abstract = {BACKGROUND: Chitosan oligosaccharide (COS), a deacetylated derivative of chitin, is an abundant, and renewable natural polymer. COS has higher antimicrobial properties than chitosan and is presumed to act by disrupting/permeabilizing the cell membranes of bacteria, yeast and fungi. COS is relatively non-toxic to mammals. By identifying the molecular and genetic targets of COS, we hope to gain a better understanding of the antifungal mode of action of COS. RESULTS: Three different chemogenomic fitness assays, haploinsufficiency (HIP), homozygous deletion (HOP), and multicopy suppression (MSP) profiling were combined with a transcriptomic analysis to gain insight in to the mode of action and mechanisms of resistance to chitosan oligosaccharides. The fitness assays identified 39 yeast deletion strains sensitive to COS and 21 suppressors of COS sensitivity. The genes identified are involved in processes such as RNA biology (transcription, translation and regulatory mechanisms), membrane functions (e.g. signalling, transport and targeting), membrane structural components, cell division, and proteasome processes. The transcriptomes of control wild type and 5 suppressor strains overexpressing ARL1, BCK2, ERG24, MSG5, or RBA50, were analyzed in the presence and absence of COS. Some of the up-regulated transcripts in the suppressor overexpressing strains exposed to COS included genes involved in transcription, cell cycle, stress response and the Ras signal transduction pathway. Down-regulated transcripts included those encoding protein folding components and respiratory chain proteins. The COS-induced transcriptional response is distinct from previously described environmental stress responses (i.e. thermal, salt, osmotic and oxidative stress) and pre-treatment with these well characterized environmental stressors provided little or any resistance to COS. CONCLUSIONS: Overexpression of the ARL1 gene, a member of the Ras superfamily that regulates membrane trafficking, provides protection against COS-induced cell membrane permeability and damage. We found that the ARL1 COS-resistant over-expression strain was as sensitive to Amphotericin B, Fluconazole and Terbinafine as the wild type cells and that when COS and Fluconazole are used in combination they act in a synergistic fashion. The gene targets of COS identified in this study indicate that COS{\textquoteright}s mechanism of action is different from other commonly studied fungicides that target membranes, suggesting that COS may be an effective fungicide for drug-resistant fungal pathogens.}, issn = {1471-2164}, doi = {10.1186/1471-2164-13-267}, author = {Jaime, Mar{\'\i}a D L A and Lopez-Llorca, Luis Vicente and Ana Conesa and Lee, Anna Y and Proctor, Michael and Heisler, Lawrence E and Gebbia, Marinella and Giaever, Guri and Westwood, J Timothy and Nislow, Corey} } @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 {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 {878, title = {ARSyN: a method for the identification and removal of systematic noise in multifactorial time course microarray experiments.}, journal = {Biostatistics (Oxford, England)}, year = {2011}, month = {2011 Nov 14}, abstract = {Transcriptomic profiling experiments that aim to the identification of responsive genes in specific biological conditions are commonly set up under defined experimental designs that try to assess the effects of factors and their interactions on gene expression. Data from these controlled experiments, however, may also contain sources of unwanted noise that can distort the signal under study, affect the residuals of applied statistical models, and hamper data analysis. Commonly, normalization methods are applied to transcriptomics data to remove technical artifacts, but these are normally based on general assumptions of transcript distribution and greatly ignore both the characteristics of the experiment under consideration and the coordinative nature of gene expression. In this paper, we propose a novel methodology, ARSyN, for the preprocessing of microarray data that takes into account these 2 last aspects. By combining analysis of variance (ANOVA) modeling of gene expression values and multivariate analysis of estimated effects, the method identifies the nonstructured part of the signal associated to the experimental factors (the noise within the signal) and the structured variation of the ANOVA errors (the signal of the noise). By removing these noise fractions from the original data, we create a filtered data set that is rich in the information of interest and includes only the random noise required for inferential analysis. In this work, we focus on multifactorial time course microarray (MTCM) experiments with 2 factors: one quantitative such as time or dosage and the other qualitative, as tissue, strain, or treatment. However, the method can be used in other situations such as experiments with only one factor or more complex designs with more than 2 factors. The filtered data obtained after applying ARSyN can be further analyzed with the appropriate statistical technique to obtain the biological information required. To evaluate the performance of the filtering strategy, we have applied different statistical approaches for MTCM analysis to several real and simulated data sets, studying also the efficiency of these techniques. By comparing the results obtained with the original and ARSyN filtered data and also with other filtering techniques, we can conclude that the proposed method increases the statistical power to detect biological signals, especially in cases where there are high levels of structural noise. Software for ARSyN is freely available at http://www.ua.es/personal/mj.nueda.}, issn = {1468-4357}, author = {Nueda, Maria J and Alberto Ferrer and Ana Conesa} } @article {21266330, title = {Differential Lipid Partitioning Between Adipocytes and Tissue Macrophages Modulates Macrophage Lipotoxicity and M2/M1 Polarization in Obese Mice.}, journal = {Diabetes}, volume = {60}, number = {3}, year = {2011}, month = {2011 Jan 24}, pages = {797-809}, abstract = {

OBJECTIVE Obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response. RESEARCH DESIGN AND METHODS We addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment. RESULTS We show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell-like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization. CONCLUSIONS Our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization.

}, author = {Prieur, Xavier and Mok, Crystal Y L and Velagapudi, Vidya R and N{\'u}{\~n}ez, Vanessa and Fuentes, Luc{\'\i}a and Montaner, David and Ishikawa, Ko and Camacho, Alberto and Barbarroja, Nuria and O{\textquoteright}Rahilly, Stephen and Sethi, Jaswinder and Dopazo, Joaquin and Oresic, Matej and Ricote, Mercedes and Vidal-Puig, Antonio} } @article {22039362, title = {Discovery of an ebolavirus-like filovirus in europe.}, journal = {PLoS pathogens}, volume = {7}, year = {2011}, month = {2011 Oct}, pages = {e1002304}, abstract = {

Filoviruses, amongst the most lethal of primate pathogens, have only been reported as natural infections in sub-Saharan Africa and the Philippines. Infections of bats with the ebolaviruses and marburgviruses do not appear to be associated with disease. Here we report identification in dead insectivorous bats of a genetically distinct filovirus, provisionally named Lloviu virus, after the site of detection, Cueva del Lloviu, in Spain.

}, author = {Negredo, Ana and Palacios, Gustavo and V{\'a}zquez-Mor{\'o}n, Sonia and Gonz{\'a}lez, F{\'e}lix and Dopazo, Hern{\'a}n and Molero, Francisca and Juste, Javier and Quetglas, Juan and Savji, Nazir and de la Cruz Mart{\'\i}nez, Maria and Herrera, Jesus Enrique and Pizarro, Manuel and Hutchison, Stephen K and Echevarr{\'\i}a, Juan E and Lipkin, W Ian and Tenorio, Antonio} } @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 {21261943, title = {Recent human evolution has shaped geographical differences in susceptibility to disease.}, journal = {BMC genomics}, volume = {12}, year = {2011}, month = {2011}, pages = {55}, abstract = {

Searching for associations between genetic variants and complex diseases has been a very active area of research for over two decades. More than 51,000 potential associations have been studied and published, a figure that keeps increasing, especially with the recent explosion of array-based Genome-Wide Association Studies. Even if the number of true associations described so far is high, many of the putative risk variants detected so far have failed to be consistently replicated and are widely considered false positives. Here, we focus on the world-wide patterns of replicability of published association studies.

}, author = {Marigorta, Urko M and Lao, Oscar and Casals, Ferran and Calafell, Francesc and Morcillo-Suarez, Carlos and Faria, Rui and Bosch, Elena and Serra, Fran{\c c}ois and Bertranpetit, Jaume and Dopazo, Hern{\'a}n and Navarro, Arcadi} } @article {20478823, title = {Babelomics: an integrative platform for the analysis of transcriptomics, proteomics and genomic data with advanced functional profiling.}, journal = {Nucleic Acids Research}, volume = {38}, year = {2010}, month = {2010 May 16}, pages = {W210-W213. Featured in NAR}, chapter = {Featured in NAR}, abstract = {

Babelomics is a response to the growing necessity of integrating and analyzing different types of genomic data in an environment that allows an easy functional interpretation of the results. Babelomics includes a complete suite of methods for the analysis of gene expression data that include normalization (covering most commercial platforms), pre-processing, differential gene expression (case-controls, multiclass, survival or continuous values), predictors, clustering; large-scale genotyping assays (case controls and TDTs, and allows population stratification analysis and correction). All these genomic data analysis facilities are integrated and connected to multiple options for the functional interpretation of the experiments. Different methods of functional enrichment or gene set enrichment can be used to understand the functional basis of the experiment analyzed. Many sources of biological information, which include functional (GO, KEGG, Biocarta, Reactome, etc.), regulatory (Transfac, Jaspar, ORegAnno, miRNAs, etc.), text-mining or protein-protein interaction modules can be used for this purpose. Finally a tool for the de novo functional annotation of sequences has been included in the system. This provides support for the functional analysis of non-model species. Mirrors of Babelomics or command line execution of their individual components are now possible. Babelomics is available at http://www.babelomics.org.

}, keywords = {babelomics, gene expression, genotyping, gepas, GSA, GWAS}, url = {http://nar.oxfordjournals.org/content/38/suppl_2/W210.full}, author = {Medina, Ignacio and Carbonell, Jos{\'e} and Pulido, Luis and Madeira, Sara C and Goetz, Stefan and Ana Conesa and T{\'a}rraga, Joaqu{\'\i}n and Pascual-Montano, Alberto and Nogales-Cadenas, Ruben and Santoyo, Javier and Garc{\'\i}a, Francisco and Marb{\`a}, Martina and Montaner, David and Joaqu{\'\i}n Dopazo} } @article {549, title = {Exploring the link between germline and somatic genetic alterations in breast carcinogenesis.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010 Nov 22}, pages = {e14078}, abstract = {

Recent genome-wide association studies (GWASs) have identified candidate genes contributing to cancer risk through low-penetrance mutations. Many of these genes were unexpected and, intriguingly, included well-known players in carcinogenesis at the somatic level. To assess the hypothesis of a germline-somatic link in carcinogenesis, we evaluated the distribution of somatic gene labels within the ordered results of a breast cancer risk GWAS. This analysis suggested frequent influence on risk of genetic variation in loci encoding for "driver kinases" (i.e., kinases encoded by genes that showed higher somatic mutation rates than expected by chance and, therefore, whose deregulation may contribute to cancer development and/or progression). Assessment of these predictions using a population-based case-control study in Poland replicated the association for rs3732568 in EPHB1 (odds ratio (OR) = 0.79; 95\% confidence interval (CI): 0.63-0.98; P(trend) = 0.031). Analyses by early age at diagnosis and by estrogen receptor α (ERα) tumor status indicated potential associations for rs6852678 in CDKL2 (OR = 0.32, 95\% CI: 0.10-1.00; P(recessive) = 0.044) and rs10878640 in DYRK2 (OR = 2.39, 95\% CI: 1.32-4.30; P(dominant) = 0.003), and for rs12765929, rs9836340, rs4707795 in BMPR1A, EPHA3 and EPHA7, respectively (ERα tumor status P(interaction)<0.05). The identification of three novel candidates as EPH receptor genes might indicate a link between perturbed compartmentalization of early neoplastic lesions and breast cancer risk and progression. Together, these data may lay the foundations for replication in additional populations and could potentially increase our knowledge of the underlying molecular mechanisms of breast carcinogenesis.

}, keywords = {Adult, Bone Morphogenetic Protein Receptors, Type I, Breast, Breast Neoplasms, Calcium-Calmodulin-Dependent Protein Kinases, Case-Control Studies, Cyclin-Dependent Kinases, Disease Progression, Estrogen Receptor alpha, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Germ-Line Mutation, Humans, Odds Ratio, Poland, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases, Protein-Tyrosine Kinases, Receptor Protein-Tyrosine Kinases, Receptor, EphA3, Receptor, EphA7, Receptor, EphB1, Risk Factors}, issn = {1932-6203}, doi = {10.1371/journal.pone.0014078}, author = {Bonifaci, N{\'u}ria and G{\'o}rski, Bohdan and Masoj{\'c}, Bartlomiej and Woko{\l}orczyk, Dominika and Jakubowska, Anna and D{\k e}bniak, Tadeusz and Berenguer, Antoni and Serra Musach, Jordi and Brunet, Joan and Dopazo, Joaquin and Narod, Steven A and Lubi{\'n}ski, Jan and L{\'a}zaro, Conxi and Cybulski, Cezary and Pujana, Miguel Angel} } @article {542, title = {Functional analysis of multiple genomic signatures demonstrates that classification algorithms choose phenotype-related genes.}, journal = {Pharmacogenomics J}, volume = {10}, year = {2010}, month = {2010 Aug}, pages = {310-23}, abstract = {

Gene expression signatures of toxicity and clinical response benefit both safety assessment and clinical practice; however, difficulties in connecting signature genes with the predicted end points have limited their application. The Microarray Quality Control Consortium II (MAQCII) project generated 262 signatures for ten clinical and three toxicological end points from six gene expression data sets, an unprecedented collection of diverse signatures that has permitted a wide-ranging analysis on the nature of such predictive models. A comprehensive analysis of the genes of these signatures and their nonredundant unions using ontology enrichment, biological network building and interactome connectivity analyses demonstrated the link between gene signatures and the biological basis of their predictive power. Different signatures for a given end point were more similar at the level of biological properties and transcriptional control than at the gene level. Signatures tended to be enriched in function and pathway in an end point and model-specific manner, and showed a topological bias for incoming interactions. Importantly, the level of biological similarity between different signatures for a given end point correlated positively with the accuracy of the signature predictions. These findings will aid the understanding, and application of predictive genomic signatures, and support their broader application in predictive medicine.

}, keywords = {Algorithms, Databases, Genetic, Endpoint Determination, Gene Expression Profiling, Genomics, Humans, Neural Networks, Computer, Oligonucleotide Array Sequence Analysis, Phenotype, Predictive Value of Tests, Proteins, Quality Control}, issn = {1473-1150}, doi = {10.1038/tpj.2010.35}, author = {Shi, W and Bessarabova, M and Dosymbekov, D and Dezso, Z and Nikolskaya, T and Dudoladova, M and Serebryiskaya, T and Bugrim, A and Guryanov, A and Brennan, R J and Shah, R and Dopazo, J and Chen, M and Deng, Y and Shi, T and Jurman, G and Furlanello, C and Thomas, R S and Corton, J C and Tong, W and Shi, L and Nikolsky, Y} } @article {20361057, title = {Initial genomics of the human nucleolus.}, journal = {PLoS genetics}, volume = {6}, year = {2010}, month = {2010}, pages = {e1000889}, abstract = {

We report for the first time the genomics of a nuclear compartment of the eukaryotic cell. 454 sequencing and microarray analysis revealed the pattern of nucleolus-associated chromatin domains (NADs) in the linear human genome and identified different gene families and certain satellite repeats as the major building blocks of NADs, which constitute about 4\% of the genome. Bioinformatic evaluation showed that NAD-localized genes take part in specific biological processes, like the response to other organisms, odor perception, and tissue development. 3D FISH and immunofluorescence experiments illustrated the spatial distribution of NAD-specific chromatin within interphase nuclei and its alteration upon transcriptional changes. Altogether, our findings describe the nature of DNA sequences associated with the human nucleolus and provide insights into the function of the nucleolus in genome organization and establishment of nuclear architecture.

}, keywords = {NGS, nucleolus}, doi = {10.1371/journal.pgen.1000889}, url = {http://www.plosgenetics.org/article/info\%3Adoi\%2F10.1371\%2Fjournal.pgen.1000889}, author = {N{\'e}meth, Attila and Ana Conesa and Santoyo-L{\'o}pez, Javier and Medina, Ignacio and Montaner, David and P{\'e}terfia, B{\'a}lint and Solovei, Irina and Cremer, Thomas and Dopazo, Joaquin and L{\"a}ngst, Gernot} } @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 {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 {576, title = {Serial Expression Analysis: a web tool for the analysis of serial gene expression data.}, journal = {Nucleic Acids Res}, volume = {38}, year = {2010}, month = {2010 Jul}, pages = {W239-45}, abstract = {

Serial transcriptomics experiments investigate the dynamics of gene expression changes associated with a quantitative variable such as time or dosage. The statistical analysis of these data implies the study of global and gene-specific expression trends, the identification of significant serial changes, the comparison of expression profiles and the assessment of transcriptional changes in terms of cellular processes. We have created the SEA (Serial Expression Analysis) suite to provide a complete web-based resource for the analysis of serial transcriptomics data. SEA offers five different algorithms based on univariate, multivariate and functional profiling strategies framed within a user-friendly interface and a project-oriented architecture to facilitate the analysis of serial gene expression data sets from different perspectives. SEA is available at sea.bioinfo.cipf.es.

}, keywords = {Algorithms, Gene Expression Profiling, Internet, Kinetics, Linear Models, Oligonucleotide Array Sequence Analysis, Software}, issn = {1362-4962}, doi = {10.1093/nar/gkq488}, author = {Nueda, Maria Jos{\'e} and Carbonell, Jos{\'e} and Medina, Ignacio and Dopazo, Joaquin and Conesa, Ana} } @book {762, title = {Evoluci{\'o}n y Adaptaci{\'o}n.150 a{\~n}os despu{\'e}s del Origen de las Especies}, year = {2009}, pages = {510}, publisher = {Obrapropia.}, organization = {Obrapropia.}, address = {Valencia. Espa{\~n}a}, abstract = {

Evoluci\ón y Adaptaci\ón: 150 a\ños despu\és del Origen de las Especies es un homenaje a la figura de Charles Darwin al cumplirse 200 a\ños de su nacimiento y 150 a\ños de la publicaci\ón que lo hiciese mundialmente famoso. En esta edici\ón 101 autores convocados por la Sociedad Espa\ñola de Biolog\ía Evolutiva han resumido su trabajo de investigaci\ón en 51 art\ículos. Estos se han agrupado en tem\áticas que abarcan los problemas de la evoluci\ón molecular,\ el cambio morfol\ógico, la evoluci\ón del desarrollo,\ el origen de las especies y su interacci\ón, la diversidad biol\ógica, la evoluci\ón del comportamiento, la paleobiolog\ía, la evoluci\ón experimental, la evoluci\ón cultural y la evoluci\ón en la filosof\ía y la docencia. Muchos de estos trabajos representan d\écadas de constante investigaci\ón en el laboratorio y en el campo. El com\ún denominador de los art\ículos que contiene este libro es el esfuerzo por transmitir a un p\úblico no necesariamente experto la actualidad de las investigaciones que en el campo de la adaptaci\ón y la evoluci\ón se desarrolla en diferentes laboratorios. Esta obra resume por lo tanto, gran parte de las investigaciones que \ en materia de evoluci\ón biol\ógica se realiza en Espa\ña. Esta edici\ón deja constancia entonces del \"Hecho de la Evoluci\ón\", y de la actualidad de teor\ía evolutiva moderna como cuerpo explicativo del mundo biol\ógico 150 a\ños despu\és del origen de las especies.\ 

}, issn = {978-84-92910-06-9}, editor = {H. Dopazo and Navarro, A.} } @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 {580, title = {Functional assessment of time course microarray data.}, journal = {BMC Bioinformatics}, volume = {10 Suppl 6}, year = {2009}, month = {2009 Jun 16}, pages = {S9}, abstract = {

MOTIVATION: Time-course microarray experiments study the progress of gene expression along time across one or several experimental conditions. Most developed analysis methods focus on the clustering or the differential expression analysis of genes and do not integrate functional information. The assessment of the functional aspects of time-course transcriptomics data requires the use of approaches that exploit the activation dynamics of the functional categories to where genes are annotated.

METHODS: We present three novel methodologies for the functional assessment of time-course microarray data. i) maSigFun derives from the maSigPro method, a regression-based strategy to model time-dependent expression patterns and identify genes with differences across series. maSigFun fits a regression model for groups of genes labeled by a functional class and selects those categories which have a significant model. ii) PCA-maSigFun fits a PCA model of each functional class-defined expression matrix to extract orthogonal patterns of expression change, which are then assessed for their fit to a time-dependent regression model. iii) ASCA-functional uses the ASCA model to rank genes according to their correlation to principal time expression patterns and assess functional enrichment on a GSA fashion. We used simulated and experimental datasets to study these novel approaches. Results were compared to alternative methodologies.

RESULTS: Synthetic and experimental data showed that the different methods are able to capture different aspects of the relationship between genes, functions and co-expression that are biologically meaningful. The methods should not be considered as competitive but they provide different insights into the molecular and functional dynamic events taking place within the biological system under study.

}, keywords = {Computer Simulation, Gene Expression Profiling, Oligonucleotide Array Sequence Analysis, Time Factors}, issn = {1471-2105}, doi = {10.1186/1471-2105-10-S6-S9}, author = {Nueda, Maria Jos{\'e} and Sebasti{\'a}n, Patricia and Tarazona, Sonia and Garcia-Garcia, Francisco and Dopazo, Joaquin and Ferrer, Alberto and Conesa, Ana} } @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.} } @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} } @inbook {684, title = {Protein Interactions for Functional Genomics}, booktitle = {Biological Data Mining in Protein Interaction Networks}, year = {2009}, pages = {223-238}, publisher = {Idea Group Inc (IGI)}, organization = {Idea Group Inc (IGI)}, address = {Hershey, USA}, issn = {1605663980, 978160566398}, url = {http://books.google.es/books?id=pNyCy5GsqtkC}, author = {Minguez, P. and Dopazo, J.}, editor = {Li, Xiao-Li and Ng, See-Kiong} } @article {594, title = {High-throughput functional annotation and data mining with the Blast2GO suite.}, journal = {Nucleic Acids Res}, volume = {36}, year = {2008}, month = {2008 Jun}, pages = {3420-35}, abstract = {

Functional genomics technologies have been widely adopted in the biological research of both model and non-model species. An efficient functional annotation of DNA or protein sequences is a major requirement for the successful application of these approaches as functional information on gene products is often the key to the interpretation of experimental results. Therefore, there is an increasing need for bioinformatics resources which are able to cope with large amount of sequence data, produce valuable annotation results and are easily accessible to laboratories where functional genomics projects are being undertaken. We present the Blast2GO suite as an integrated and biologist-oriented solution for the high-throughput and automatic functional annotation of DNA or protein sequences based on the Gene Ontology vocabulary. The most outstanding Blast2GO features are: (i) the combination of various annotation strategies and tools controlling type and intensity of annotation, (ii) the numerous graphical features such as the interactive GO-graph visualization for gene-set function profiling or descriptive charts, (iii) the general sequence management features and (iv) high-throughput capabilities. We used the Blast2GO framework to carry out a detailed analysis of annotation behaviour through homology transfer and its impact in functional genomics research. Our aim is to offer biologists useful information to take into account when addressing the task of functionally characterizing their sequence data.

}, keywords = {Animals, Computational Biology, Computer Graphics, Databases, Genetic, Expressed Sequence Tags, Genes, Genomics, Sequence Analysis, DNA, Sequence Analysis, Protein, Software, Vocabulary, Controlled}, issn = {1362-4962}, doi = {10.1093/nar/gkn176}, author = {G{\"o}tz, Stefan and Garc{\'\i}a-G{\'o}mez, Juan Miguel and Terol, Javier and Williams, Tim D and Nagaraj, Shivashankar H and Nueda, Maria Jos{\'e} and Robles, Montserrat and Talon, Manuel and Dopazo, Joaquin and Conesa, Ana} } @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 {17519250, title = {Discovering gene expression patterns in time course microarray experiments by ANOVA-SCA}, journal = {Bioinformatics}, volume = {23}, number = {14}, year = {2007}, note = {Nueda, Maria Jose Conesa, Ana Westerhuis, Johan A Hoefsloot, Huub C J Smilde, Age K Talon, Manuel Ferrer, Alberto Research Support, Non-U.S. Gov{\textquoteright}t England Bioinformatics (Oxford, England) Bioinformatics. 2007 Jul 15;23(14):1792-800. Epub 2007 May 22.}, pages = {1792-800}, abstract = {MOTIVATION: Designed microarray experiments are used to investigate the effects that controlled experimental factors have on gene expression and learn about the transcriptional responses associated with external variables. In these datasets, signals of interest coexist with varying sources of unwanted noise in a framework of (co)relation among the measured variables and with the different levels of the studied factors. Discovering experimentally relevant transcriptional changes require methodologies that take all these elements into account. RESULTS: In this work, we develop the application of the Analysis of variance-simultaneous component analysis (ANOVA-SCA) Smilde et al. Bioinformatics, (2005) to the analysis of multiple series time course microarray data as an example of multifactorial gene expression profiling experiments. We denoted this implementation as ASCA-genes. We show how the combination of ANOVA-modeling and a dimension reduction technique is effective in extracting targeted signals from data by-passing structural noise. The methodology is valuable for identifying main and secondary responses associated with the experimental factors and spotting relevant experimental conditions. We additionally propose a novel approach for gene selection in the context of the relation of individual transcriptional patterns to global gene expression signals. We demonstrate the methodology on both real and synthetic datasets. AVAILABILITY: ASCA-genes has been implemented in the statistical language R and is available at http://www.ivia.es/centrodegenomica/bioinformatics.htm. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.}, keywords = {Algorithms *Analysis of Variance Computational Biology/*methods Computer Simulation Data Interpretation, Genetic, Genetic Models, Statistical Gene Expression Profiling/*methods Models, Statistical Oligonucleotide Array Sequence Analysis/*methods Principal Component Analysis Time Factors Transcription}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17519250}, author = {Nueda, M. J. and A. Conesa and Westerhuis, J. A. and Hoefsloot, H. C. and Smilde, A. K. and Talon, M. and Ferrer, A.} } @article {17018596, title = {ERCC4 associated with breast cancer risk: a two-stage case-control study using high-throughput genotyping}, journal = {Cancer Res}, volume = {66}, number = {19}, year = {2006}, note = {Milne, Roger Laughlin Ribas, Gloria Gonzalez-Neira, Anna Fagerholm, Rainer Salas, Antonio Gonzalez, Emilio Dopazo, Joaquin Nevanlinna, Heli Robledo, Mercedes Benitez, Javier Comparative Study Multicenter Study Research Support, Non-U.S. Gov{\textquoteright}t United States Cancer research Cancer Res. 2006 Oct 1;66(19):9420-7.}, pages = {9420-7}, abstract = {The failure of linkage studies to identify further high-penetrance susceptibility genes for breast cancer points to a polygenic model, with more common variants having modest effects on risk, as the most likely candidate. We have carried out a two-stage case-control study in two European populations to identify low-penetrance genes for breast cancer using high-throughput genotyping. Single-nucleotide polymorphisms (SNPs) were selected across preselected cancer-related genes, choosing tagSNPs and functional variants where possible. In stage 1, genotype frequencies for 640 SNPs in 111 genes were compared between 864 breast cancer cases and 845 controls from the Spanish population. In stage 2, candidate SNPs identified in stage 1 (nominal P < 0.01) were tested in a Finnish series of 884 cases and 1,104 controls. Of the 10 candidate SNPs in seven genes identified in stage 1, one (rs744154) on intron 1 of ERCC4, a gene belonging to the nucleotide excision repair pathway, was associated with recessive protection from breast cancer after adjustment for multiple testing in stage 2 (odds ratio, 0.57; Bonferroni-adjusted P = 0.04). After considering potential functional SNPs in the region of high linkage disequilibrium that extends across the entire gene and upstream into the promoter region, we concluded that rs744154 itself could be causal. Although intronic, it is located on the first intron, in a region that is highly conserved across species, and could therefore be functionally important. This study suggests that common intronic variation in ERCC4 is associated with protection from breast cancer.}, keywords = {80 and over Breast Neoplasms/epidemiology/*genetics/pathology Case-Control Studies DNA-Binding Proteins/genetics/*physiology Female Finland/epidemiology Genes, Adult Aged Aged, Recessive Genetic Predisposition to Disease Genotype Humans Introns/genetics Linkage Disequilibrium Middle Aged Neoplasm Proteins/genetics/*physiology Neoplasm Staging *Polymorphism, Single Nucleotide Risk Spain/epidemiology}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17018596}, author = {Milne, R. L. and Ribas, G. and Gonzalez-Neira, A. and Fagerholm, R. and Salas, A. and Gonzalez, E. and Dopazo, J. and Nevanlinna, H. and M. Robledo and Benitez, J.} } @article {16481333, title = {maSigPro: a method to identify significantly differential expression profiles in time-course microarray experiments}, journal = {Bioinformatics}, volume = {22}, number = {9}, year = {2006}, note = {Conesa, Ana Nueda, Maria Jose Ferrer, Alberto Talon, Manuel England Bioinformatics (Oxford, England) Bioinformatics. 2006 May 1;22(9):1096-102. Epub 2006 Feb 15.}, pages = {1096-102}, abstract = {MOTIVATION: Multi-series time-course microarray experiments are useful approaches for exploring biological processes. In this type of experiments, the researcher is frequently interested in studying gene expression changes along time and in evaluating trend differences between the various experimental groups. The large amount of data, multiplicity of experimental conditions and the dynamic nature of the experiments poses great challenges to data analysis. RESULTS: In this work, we propose a statistical procedure to identify genes that show different gene expression profiles across analytical groups in time-course experiments. The method is a two-regression step approach where the experimental groups are identified by dummy variables. The procedure first adjusts a global regression model with all the defined variables to identify differentially expressed genes, and in second a variable selection strategy is applied to study differences between groups and to find statistically significant different profiles. The methodology is illustrated on both a real and a simulated microarray dataset.}, keywords = {*Algorithms Computer Simulation Gene Expression/*physiology Gene Expression Profiling/*methods *Models, Genetic Models, Statistical Oligonucleotide Array Sequence Analysis/*methods *Software Time Factors}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16481333}, author = {A. Conesa and Nueda, M. J. and Ferrer, A. and Talon, M.} } @article {16170324, title = {The C-type lectin fold as an evolutionary solution for massive sequence variation}, journal = {Nat Struct Mol Biol}, volume = {12}, number = {10}, year = {2005}, note = {McMahon, Stephen A Miller, Jason L Lawton, Jeffrey A Kerkow, Donald E Hodes, Asher Marti-Renom, Marc A Doulatov, Sergei Narayanan, Eswar Sali, Andrej Miller, Jeff F Ghosh, Partho F31AI061840/AI/NIAID NIH HHS/United States F32AI49695/AI/NIAID NIH HHS/United States T32GM008326/GM/NIGMS NIH HHS/United States 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 Nature structural \& molecular biology Nat Struct Mol Biol. 2005 Oct;12(10):886-92. Epub 2005 Sep 18.}, pages = {886-92}, abstract = {Only few instances are known of protein folds that tolerate massive sequence variation for the sake of binding diversity. The most extensively characterized is the immunoglobulin fold. We now add to this the C-type lectin (CLec) fold, as found in the major tropism determinant (Mtd), a retroelement-encoded receptor-binding protein of Bordetella bacteriophage. Variation in Mtd, with its approximately 10(13) possible sequences, enables phage adaptation to Bordetella spp. Mtd is an intertwined, pyramid-shaped trimer, with variable residues organized by its CLec fold into discrete receptor-binding sites. The CLec fold provides a highly static scaffold for combinatorial display of variable residues, probably reflecting a different evolutionary solution for balancing diversity against stability from that in the immunoglobulin fold. Mtd variants are biased toward the receptor pertactin, and there is evidence that the CLec fold is used broadly for sequence variation by related retroelements.}, keywords = {Amino Acid Sequence Bacterial Outer Membrane Proteins/*chemistry Bacteriophages/*metabolism Bordetella/*virology Evolution, Bordetella/*chemistry, C-Type/*chemistry Molecular Sequence Data Protein Conformation Protein Folding Viral Proteins/*chemistry/*genetics Virulence Factors, Molecular Genetic Variation Genome, Viral Lectins}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16170324}, author = {McMahon, S. A. and Miller, J. L. and Lawton, J. A. and Kerkow, D. E. and Hodes, A. and M. A. Marti-Renom and Doulatov, S. and Narayanan, E. and Sali, A. and Miller, J. F. and Ghosh, P.} } @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 {11254175, title = {Identification of optimal regions for phylogenetic studies on VP1 gene of foot-and-mouth disease virus: analysis of types A and O Argentinean viruses}, journal = {Vet Res}, volume = {32}, number = {1}, year = {2001}, note = {Nunez, J I Martin, M J Piccone, M E Carrillo, E Palma, E L Dopazo, J Sobrino, F Research Support, Non-U.S. Gov{\textquoteright}t France Veterinary research Vet Res. 2001 Jan-Feb;32(1):31-45.}, pages = {31-45}, abstract = {An analysis of the informative content of sequence stretches on the foot-and-mouth disease virus (FMDV) VPI gene was applied to two important viral serotypes: A and O. Several sequence regions were identified to allow the reconstruction of phylogenetic trees equivalent to those derived from the whole VPI gene. The optimal informative regions for sequence windows of 150 to 250 nt were predicted between positions 250 and 550 of the gene. The sequences spanning the 250 nt of the 3{\textquoteright} end (positions 400 to 650), extensively used for FMDV phylogenetic analyses, showed a lower informative content. In spite of this, the use of sequences from this region allowed the derivation of phylogenetic trees for type A and type O FMDVs which showed topologies similar to those previously reported for the whole VP1 gene. When the sequences determined for viruses isolated in Argentina, between 1990 and 1993, were included in these analyses, the results obtained revealed features of the circulation of type A and type O viruses in the field, in the months that preceded the eradication of the disease in this country. Type A viruses were closely related to an Argentinean vaccine strain, and defined an independent cluster within this serotype. Among the type O viruses analysed, two groups were distinguished; one was closely related to the South American vaccine strains, while the other was grouped with viruses of the O3 subtype. In addition, a detailed phylogeny for type A FMDV is presented.}, keywords = {Amino Acid Sequence Animals Aphthovirus/classification/*genetics Base Sequence Capsid/chemistry/*genetics Capsid Proteins DNA, Complementary/chemistry Molecular Sequence Data *Phylogeny Polymerase Chain Reaction RNA, Viral/chemistry/genetics Serotyping Viral Proteins/analysis/*genetics}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=11254175}, author = {Nunez, J. I. and Martin, M. J. and Piccone, M. E. and Carrillo, E. and Palma, E. L. and Dopazo, J. and Sobrino, F.} }