%0 Journal Article %J Front Immunol %D 2024 %T Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches. %A Niarakis, Anna %A Ostaszewski, Marek %A Mazein, Alexander %A Kuperstein, Inna %A Kutmon, Martina %A Gillespie, Marc E %A Funahashi, Akira %A Acencio, Marcio Luis %A Hemedan, Ahmed %A Aichem, Michael %A Klein, Karsten %A Czauderna, Tobias %A Burtscher, Felicia %A Yamada, Takahiro G %A Hiki, Yusuke %A Hiroi, Noriko F %A Hu, Finterly %A Pham, Nhung %A Ehrhart, Friederike %A Willighagen, Egon L %A Valdeolivas, Alberto %A Dugourd, Aurélien %A Messina, Francesco %A Esteban-Medina, Marina %A Peña-Chilet, Maria %A Rian, Kinza %A Soliman, Sylvain %A Aghamiri, Sara Sadat %A Puniya, Bhanwar Lal %A Naldi, Aurélien %A Helikar, Tomáš %A Singh, Vidisha %A Fernández, Marco Fariñas %A Bermudez, Viviam %A Tsirvouli, Eirini %A Montagud, Arnau %A Noël, Vincent %A Ponce-de-Leon, Miguel %A Maier, Dieter %A Bauch, Angela %A Gyori, Benjamin M %A Bachman, John A %A Luna, Augustin %A Piñero, Janet %A Furlong, Laura I %A Balaur, Irina %A Rougny, Adrien %A Jarosz, Yohan %A Overall, Rupert W %A Phair, Robert %A Perfetto, Livia %A Matthews, Lisa %A Rex, Devasahayam Arokia Balaya %A Orlic-Milacic, Marija %A Gomez, Luis Cristobal Monraz %A De Meulder, Bertrand %A Ravel, Jean Marie %A Jassal, Bijay %A Satagopam, Venkata %A Wu, Guanming %A Golebiewski, Martin %A Gawron, Piotr %A Calzone, Laurence %A Beckmann, Jacques S %A Evelo, Chris T %A D'Eustachio, Peter %A Schreiber, Falk %A Saez-Rodriguez, Julio %A Dopazo, Joaquin %A Kuiper, Martin %A Valencia, Alfonso %A Wolkenhauer, Olaf %A Kitano, Hiroaki %A Barillot, Emmanuel %A Auffray, Charles %A Balling, Rudi %A Schneider, Reinhard %K Computer Simulation %K COVID-19 %K drug repositioning %K Humans %K SARS-CoV-2 %K Systems biology %X

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.

%B Front Immunol %V 14 %P 1282859 %8 2023 %G eng %R 10.3389/fimmu.2023.1282859 %0 Journal Article %J Hum Genomics %D 2023 %T A crowdsourcing database for the copy-number variation of the Spanish population. %A López-López, Daniel %A Roldán, Gema %A Fernandez-Rueda, Jose L %A Bostelmann, Gerrit %A Carmona, Rosario %A Aquino, Virginia %A Perez-Florido, Javier %A Ortuno, Francisco %A Pita, Guillermo %A Núñez-Torres, Rocío %A González-Neira, Anna %A Peña-Chilet, Maria %A Dopazo, Joaquin %X

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.

%B Hum Genomics %V 17 %P 20 %8 2023 Mar 09 %G eng %N 1 %R 10.1186/s40246-023-00466-8 %0 Journal Article %J Cell Rep %D 2023 %T Defective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis. %A Pellegrinelli, Vanessa %A Figueroa-Juárez, Elizabeth %A Samuelson, Isabella %A U-Din, Mueez %A Rodriguez-Fdez, Sonia %A Virtue, Samuel %A Leggat, Jennifer %A Cubuk, Cankut %A Peirce, Vivian J %A Niemi, Tarja %A Campbell, Mark %A Rodriguez-Cuenca, Sergio %A Dopazo, Joaquin %A Carobbio, Stefania %A Virtanen, Kirsi A %A Vidal-Puig, Antonio %X

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.

%B Cell Rep %V 42 %P 112640 %8 2023 Jun 13 %G eng %N 6 %R 10.1016/j.celrep.2023.112640 %0 Journal Article %J Int J Mol Sci %D 2023 %T Detection of High Level of Co-Infection and the Emergence of Novel SARS CoV-2 Delta-Omicron and Omicron-Omicron Recombinants in the Epidemiological Surveillance of Andalusia. %A Perez-Florido, Javier %A Casimiro-Soriguer, Carlos S %A Ortuno, Francisco %A Fernandez-Rueda, Jose L %A Aguado, Andrea %A Lara, María %A Riazzo, Cristina %A Rodriguez-Iglesias, Manuel A %A Camacho-Martinez, Pedro %A Merino-Diaz, Laura %A Pupo-Ledo, Inmaculada %A de Salazar, Adolfo %A Viñuela, Laura %A Fuentes, Ana %A Chueca, Natalia %A García, Federico %A Dopazo, Joaquin %A Lepe, Jose A %X

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

%B Int J Mol Sci %V 24 %8 2023 Jan 26 %G eng %N 3 %R 10.3390/ijms24032419 %0 Journal Article %J Epidemiol Infect %D 2023 %T Evaluation of a combined detection of SARS-CoV-2 and its variants using real-time allele-specific PCR strategy: an advantage for clinical practice. %A Chaves-Blanco, Lucía %A de Salazar, Adolfo %A Fuentes, Ana %A Viñuela, Laura %A Perez-Florido, Javier %A Dopazo, Joaquin %A García, Federico %K Alleles %K COVID-19 %K COVID-19 Testing %K Humans %K Real-Time Polymerase Chain Reaction %K SARS-CoV-2 %K Sensitivity and Specificity %X

This study aimed to assess the ability of a real-time reverse transcription polymerase chain reaction (RT-PCR) with multiple targets to detect SARS-CoV-2 and its variants in a single test. Nasopharyngeal specimens were collected from patients in Granada, Spain, between January 2021 and December 2022. Five allele-specific RT-PCR kits were used sequentially, with each kit designed to detect a predominant variant at the time. When the Alpha variant was dominant, the kit included the HV69/70 deletion, E and N genes. When Delta replaced Alpha, the kit incorporated the L452R mutation in addition to E and N genes. When Omicron became dominant, L452R was replaced with the N679K mutation. Before incorporating each variant kit, a comparative analysis was carried out with SARS-CoV-2 whole genome sequencing (WGS). The results demonstrated that RT-PCR with multiple targets can provide rapid and effective detection of SARS-CoV-2 and its variants in a single test. A very high degree of agreement (96.2%) was obtained between the comparison of RT-PCR and WGS. Allele-specific RT-PCR assays make it easier to implement epidemiological surveillance systems for effective public health decision making.

%B Epidemiol Infect %V 151 %P e201 %8 2023 Nov 24 %G eng %R 10.1017/S095026882300184X %0 Journal Article %J Front Bioinform %D 2023 %T Visualization of automatically combined disease maps and pathway diagrams for rare diseases. %A Gawron, Piotr %A Hoksza, David %A Piñero, Janet %A Peña-Chilet, Maria %A Esteban-Medina, Marina %A Fernandez-Rueda, Jose Luis %A Colonna, Vincenza %A Smula, Ewa %A Heirendt, Laurent %A Ancien, François %A Grouès, Valentin %A Satagopam, Venkata P %A Schneider, Reinhard %A Dopazo, Joaquin %A Furlong, Laura I %A Ostaszewski, Marek %X

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

%B Front Bioinform %V 3 %P 1101505 %8 2023 %G eng %R 10.3389/fbinf.2023.1101505 %0 Journal Article %J Clin Genet %D 2022 %T CIBERER: Spanish National Network for Research on Rare Diseases: a highly productive collaborative initiative. %A Luque, Juan %A Mendes, Ingrid %A Gómez, Beatriz %A Morte, Beatriz %A de Heredia, Miguel López %A Herreras, Enrique %A Corrochano, Virginia %A Bueren, Juan %A Gallano, Pia %A Artuch, Rafael %A Fillat, Cristina %A Pérez-Jurado, Luis A %A Montoliu, Lluis %A Carracedo, Ángel %A Millán, José M %A Webb, Susan M %A Palau, Francesc %A Lapunzina, Pablo %X

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

%B Clin Genet %8 2022 Jan 20 %G eng %R 10.1111/cge.14113 %0 Journal Article %J Arch Bronconeumol %D 2022 %T Incidence and Prevalence of Children's Diffuse Lung Disease in Spain. %A Torrent-Vernetta, Alba %A Gaboli, Mirella %A Castillo-Corullón, Silvia %A Mondéjar-López, Pedro %A Sanz Santiago, Verónica %A Costa-Colomer, Jordi %A Osona, Borja %A Torres-Borrego, Javier %A de la Serna-Blázquez, Olga %A Bellón Alonso, Sara %A Caro Aguilera, Pilar %A Gimeno-Díaz de Atauri, Álvaro %A Valenzuela Soria, Alfredo %A Ayats, Roser %A Martin de Vicente, Carlos %A Velasco González, Valle %A Moure González, José Domingo %A Canino Calderín, Elisa María %A Pastor-Vivero, María Dolores %A Villar Álvarez, María Ángeles %A Rovira-Amigo, Sandra %A Iglesias Serrano, Ignacio %A Díez Izquierdo, Ana %A de Mir Messa, Inés %A Gartner, Silvia %A Navarro, Alexandra %A Baz-Redón, Noelia %A Carmona, Rosario %A Camats-Tarruella, Núria %A Fernández-Cancio, Mónica %A Rapp, Christina %A Dopazo, Joaquin %A Griese, Matthias %A Moreno-Galdó, Antonio %X

BACKGROUND: Children's diffuse lung disease, also known as children'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.

%B Arch Bronconeumol %V 58 %P 22-29 %8 2022 Jan %G eng %N 1 %R 10.1016/j.arbres.2021.06.001 %0 Journal Article %J Hum Mol Genet %D 2022 %T Novel genes and sex differences in COVID-19 severity. %A Cruz, Raquel %A Almeida, Silvia Diz-de %A Heredia, Miguel López %A Quintela, Inés %A Ceballos, Francisco C %A Pita, Guillermo %A Lorenzo-Salazar, José M %A González-Montelongo, Rafaela %A Gago-Domínguez, Manuela %A Porras, Marta Sevilla %A Castaño, Jair Antonio Tenorio %A Nevado, Julián %A Aguado, Jose María %A Aguilar, Carlos %A Aguilera-Albesa, Sergio %A Almadana, Virginia %A Almoguera, Berta %A Alvarez, Nuria %A Andreu-Bernabeu, Álvaro %A Arana-Arri, Eunate %A Arango, Celso %A Arranz, María J %A Artiga, Maria-Jesus %A Baptista-Rosas, Raúl C %A Barreda-Sánchez, María %A Belhassen-Garcia, Moncef %A Bezerra, Joao F %A Bezerra, Marcos A C %A Boix-Palop, Lucía %A Brión, Maria %A Brugada, Ramón %A Bustos, Matilde %A Calderón, Enrique J %A Carbonell, Cristina %A Castano, Luis %A Castelao, Jose E %A Conde-Vicente, Rosa %A Cordero-Lorenzana, M Lourdes %A Cortes-Sanchez, Jose L %A Corton, Marta %A Darnaude, M Teresa %A De Martino-Rodríguez, Alba %A Campo-Pérez, Victor %A Bustamante, Aranzazu Diaz %A Domínguez-Garrido, Elena %A Luchessi, André D %A Eirós, Rocío %A Sanabria, Gladys Mercedes Estigarribia %A Fariñas, María Carmen %A Fernández-Robelo, Uxía %A Fernández-Rodríguez, Amanda %A Fernández-Villa, Tania %A Gil-Fournier, Belén %A Gómez-Arrue, Javier %A Álvarez, Beatriz González %A Quirós, Fernan Gonzalez Bernaldo %A González-Peñas, Javier %A Gutiérrez-Bautista, Juan F %A Herrero, María José %A Herrero-Gonzalez, Antonio %A Jimenez-Sousa, María A %A Lattig, María Claudia %A Borja, Anabel Liger %A Lopez-Rodriguez, Rosario %A Mancebo, Esther %A Martín-López, Caridad %A Martín, Vicente %A Martinez-Nieto, Oscar %A Martinez-Lopez, Iciar %A Martinez-Resendez, Michel F %A Martinez-Perez, Ángel %A Mazzeu, Juliana A %A Macías, Eleuterio Merayo %A Minguez, Pablo %A Cuerda, Victor Moreno %A Silbiger, Vivian N %A Oliveira, Silviene F %A Ortega-Paino, Eva %A Parellada, Mara %A Paz-Artal, Estela %A Santos, Ney P C %A Pérez-Matute, Patricia %A Perez, Patricia %A Pérez-Tomás, M Elena %A Perucho, Teresa %A Pinsach-Abuin, Mel Lina %A Pompa-Mera, Ericka N %A Porras-Hurtado, Gloria L %A Pujol, Aurora %A León, Soraya Ramiro %A Resino, Salvador %A Fernandes, Marianne R %A Rodríguez-Ruiz, Emilio %A Rodriguez-Artalejo, Fernando %A Rodriguez-Garcia, José A %A Ruiz-Cabello, Francisco %A Ruiz-Hornillos, Javier %A Ryan, Pablo %A Soria, José Manuel %A Souto, Juan Carlos %A Tamayo, Eduardo %A Tamayo-Velasco, Alvaro %A Taracido-Fernandez, Juan Carlos %A Teper, Alejandro %A Torres-Tobar, Lilian %A Urioste, Miguel %A Valencia-Ramos, Juan %A Yáñez, Zuleima %A Zarate, Ruth %A Nakanishi, Tomoko %A Pigazzini, Sara %A Degenhardt, Frauke %A Butler-Laporte, Guillaume %A Maya-Miles, Douglas %A Bujanda, Luis %A Bouysran, Youssef %A Palom, Adriana %A Ellinghaus, David %A Martínez-Bueno, Manuel %A Rolker, Selina %A Amitrano, Sara %A Roade, Luisa %A Fava, Francesca %A Spinner, Christoph D %A Prati, Daniele %A Bernardo, David %A García, Federico %A Darcis, Gilles %A Fernández-Cadenas, Israel %A Holter, Jan Cato %A Banales, Jesus M %A Frithiof, Robert %A Duga, Stefano %A Asselta, Rosanna %A Pereira, Alexandre C %A Romero-Gómez, Manuel %A Nafría-Jiménez, Beatriz %A Hov, Johannes R %A Migeotte, Isabelle %A Renieri, Alessandra %A Planas, Anna M %A Ludwig, Kerstin U %A Buti, Maria %A Rahmouni, Souad %A Alarcón-Riquelme, Marta E %A Schulte, Eva C %A Franke, Andre %A Karlsen, Tom H %A Valenti, Luca %A Zeberg, Hugo %A Richards, Brent %A Ganna, Andrea %A Boada, Mercè %A Rojas, Itziar %A Ruiz, Agustín %A Sánchez, Pascual %A Real, Luis Miguel %A Guillén-Navarro, Encarna %A Ayuso, Carmen %A González-Neira, Anna %A Riancho, José A %A Rojas-Martinez, Augusto %A Flores, Carlos %A Lapunzina, Pablo %A Carracedo, Ángel %X

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.

%B Hum Mol Genet %8 2022 Jun 16 %G eng %R 10.1093/hmg/ddac132 %0 Journal Article %J Mol Syst Biol %D 2021 %T COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms. %A Ostaszewski, Marek %A Niarakis, Anna %A Mazein, Alexander %A Kuperstein, Inna %A Phair, Robert %A Orta-Resendiz, Aurelio %A Singh, Vidisha %A Aghamiri, Sara Sadat %A Acencio, Marcio Luis %A Glaab, Enrico %A Ruepp, Andreas %A Fobo, Gisela %A Montrone, Corinna %A Brauner, Barbara %A Frishman, Goar %A Monraz Gómez, Luis Cristóbal %A Somers, Julia %A Hoch, Matti %A Kumar Gupta, Shailendra %A Scheel, Julia %A Borlinghaus, Hanna %A Czauderna, Tobias %A Schreiber, Falk %A Montagud, Arnau %A Ponce de Leon, Miguel %A Funahashi, Akira %A Hiki, Yusuke %A Hiroi, Noriko %A Yamada, Takahiro G %A Dräger, Andreas %A Renz, Alina %A Naveez, Muhammad %A Bocskei, Zsolt %A Messina, Francesco %A Börnigen, Daniela %A Fergusson, Liam %A Conti, Marta %A Rameil, Marius %A Nakonecnij, Vanessa %A Vanhoefer, Jakob %A Schmiester, Leonard %A Wang, Muying %A Ackerman, Emily E %A Shoemaker, Jason E %A Zucker, Jeremy %A Oxford, Kristie %A Teuton, Jeremy %A Kocakaya, Ebru %A Summak, Gökçe Yağmur %A Hanspers, Kristina %A Kutmon, Martina %A Coort, Susan %A Eijssen, Lars %A Ehrhart, Friederike %A Rex, Devasahayam Arokia Balaya %A Slenter, Denise %A Martens, Marvin %A Pham, Nhung %A Haw, Robin %A Jassal, Bijay %A Matthews, Lisa %A Orlic-Milacic, Marija %A Senff Ribeiro, Andrea %A Rothfels, Karen %A Shamovsky, Veronica %A Stephan, Ralf %A Sevilla, Cristoffer %A Varusai, Thawfeek %A Ravel, Jean-Marie %A Fraser, Rupsha %A Ortseifen, Vera %A Marchesi, Silvia %A Gawron, Piotr %A Smula, Ewa %A Heirendt, Laurent %A Satagopam, Venkata %A Wu, Guanming %A Riutta, Anders %A Golebiewski, Martin %A Owen, Stuart %A Goble, Carole %A Hu, Xiaoming %A Overall, Rupert W %A Maier, Dieter %A Bauch, Angela %A Gyori, Benjamin M %A Bachman, John A %A Vega, Carlos %A Grouès, Valentin %A Vazquez, Miguel %A Porras, Pablo %A Licata, Luana %A Iannuccelli, Marta %A Sacco, Francesca %A Nesterova, Anastasia %A Yuryev, Anton %A de Waard, Anita %A Turei, Denes %A Luna, Augustin %A Babur, Ozgun %A Soliman, Sylvain %A Valdeolivas, Alberto %A Esteban-Medina, Marina %A Peña-Chilet, Maria %A Rian, Kinza %A Helikar, Tomáš %A Puniya, Bhanwar Lal %A Modos, Dezso %A Treveil, Agatha %A Olbei, Marton %A De Meulder, Bertrand %A Ballereau, Stephane %A Dugourd, Aurélien %A Naldi, Aurélien %A Noël, Vincent %A Calzone, Laurence %A Sander, Chris %A Demir, Emek %A Korcsmaros, Tamas %A Freeman, Tom C %A Augé, Franck %A Beckmann, Jacques S %A Hasenauer, Jan %A Wolkenhauer, Olaf %A Wilighagen, Egon L %A Pico, Alexander R %A Evelo, Chris T %A Gillespie, Marc E %A Stein, Lincoln D %A Hermjakob, Henning %A D'Eustachio, Peter %A Saez-Rodriguez, Julio %A Dopazo, Joaquin %A Valencia, Alfonso %A Kitano, Hiroaki %A Barillot, Emmanuel %A Auffray, Charles %A Balling, Rudi %A Schneider, Reinhard %K Antiviral Agents %K Computational Biology %K Computer Graphics %K COVID-19 %K Cytokines %K Data Mining %K Databases, Factual %K Gene Expression Regulation %K Host Microbial Interactions %K Humans %K Immunity, Cellular %K Immunity, Humoral %K Immunity, Innate %K Lymphocytes %K Metabolic Networks and Pathways %K Myeloid Cells %K Protein Interaction Mapping %K SARS-CoV-2 %K Signal Transduction %K Software %K Transcription Factors %K Viral Proteins %X

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.

%B Mol Syst Biol %V 17 %P e10387 %8 2021 10 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/34664389?dopt=Abstract %R 10.15252/msb.202110387 %0 Journal Article %J Nucleic Acids Res %D 2021 %T CSVS, a crowdsourcing database of the Spanish population genetic variability. %A Peña-Chilet, Maria %A Roldán, Gema %A Perez-Florido, Javier %A Ortuno, Francisco M %A Carmona, Rosario %A Aquino, Virginia %A López-López, Daniel %A Loucera, Carlos %A Fernandez-Rueda, Jose L %A Gallego, Asunción %A Garcia-Garcia, Francisco %A González-Neira, Anna %A Pita, Guillermo %A Núñez-Torres, Rocío %A Santoyo-López, Javier %A Ayuso, Carmen %A Minguez, Pablo %A Avila-Fernandez, Almudena %A Corton, Marta %A Moreno-Pelayo, Miguel Ángel %A Morin, Matías %A Gallego-Martinez, Alvaro %A Lopez-Escamez, Jose A %A Borrego, Salud %A Antiňolo, Guillermo %A Amigo, Jorge %A Salgado-Garrido, Josefa %A Pasalodos-Sanchez, Sara %A Morte, Beatriz %A Carracedo, Ángel %A Alonso, Ángel %A Dopazo, Joaquin %K Alleles %K Chromosome Mapping %K Crowdsourcing %K Databases, Genetic %K Exome %K Gene Frequency %K Genetic Variation %K Genetics, Population %K Genome, Human %K Genomics %K Humans %K Internet %K Precision Medicine %K Software %K Spain %X

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/.

%B Nucleic Acids Res %V 49 %P D1130-D1137 %8 2021 01 08 %G eng %N D1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32990755?dopt=Abstract %R 10.1093/nar/gkaa794 %0 Journal Article %J Mol Oncol %D 2021 %T A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin. %A Moura, David S %A Peña-Chilet, Maria %A Cordero Varela, Juan Antonio %A Alvarez-Alegret, Ramiro %A Agra-Pujol, Carolina %A Izquierdo, Francisco %A Ramos, Rafael %A Ortega-Medina, Luis %A Martin-Davila, Francisco %A Castilla-Ramirez, Carolina %A Hernandez-Leon, Carmen Nieves %A Romagosa, Cleofe %A Vaz Salgado, Maria Angeles %A Lavernia, Javier %A Bagué, Silvia %A Mayodormo-Aranda, Empar %A Vicioso, Luis %A Hernández Barceló, Jose Emilio %A Rubio-Casadevall, Jordi %A de Juan, Ana %A Fiaño-Valverde, Maria Concepcion %A Hindi, Nadia %A Lopez-Alvarez, Maria %A Lacerenza, Serena %A Dopazo, Joaquin %A Gutierrez, Antonio %A Alvarez, Rosa %A Valverde, Claudia %A Martinez-Trufero, Javier %A Martin-Broto, Javier %X

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

%B Mol Oncol %V 15 %P 3691-3705 %8 2021 12 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/33983674?dopt=Abstract %R 10.1002/1878-0261.12996 %0 Journal Article %J Nat Methods %D 2021 %T DOME: recommendations for supervised machine learning validation in biology. %A Walsh, Ian %A Fishman, Dmytro %A Garcia-Gasulla, Dario %A Titma, Tiina %A Pollastri, Gianluca %A Harrow, Jennifer %A Psomopoulos, Fotis E %A Tosatto, Silvio C E %K Algorithms %K Computational Biology %K Guidelines as Topic %K Humans %K Models, Biological %K Research Design %K Supervised Machine Learning %B Nat Methods %V 18 %P 1122-1127 %8 2021 10 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/34316068?dopt=Abstract %R 10.1038/s41592-021-01205-4 %0 Journal Article %J Computational and Structural Biotechnology Journal %D 2021 %T Genome-scale mechanistic modeling of signaling pathways made easy: A bioconductor/cytoscape/web server framework for the analysis of omic data %A Rian, Kinza %A Hidalgo, Marta R. %A Cubuk, Cankut %A Falco, Matias M. %A Loucera, Carlos %A Esteban-Medina, Marina %A Alamo-Alvarez, Inmaculada %A Peña-Chilet, Maria %A Dopazo, Joaquin %B Computational and Structural Biotechnology Journal %V 19 %P 2968 - 2978 %8 Jan-01-2021 %G eng %U https://linkinghub.elsevier.com/retrieve/pii/S2001037021002038 %! Computational and Structural Biotechnology Journal %R 10.1016/j.csbj.2021.05.022 %0 Journal Article %J Clinical Epigenetics %D 2021 %T Genome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system developmentAbstractBackgroundResultsConclusionsGraphic abstract %A Villalba-Benito, Leticia %A López-López, Daniel %A Torroglosa, Ana %A Casimiro-Soriguer, Carlos S. %A Luzón-Toro, Berta %A Fernández, Raquel María %A Moya-Jiménez, María José %A Antiňolo, Guillermo %A Dopazo, Joaquin %A Borrego, Salud %B Clinical Epigenetics %V 13 %8 Jan-12-2021 %G eng %U http://link.springer.com/article/10.1186/s13148-021-01040-6/fulltext.html %N 1 %! Clin Epigenet %R 10.1186/s13148-021-01040-6 %0 Journal Article %J BioData Min %D 2021 %T Mechanistic modeling of the SARS-CoV-2 disease map. %A Rian, Kinza %A Esteban-Medina, Marina %A Hidalgo, Marta R %A Cubuk, Cankut %A Falco, Matias M %A Loucera, Carlos %A Gunyel, Devrim %A Ostaszewski, Marek %A Peña-Chilet, Maria %A Dopazo, Joaquin %X

Here we present a web interface that implements a comprehensive mechanistic model of the SARS-CoV-2 disease map. In this framework, the detailed activity of the human signaling circuits related to the viral infection, covering from the entry and replication mechanisms to the downstream consequences as inflammation and antigenic response, can be inferred from gene expression experiments. Moreover, the effect of potential interventions, such as knock-downs, or drug effects (currently the system models the effect of more than 8000 DrugBank drugs) can be studied. This freely available tool not only provides an unprecedentedly detailed view of the mechanisms of viral invasion and the consequences in the cell but has also the potential of becoming an invaluable asset in the search for efficient antiviral treatments.

%B BioData Min %V 14 %P 5 %8 2021 Jan 21 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33478554?dopt=Abstract %R 10.1186/s13040-021-00234-1 %0 Journal Article %J Nature Genetics %D 2021 %T The NCI Genomic Data Commons %A Heath, Allison P. %A Ferretti, Vincent %A Agrawal, Stuti %A An, Maksim %A Angelakos, James C. %A Arya, Renuka %A Bajari, Rosita %A Baqar, Bilal %A Barnowski, Justin H. B. %A Burt, Jeffrey %A Catton, Ann %A Chan, Brandon F. %A Chu, Fay %A Cullion, Kim %A Davidsen, Tanja %A Do, Phuong-My %A Dompierre, Christian %A Ferguson, Martin L. %A Fitzsimons, Michael S. %A Ford, Michael %A Fukuma, Miyuki %A Gaheen, Sharon %A Ganji, Gajanan L. %A Garcia, Tzintzuni I. %A George, Sameera S. %A Gerhard, Daniela S. %A Gerthoffert, Francois %A Gomez, Fauzi %A Han, Kang %A Hernandez, Kyle M. %A Issac, Biju %A Jackson, Richard %A Jensen, Mark A. %A Joshi, Sid %A Kadam, Ajinkya %A Khurana, Aishmit %A Kim, Kyle M. J. %A Kraft, Victoria E. %A Li, Shenglai %A Lichtenberg, Tara M. %A Lodato, Janice %A Lolla, Laxmi %A Martinov, Plamen %A Mazzone, Jeffrey A. %A Miller, Daniel P. %A Miller, Ian %A Miller, Joshua S. %A Miyauchi, Koji %A Murphy, Mark W. %A Nullet, Thomas %A Ogwara, Rowland O. %A Ortuño, Francisco M. %A Pedrosa, Jesús %A Pham, Phuong L. %A Popov, Maxim Y. %A Porter, James J. %A Powell, Raymond %A Rademacher, Karl %A Reid, Colin P. %A Rich, Samantha %A Rogel, Bessie %A Sahni, Himanso %A Savage, Jeremiah H. %A Schmitt, Kyle A. %A Simmons, Trevar J. %A Sislow, Joseph %A Spring, Jonathan %A Stein, Lincoln %A Sullivan, Sean %A Tang, Yajing %A Thiagarajan, Mathangi %A Troyer, Heather D. %A Wang, Chang %A Wang, Zhining %A West, Bedford L. %A Wilmer, Alex %A Wilson, Shane %A Wu, Kaman %A Wysocki, William P. %A Xiang, Linda %A Yamada, Joseph T. %A Yang, Liming %A Yu, Christine %A Yung, Christina K. %A Zenklusen, Jean Claude %A Zhang, Junjun %A Zhang, Zhenyu %A Zhao, Yuanheng %A Zubair, Ariz %A Staudt, Louis M. %A Grossman, Robert L. %B Nature Genetics %8 Oct-02-2022 %G eng %U http://www.nature.com/articles/s41588-021-00791-5 %! Nat Genet %R 10.1038/s41588-021-00791-5 %0 Journal Article %J Viruses %D 2021 %T Phylogenetic Analysis of the 2020 West Nile Virus (WNV) Outbreak in Andalusia (Spain) %A Casimiro-Soriguer, Carlos S. %A Perez-Florido, Javier %A Fernandez-Rueda, Jose L. %A Pedrosa-Corral, Irene %A Guillot-Sulay, Vicente %A Lorusso, Nicola %A Martinez-Gonzalez, Luis Javier %A Navarro-Marí, Jose M. %A Dopazo, Joaquin %A Sanbonmatsu-Gámez, Sara %B Viruses %V 13 %P 836 %8 Jan-05-2021 %G eng %U https://www.mdpi.com/1999-4915/13/5/836 %N 5 %! Viruses %R 10.3390/v13050836 %0 Journal Article %J Nat Med %D 2021 %T Reporting guidelines for human microbiome research: the STORMS checklist. %A Mirzayi, Chloe %A Renson, Audrey %A Zohra, Fatima %A Elsafoury, Shaimaa %A Geistlinger, Ludwig %A Kasselman, Lora J %A Eckenrode, Kelly %A van de Wijgert, Janneke %A Loughman, Amy %A Marques, Francine Z %A MacIntyre, David A %A Arumugam, Manimozhiyan %A Azhar, Rimsha %A Beghini, Francesco %A Bergstrom, Kirk %A Bhatt, Ami %A Bisanz, Jordan E %A Braun, Jonathan %A Bravo, Hector Corrada %A Buck, Gregory A %A Bushman, Frederic %A Casero, David %A Clarke, Gerard %A Collado, Maria Carmen %A Cotter, Paul D %A Cryan, John F %A Demmer, Ryan T %A Devkota, Suzanne %A Elinav, Eran %A Escobar, Juan S %A Fettweis, Jennifer %A Finn, Robert D %A Fodor, Anthony A %A Forslund, Sofia %A Franke, Andre %A Furlanello, Cesare %A Gilbert, Jack %A Grice, Elizabeth %A Haibe-Kains, Benjamin %A Handley, Scott %A Herd, Pamela %A Holmes, Susan %A Jacobs, Jonathan P %A Karstens, Lisa %A Knight, Rob %A Knights, Dan %A Koren, Omry %A Kwon, Douglas S %A Langille, Morgan %A Lindsay, Brianna %A McGovern, Dermot %A McHardy, Alice C %A McWeeney, Shannon %A Mueller, Noel T %A Nezi, Luigi %A Olm, Matthew %A Palm, Noah %A Pasolli, Edoardo %A Raes, Jeroen %A Redinbo, Matthew R %A Rühlemann, Malte %A Balfour Sartor, R %A Schloss, Patrick D %A Schriml, Lynn %A Segal, Eran %A Shardell, Michelle %A Sharpton, Thomas %A Smirnova, Ekaterina %A Sokol, Harry %A Sonnenburg, Justin L %A Srinivasan, Sujatha %A Thingholm, Louise B %A Turnbaugh, Peter J %A Upadhyay, Vaibhav %A Walls, Ramona L %A Wilmes, Paul %A Yamada, Takuji %A Zeller, Georg %A Zhang, Mingyu %A Zhao, Ni %A Zhao, Liping %A Bao, Wenjun %A Culhane, Aedin %A Devanarayan, Viswanath %A Dopazo, Joaquin %A Fan, Xiaohui %A Fischer, Matthias %A Jones, Wendell %A Kusko, Rebecca %A Mason, Christopher E %A Mercer, Tim R %A Sansone, Susanna-Assunta %A Scherer, Andreas %A Shi, Leming %A Thakkar, Shraddha %A Tong, Weida %A Wolfinger, Russ %A Hunter, Christopher %A Segata, Nicola %A Huttenhower, Curtis %A Dowd, Jennifer B %A Jones, Heidi E %A Waldron, Levi %K Computational Biology %K Dysbiosis %K Humans %K Microbiota %K Observational Studies as Topic %K Research Design %K Translational Science, Biomedical %X

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 'Strengthening The Organization and Reporting of Microbiome Studies' (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.

%B Nat Med %V 27 %P 1885-1892 %8 2021 11 %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/34789871?dopt=Abstract %R 10.1038/s41591-021-01552-x %0 Journal Article %J Mol Med %D 2021 %T Taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism. %A Méndez-Salazar, Eder Orlando %A Vázquez-Mellado, Janitzia %A Casimiro-Soriguer, Carlos S %A Dopazo, Joaquin %A Cubuk, Cankut %A Zamudio-Cuevas, Yessica %A Francisco-Balderas, Adriana %A Martínez-Flores, Karina %A Fernández-Torres, Javier %A Lozada-Pérez, Carlos %A Pineda, Carlos %A Sánchez-González, Austreberto %A Silveira, Luis H %A Burguete-García, Ana I %A Orbe-Orihuela, Citlalli %A Lagunas-Martínez, Alfredo %A Vazquez-Gomez, Alonso %A López-Reyes, Alberto %A Palacios-González, Berenice %A Martínez-Nava, Gabriela Angélica %K Biodiversity %K Computational Biology %K Dysbiosis %K Gastrointestinal Microbiome %K Gout %K Humans %K Metagenome %K metagenomics %K Protein Interaction Mapping %K Protein Interaction Maps %K Uric Acid %X

OBJECTIVE: To evaluate the taxonomic composition of the gut microbiome in gout patients with and without tophi formation, and predict bacterial functions that might have an impact on urate metabolism.

METHODS: Hypervariable V3-V4 regions of the bacterial 16S rRNA gene from fecal samples of gout patients with and without tophi (n = 33 and n = 25, respectively) were sequenced and compared to fecal samples from 53 healthy controls. We explored predictive functional profiles using bioinformatics in order to identify differences in taxonomy and metabolic pathways.

RESULTS: We identified a microbiome characterized by the lowest richness and a higher abundance of Phascolarctobacterium, Bacteroides, Akkermansia, and Ruminococcus_gnavus_group genera in patients with gout without tophi when compared to controls. The Proteobacteria phylum and the Escherichia-Shigella genus were more abundant in patients with tophaceous gout than in controls. Fold change analysis detected nine genera enriched in healthy controls compared to gout groups (Bifidobacterium, Butyricicoccus, Oscillobacter, Ruminococcaceae_UCG_010, Lachnospiraceae_ND2007_group, Haemophilus, Ruminococcus_1, Clostridium_sensu_stricto_1, and Ruminococcaceae_UGC_013). We found that the core microbiota of both gout groups shared Bacteroides caccae, Bacteroides stercoris ATCC 43183, and Bacteroides coprocola DSM 17136. These bacteria might perform functions linked to one-carbon metabolism, nucleotide binding, amino acid biosynthesis, and purine biosynthesis. Finally, we observed differences in key bacterial enzymes involved in urate synthesis, degradation, and elimination.

CONCLUSION: Our findings revealed that taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.

%B Mol Med %V 27 %P 50 %8 2021 05 24 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34030623?dopt=Abstract %R 10.1186/s10020-021-00311-5 %0 Journal Article %J Cell Syst %D 2020 %T Community Assessment of the Predictability of Cancer Protein and Phosphoprotein Levels from Genomics and Transcriptomics. %A Yang, Mi %A Petralia, Francesca %A Li, Zhi %A Li, Hongyang %A Ma, Weiping %A Song, Xiaoyu %A Kim, Sunkyu %A Lee, Heewon %A Yu, Han %A Lee, Bora %A Bae, Seohui %A Heo, Eunji %A Kaczmarczyk, Jan %A Stępniak, Piotr %A Warchoł, Michał %A Yu, Thomas %A Calinawan, Anna P %A Boutros, Paul C %A Payne, Samuel H %A Reva, Boris %A Boja, Emily %A Rodriguez, Henry %A Stolovitzky, Gustavo %A Guan, Yuanfang %A Kang, Jaewoo %A Wang, Pei %A Fenyö, David %A Saez-Rodriguez, Julio %K Crowdsourcing %K Female %K Genomics %K Humans %K Machine Learning %K Male %K Neoplasms %K Phosphoproteins %K Proteins %K Proteomics %K Transcriptome %X

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's transparent peer review process is included in the Supplemental Information.

%B Cell Syst %V 11 %P 186-195.e9 %8 2020 08 26 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32710834?dopt=Abstract %R 10.1016/j.cels.2020.06.013 %0 Journal Article %J Sci Data %D 2020 %T COVID-19 Disease Map, building a computational repository of SARS-CoV-2 virus-host interaction mechanisms. %A Ostaszewski, Marek %A Mazein, Alexander %A Gillespie, Marc E %A Kuperstein, Inna %A Niarakis, Anna %A Hermjakob, Henning %A Pico, Alexander R %A Willighagen, Egon L %A Evelo, Chris T %A Hasenauer, Jan %A Schreiber, Falk %A Dräger, Andreas %A Demir, Emek %A Wolkenhauer, Olaf %A Furlong, Laura I %A Barillot, Emmanuel %A Dopazo, Joaquin %A Orta-Resendiz, Aurelio %A Messina, Francesco %A Valencia, Alfonso %A Funahashi, Akira %A Kitano, Hiroaki %A Auffray, Charles %A Balling, Rudi %A Schneider, Reinhard %K Betacoronavirus %K Computational Biology %K Coronavirus Infections %K COVID-19 %K Databases, Factual %K Host Microbial Interactions %K Host-Pathogen Interactions %K Humans %K International Cooperation %K Models, Biological %K Pandemics %K Pneumonia, Viral %K SARS-CoV-2 %B Sci Data %V 7 %P 136 %8 2020 05 05 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32371892?dopt=Abstract %R 10.1038/s41597-020-0477-8 %0 Journal Article %J Signal Transduct Target Ther %D 2020 %T Drug repurposing for COVID-19 using machine learning and mechanistic models of signal transduction circuits related to SARS-CoV-2 infection. %A Loucera, Carlos %A Esteban-Medina, Marina %A Rian, Kinza %A Falco, Matias M %A Dopazo, Joaquin %A Peña-Chilet, Maria %K Computational Chemistry %K COVID-19 %K drug repositioning %K Humans %K Machine Learning %K Molecular Docking Simulation %K Molecular Targeted Therapy %K Proteins %K SARS-CoV-2 %K Signal Transduction %B Signal Transduct Target Ther %V 5 %P 290 %8 2020 12 11 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33311438?dopt=Abstract %R 10.1038/s41392-020-00417-y %0 Journal Article %J F1000Res %D 2020 %T The ELIXIR Human Copy Number Variations Community: building bioinformatics infrastructure for research. %A Salgado, David %A Armean, Irina M %A Baudis, Michael %A Beltran, Sergi %A Capella-Gutíerrez, Salvador %A Carvalho-Silva, Denise %A Dominguez Del Angel, Victoria %A Dopazo, Joaquin %A Furlong, Laura I %A Gao, Bo %A Garcia, Leyla %A Gerloff, Dietlind %A Gut, Ivo %A Gyenesei, Attila %A Habermann, Nina %A Hancock, John M %A Hanauer, Marc %A Hovig, Eivind %A Johansson, Lennart F %A Keane, Thomas %A Korbel, Jan %A Lauer, Katharina B %A Laurie, Steve %A Leskošek, Brane %A Lloyd, David %A Marqués-Bonet, Tomás %A Mei, Hailiang %A Monostory, Katalin %A Piñero, Janet %A Poterlowicz, Krzysztof %A Rath, Ana %A Samarakoon, Pubudu %A Sanz, Ferran %A Saunders, Gary %A Sie, Daoud %A Swertz, Morris A %A Tsukanov, Kirill %A Valencia, Alfonso %A Vidak, Marko %A Yenyxe González, Cristina %A Ylstra, Bauke %A Béroud, Christophe %K Computational Biology %K DNA Copy Number Variations %K High-Throughput Nucleotide Sequencing %K Humans %X

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

%B F1000Res %V 9 %8 2020 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/34367618?dopt=Abstract %& 1229 %R 10.12688/f1000research.24887.1 %0 Journal Article %J iScience %D 2020 %T Immune Cell Associations with Cancer Risk. %A Palomero, Luis %A Galván-Femenía, Ivan %A de Cid, Rafael %A Espín, Roderic %A Barnes, Daniel R %A Blommaert, Eline %A Gil-Gil, Miguel %A Falo, Catalina %A Stradella, Agostina %A Ouchi, Dan %A Roso-Llorach, Albert %A Violan, Concepció %A Peña-Chilet, Maria %A Dopazo, Joaquin %A Extremera, Ana Isabel %A García-Valero, Mar %A Herranz, Carmen %A Mateo, Francesca %A Mereu, Elisabetta %A Beesley, Jonathan %A Chenevix-Trench, Georgia %A Roux, Cecilia %A Mak, Tak %A Brunet, Joan %A Hakem, Razq %A Gorrini, Chiara %A Antoniou, Antonis C %A Lázaro, Conxi %A Pujana, Miquel Angel %X

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

%B iScience %V 23 %P 101296 %8 2020 Jul 24 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/32622267?dopt=Abstract %R 10.1016/j.isci.2020.101296 %0 Journal Article %J NAR Cancer %D 2020 %T Mechanistic models of signaling pathways deconvolute the glioblastoma single-cell functional landscapeAbstract %A Falco, Matias M %A Peña-Chilet, Maria %A Loucera, Carlos %A Hidalgo, Marta R %A Dopazo, Joaquin %B NAR Cancer %V 2 %8 Jan-06-2020 %G eng %U https://academic.oup.com/narcancer/article/doi/10.1093/narcan/zcaa011/5862620http://academic.oup.com/narcancer/article-pdf/2/2/zcaa011/33428092/zcaa011.pdfhttp://academic.oup.com/narcancer/article-pdf/2/2/zcaa011/33428092/zcaa011.pdf %N 2 %R 10.1093/narcan/zcaa011 %0 Journal Article %J J Med Genet %D 2020 %T Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies. %A Bogliolo, Massimo %A Pujol, Roser %A Aza-Carmona, Miriam %A Muñoz-Subirana, Núria %A Rodriguez-Santiago, Benjamin %A Casado, José Antonio %A Rio, Paula %A Bauser, Christopher %A Reina-Castillón, Judith %A Lopez-Sanchez, Marcos %A Gonzalez-Quereda, Lidia %A Gallano, Pia %A Catalá, Albert %A Ruiz-Llobet, Ana %A Badell, Isabel %A Diaz-Heredia, Cristina %A Hladun, Raquel %A Senent, Leonort %A Argiles, Bienvenida %A Bergua Burgues, Juan Miguel %A Bañez, Fatima %A Arrizabalaga, Beatriz %A López Almaraz, Ricardo %A Lopez, Monica %A Figuera, Ángela %A Molinés, Antonio %A Pérez de Soto, Inmaculada %A Hernando, Inés %A Muñoz, Juan Antonio %A Del Rosario Marin, Maria %A Balmaña, Judith %A Stjepanovic, Neda %A Carrasco, Estela %A Cuesta, Isabel %A Cosuelo, José Miguel %A Regueiro, Alexandra %A Moraleda Jimenez, José %A Galera-Miñarro, Ana Maria %A Rosiñol, Laura %A Carrió, Anna %A Beléndez-Bieler, Cristina %A Escudero Soto, Antonio %A Cela, Elena %A de la Mata, Gregorio %A Fernández-Delgado, Rafael %A Garcia-Pardos, Maria Carmen %A Sáez-Villaverde, Raquel %A Barragaño, Marta %A Portugal, Raquel %A Lendinez, Francisco %A Hernadez, Ines %A Vagace, José Manue %A Tapia, Maria %A Nieto, José %A Garcia, Marta %A Gonzalez, Macarena %A Vicho, Cristina %A Galvez, Eva %A Valiente, Alberto %A Antelo, Maria Luisa %A Ancliff, Phil %A García, Francisco %A Dopazo, Joaquin %A Sevilla, Julian %A Paprotka, Tobias %A Pérez-Jurado, Luis Alberto %A Bueren, Juan %A Surralles, Jordi %K Cell Line %K DNA Copy Number Variations %K DNA Repair %K DNA-Binding Proteins %K Fanconi Anemia %K Fanconi Anemia Complementation Group A Protein %K Female %K Gene Knockout Techniques %K Genetic Predisposition to Disease %K Humans %K Male %K Mutation, Missense %K Polymorphism, Single Nucleotide %K whole exome sequencing %X

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' 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 'affecting functions' are SNPs. Deep analysis of sequencing data revealed patients' 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.

%B J Med Genet %V 57 %P 258-268 %8 2020 04 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/31586946?dopt=Abstract %R 10.1136/jmedgenet-2019-106249 %0 Journal Article %J Lancet Oncol %D 2020 %T Pazopanib for treatment of typical solitary fibrous tumours: a multicentre, single-arm, phase 2 trial. %A Martin-Broto, Javier %A Cruz, Josefina %A Penel, Nicolas %A Le Cesne, Axel %A Hindi, Nadia %A Luna, Pablo %A Moura, David S %A Bernabeu, Daniel %A de Alava, Enrique %A Lopez-Guerrero, Jose Antonio %A Dopazo, Joaquin %A Peña-Chilet, Maria %A Gutierrez, Antonio %A Collini, Paola %A Karanian, Marie %A Redondo, Andres %A Lopez-Pousa, Antonio %A Grignani, Giovanni %A Diaz-Martin, Juan %A Marcilla, David %A Fernandez-Serra, Antonio %A Gonzalez-Aguilera, Cristina %A Casali, Paolo G %A Blay, Jean-Yves %A Stacchiotti, Silvia %K Aged %K Female %K Follow-Up Studies %K Humans %K Indazoles %K Male %K Middle Aged %K Neoplasm Metastasis %K Prognosis %K Prospective Studies %K Protein Kinase Inhibitors %K Pyrimidines %K Response Evaluation Criteria in Solid Tumors %K Solitary Fibrous Tumors %K Sulfonamides %K Survival Rate %X

BACKGROUND: Solitary fibrous tumour is an ultra-rare sarcoma, which encompasses different clinicopathological subgroups. The dedifferentiated subgroup shows an aggressive course with resistance to pazopanib, whereas in the malignant subgroup, pazopanib shows higher activity than in previous studies with chemotherapy. We designed a trial to test pazopanib activity in two different cohorts of solitary fibrous tumour: the malignant-dedifferentiated cohort, which was previously published, and the typical cohort, which is presented here.

METHODS: In this single-arm, phase 2 trial, adult patients (aged ≥18 years) diagnosed with confirmed metastatic or unresectable typical solitary fibrous tumour of any location, who had progressed in the previous 6 months (by Choi criteria or Response Evaluation Criteria in Solid Tumors [RECIST]) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were enrolled at 11 tertiary hospitals in Italy, France, and Spain. Patients received pazopanib 800 mg once daily, taken orally, until progression, unacceptable toxicity, withdrawal of consent, non-compliance, or a delay in pazopanib administration of longer than 3 weeks. The primary endpoint was proportion of patients achieving an overall response measured by Choi criteria in patients who received at least 1 month of treatment with at least one radiological assessment. All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered in ClinicalTrials.gov, NCT02066285, and with the European Clinical Trials Database, EudraCT 2013-005456-15.

FINDINGS: From June 26, 2014, to Dec 13, 2018, of 40 patients who were assessed, 34 patients were enrolled and 31 patients were included in the response analysis. Median follow-up was 18 months (IQR 14-34), and 18 (58%) of 31 patients had a partial response, 12 (39%) had stable disease, and one (3%) showed progressive disease according to Choi criteria and central review. The proportion of overall response based on Choi criteria was 58% (95% CI 34-69). There were no deaths caused by toxicity, and the most frequent adverse events were diarrhoea (18 [53%] of 34 patients), fatigue (17 [50%]), and hypertension (17 [50%]).

INTERPRETATION: To our knowledge, this is the first prospective trial of pazopanib for advanced typical solitary fibrous tumour. The manageable toxicity and activity shown by pazopanib in this cohort suggest that this drug could be considered as first-line treatment for advanced typical solitary fibrous tumour.

FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.

%B Lancet Oncol %V 21 %P 456-466 %8 2020 03 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/32066540?dopt=Abstract %R 10.1016/S1470-2045(19)30826-5 %0 Journal Article %J Stem Cells %D 2020 %T Platform to study intracellular polystyrene nanoplastic pollution and clinical outcomes. %A Bojic, Sanja %A Falco, Matias M %A Stojkovic, Petra %A Ljujic, Biljana %A Gazdic Jankovic, Marina %A Armstrong, Lyle %A Markovic, Nebojsa %A Dopazo, Joaquin %A Lako, Majlinda %A Bauer, Roman %A Stojkovic, Miodrag %K Environmental Pollution %K Humans %K Induced Pluripotent Stem Cells %K Intracellular Space %K Nanoparticles %K Plastics %K Polystyrenes %K Transcriptome %K Treatment Outcome %X

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

%B Stem Cells %V 38 %P 1321-1325 %8 2020 10 01 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/32614127?dopt=Abstract %R 10.1002/stem.3244 %0 Journal Article %J Biol Direct %D 2019 %T Antibiotic resistance and metabolic profiles as functional biomarkers that accurately predict the geographic origin of city metagenomics samples. %A Casimiro-Soriguer, Carlos S %A Loucera, Carlos %A Perez Florido, Javier %A López-López, Daniel %A Dopazo, Joaquin %K biomarkers %K Cities %K Drug Resistance, Microbial %K Machine Learning %K Metabolome %K Metagenome %K metagenomics %K Microbiota %X

BACKGROUND: The availability of hundreds of city microbiome profiles allows the development of increasingly accurate predictors of the origin of a sample based on its microbiota composition. Typical microbiome studies involve the analysis of bacterial abundance profiles.

RESULTS: Here we use a transformation of the conventional bacterial strain or gene abundance profiles to functional profiles that account for bacterial metabolism and other cell functionalities. These profiles are used as features for city classification in a machine learning algorithm that allows the extraction of the most relevant features for the classification.

CONCLUSIONS: We demonstrate here that the use of functional profiles not only predict accurately the most likely origin of a sample but also to provide an interesting functional point of view of the biogeography of the microbiota. Interestingly, we show how cities can be classified based on the observed profile of antibiotic resistances.

REVIEWERS: Open peer review: Reviewed by Jin Zhuang Dou, Jing Zhou, Torsten Semmler and Eran Elhaik.

%B Biol Direct %V 14 %P 15 %8 2019 08 20 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31429791?dopt=Abstract %R 10.1186/s13062-019-0246-9 %0 Journal Article %J Nat Commun %D 2019 %T Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen. %A Menden, Michael P %A Wang, Dennis %A Mason, Mike J %A Szalai, Bence %A Bulusu, Krishna C %A Guan, Yuanfang %A Yu, Thomas %A Kang, Jaewoo %A Jeon, Minji %A Wolfinger, Russ %A Nguyen, Tin %A Zaslavskiy, Mikhail %A Jang, In Sock %A Ghazoui, Zara %A Ahsen, Mehmet Eren %A Vogel, Robert %A Neto, Elias Chaibub %A Norman, Thea %A Tang, Eric K Y %A Garnett, Mathew J %A Veroli, Giovanni Y Di %A Fawell, Stephen %A Stolovitzky, Gustavo %A Guinney, Justin %A Dry, Jonathan R %A Saez-Rodriguez, Julio %K ADAM17 Protein %K Antineoplastic Combined Chemotherapy Protocols %K Benchmarking %K Biomarkers, Tumor %K Cell Line, Tumor %K Computational Biology %K Datasets as Topic %K Drug Antagonism %K Drug Resistance, Neoplasm %K Drug Synergism %K Genomics %K Humans %K Molecular Targeted Therapy %K mutation %K Neoplasms %K pharmacogenetics %K Phosphatidylinositol 3-Kinases %K Phosphoinositide-3 Kinase Inhibitors %K Treatment Outcome %X

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'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.

%B Nat Commun %V 10 %P 2674 %8 2019 06 17 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31209238?dopt=Abstract %R 10.1038/s41467-019-09799-2 %0 Journal Article %J Scientific Reports %D 2019 %T Using mechanistic models for the clinical interpretation of complex genomic variation %A Peña-Chilet, Maria %A Esteban-Medina, Marina %A Falco, Matias M. %A Rian, Kinza %A Hidalgo, Marta R. %A Loucera, Carlos %A Dopazo, Joaquin %B Scientific Reports %V 9 %8 Jan-12-2019 %G eng %U http://www.nature.com/articles/s41598-019-55454-7http://www.nature.com/articles/s41598-019-55454-7.pdfhttp://www.nature.com/articles/s41598-019-55454-7.pdfhttp://www.nature.com/articles/s41598-019-55454-7 %N 1 %! Sci Rep %R 10.1038/s41598-019-55454-7 %0 Journal Article %J Nature Communications %D 2018 %T A crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection %A Fourati, Slim %A Talla, Aarthi %A Mahmoudian, Mehrad %A Burkhart, Joshua G. %A Klén, Riku %A Henao, Ricardo %A Yu, Thomas %A Aydın, Zafer %A Yeung, Ka Yee %A Ahsen, Mehmet Eren %A Almugbel, Reem %A Jahandideh, Samad %A Liang, Xiao %A Nordling, Torbjörn E. M. %A Shiga, Motoki %A Stanescu, Ana %A Vogel, Robert %A Pandey, Gaurav %A Chiu, Christopher %A McClain, Micah T. %A Woods, Christopher W. %A Ginsburg, Geoffrey S. %A Elo, Laura L. %A Tsalik, Ephraim L. %A Mangravite, Lara M. %A Sieberts, Solveig K. %B Nature Communications %V 9 %8 Jan-12-2018 %G eng %U 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 %N 1 %! Nat Commun %R 10.1038/s41467-018-06735-8 %0 Journal Article %J Nat Commun %D 2018 %T The effects of death and post-mortem cold ischemia on human tissue transcriptomes. %A Ferreira, Pedro G %A Muñoz-Aguirre, Manuel %A Reverter, Ferran %A Sá Godinho, Caio P %A Sousa, Abel %A Amadoz, Alicia %A Sodaei, Reza %A Hidalgo, Marta R %A Pervouchine, Dmitri %A Carbonell-Caballero, José %A Nurtdinov, Ramil %A Breschi, Alessandra %A Amador, Raziel %A Oliveira, Patrícia %A Cubuk, Cankut %A Curado, João %A Aguet, François %A Oliveira, Carla %A Dopazo, Joaquin %A Sammeth, Michael %A Ardlie, Kristin G %A Guigó, Roderic %K Blood %K Cold Ischemia %K Death %K Female %K gene expression %K Humans %K Models, Biological %K Postmortem Changes %K RNA, Messenger %K Stochastic Processes %K Transcriptome %X

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.

%B Nat Commun %V 9 %P 490 %8 2018 02 13 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/29440659?dopt=Abstract %R 10.1038/s41467-017-02772-x %0 Journal Article %J Sci Rep %D 2018 %T Evolution of the Quorum network and the mobilome (plasmids and bacteriophages) in clinical strains of Acinetobacter baumannii during a decade. %A López, M %A Rueda, A %A Florido, J P %A Blasco, L %A Fernández-García, L %A Trastoy, R %A Fernández-Cuenca, F %A Martínez-Martínez, L %A Vila, J %A Pascual, A %A Bou, G %A Tomas, M %K Acinetobacter baumannii %K Acinetobacter Infections %K Bacteriophages %K Cross Infection %K Humans %K Plasmids %K Quorum Sensing %K Retrospective Studies %X

In this study, we compared eighteen clinical strains of A. baumannii belonging to the ST-2 clone and isolated from patients in the same intensive care unit (ICU) in 2000 (9 strains referred to collectively as Ab_GEIH-2000) and 2010 (9 strains referred to collectively as Ab_GEIH-2010), during the GEIH-REIPI project (Umbrella BioProject PRJNA422585). We observed two main molecular differences between the Ab_GEIH-2010 and the Ab_GEIH-2000 collections, acquired over the course of the decade long sampling interval and involving the mobilome: i) a plasmid harbouring genes for bla ß-lactamase and abKA/abkB proteins of a toxin-antitoxin system; and ii) two temperate bacteriophages, Ab105-1ϕ (63 proteins) and Ab105-2ϕ (93 proteins), containing important viral defence proteins. Moreover, all Ab_GEIH-2010 strains contained a Quorum functional network of Quorum Sensing (QS) and Quorum Quenching (QQ) mechanisms, including a new QQ enzyme, AidA, which acts as a bacterial defence mechanism against the exogenous 3-oxo-C12-HSL. Interestingly, the infective capacity of the bacteriophages isolated in this study (Ab105-1ϕ and Ab105-2ϕ) was higher in the Ab_GEIH-2010 strains (carrying a functional Quorum network) than in the Ab_GEIH-2000 strains (carrying a deficient Quorum network), in which the bacteriophages showed little or no infectivity. This is the first study about the evolution of the Quorum network and the mobilome in clinical strains of Acinetobacter baumannii during a decade.

%B Sci Rep %V 8 %P 2523 %8 2018 02 06 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/29410443?dopt=Abstract %R 10.1038/s41598-018-20847-7 %0 Journal Article %J Microb Genom %D 2018 %T The first complete genomic structure of Butyrivibrio fibrisolvens and its chromid. %A Rodríguez Hernáez, Javier %A Cerón Cucchi, Maria Esperanza %A Cravero, Silvio %A Martinez, Maria Carolina %A Gonzalez, Sergio %A Puebla, Andrea %A Dopazo, Joaquin %A Farber, Marisa %A Paniego, Norma %A Rivarola, Máximo %K Animals %K Butyrivibrio fibrisolvens %K Cattle %K Genome, Bacterial %K Genomics %K Humans %K Milk %K Rumen %K Sequence Analysis, DNA %X

Butyrivibrio fibrisolvens forms part of the gastrointestinal microbiome of ruminants and other mammals, including humans. Indeed, it is one of the most common bacteria found in the rumen and plays an important role in ruminal fermentation of polysaccharides, yet, to date, there is no closed reference genome published for this species in any ruminant animal. We successfully assembled the nearly complete genome sequence of B. fibrisolvens strain INBov1 isolated from cow rumen using Illumina paired-end reads, 454 Roche single-end and mate pair sequencing technology. Additionally, we constructed an optical restriction map of this strain to aid in scaffold ordering and positioning, and completed the first genomic structure of this species. Moreover, we identified and assembled the first chromid of this species (pINBov266). The INBov1 genome encodes a large set of genes involved in the cellulolytic process but lacks key genes. This seems to indicate that B. fibrisolvens plays an important role in ruminal cellulolytic processes, but does not have autonomous cellulolytic capacity. When searching for genes involved in the biohydrogenation of unsaturated fatty acids, no linoleate isomerase gene was found in this strain. INBov1 does encode oleate hydratase genes known to participate in the hydrogenation of oleic acids. Furthermore, INBov1 contains an enolase gene, which has been recently determined to participate in the synthesis of conjugated linoleic acids. This work confirms the presence of a novel chromid in B. fibrisolvens and provides a new potential reference genome sequence for this species, providing new insight into its role in biohydrogenation and carbohydrate degradation.

%B Microb Genom %V 4 %8 2018 10 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/30216146?dopt=Abstract %R 10.1099/mgen.0.000216 %0 Journal Article %J Nat Commun %D 2018 %T LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus. %A Cobo-Vuilleumier, Nadia %A Lorenzo, Petra I %A Rodríguez, Noelia García %A Herrera Gómez, Irene de Gracia %A Fuente-Martin, Esther %A López-Noriega, Livia %A Mellado-Gil, José Manuel %A Romero-Zerbo, Silvana-Yanina %A Baquié, Mathurin %A Lachaud, Christian Claude %A Stifter, Katja %A Perdomo, German %A Bugliani, Marco %A De Tata, Vincenzo %A Bosco, Domenico %A Parnaud, Geraldine %A Pozo, David %A Hmadcha, Abdelkrim %A Florido, Javier P %A Toscano, Miguel G %A de Haan, Peter %A Schoonjans, Kristina %A Sánchez Palazón, Luis %A Marchetti, Piero %A Schirmbeck, Reinhold %A Martín-Montalvo, Alejandro %A Meda, Paolo %A Soria, Bernat %A Bermúdez-Silva, Francisco-Javier %A St-Onge, Luc %A Gauthier, Benoit R %K Animals %K Apoptosis %K Cell Communication %K Cell Survival %K Diabetes Mellitus, Experimental %K Diabetes Mellitus, Type 2 %K Female %K Gene Expression Regulation %K Humans %K Hypoglycemic Agents %K Immunity, Innate %K insulin %K Insulin-Secreting Cells %K Islets of Langerhans %K Islets of Langerhans Transplantation %K Macrophages %K Male %K Mice %K Mice, Inbred C57BL %K Phenalenes %K Receptors, Cytoplasmic and Nuclear %K Streptozocin %K T-Lymphocytes, Regulatory %K Transplantation, Heterologous %X

Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis. Here, we show that BL001, a small LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation of pancreas in murine models of T1DM, and beta cell apoptosis in islets of type 2 diabetic patients, while increasing beta cell mass and insulin secretion. Thus, we suggest that LRH-1 agonism favors a dialogue between immune and islet cells, which could be druggable to protect against diabetes mellitus.

%B Nat Commun %V 9 %P 1488 %8 2018 04 16 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/29662071?dopt=Abstract %R 10.1038/s41467-018-03943-0 %0 Journal Article %J BMC Bioinformatics %D 2017 %T ATGC transcriptomics: a web-based application to integrate, explore and analyze de novo transcriptomic data. %A Gonzalez, Sergio %A Clavijo, Bernardo %A Rivarola, Máximo %A Moreno, Patricio %A Fernandez, Paula %A Dopazo, Joaquin %A Paniego, Norma %K Animals %K Databases, Genetic %K Gene Expression Profiling %K High-Throughput Nucleotide Sequencing %K Internet %K Sequence Analysis, RNA %K Transcriptome %K User-Computer Interface %X

BACKGROUND: In the last years, applications based on massively parallelized RNA sequencing (RNA-seq) have become valuable approaches for studying non-model species, e.g., without a fully sequenced genome. RNA-seq is a useful tool for detecting novel transcripts and genetic variations and for evaluating differential gene expression by digital measurements. The large and complex datasets resulting from functional genomic experiments represent a challenge in data processing, management, and analysis. This problem is especially significant for small research groups working with non-model species.

RESULTS: We developed a web-based application, called ATGC transcriptomics, with a flexible and adaptable interface that allows users to work with new generation sequencing (NGS) transcriptomic analysis results using an ontology-driven database. This new application simplifies data exploration, visualization, and integration for a better comprehension of the results.

CONCLUSIONS: ATGC transcriptomics provides access to non-expert computer users and small research groups to a scalable storage option and simple data integration, including database administration and management. The software is freely available under the terms of GNU public license at http://atgcinta.sourceforge.net .

%B BMC Bioinformatics %V 18 %P 121 %8 2017 Feb 22 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/28222698?dopt=Abstract %R 10.1186/s12859-017-1494-2 %0 Journal Article %J Oncotarget %D 2017 %T Genomic expression differences between cutaneous cells from red hair color individuals and black hair color individuals based on bioinformatic analysis. %A Puig-Butille, Joan Anton %A Gimenez-Xavier, Pol %A Visconti, Alessia %A Nsengimana, Jérémie %A Garcia-Garcia, Francisco %A Tell-Marti, Gemma %A Escamez, Maria José %A Newton-Bishop, Julia %A Bataille, Veronique %A Del Rio, Marcela %A Dopazo, Joaquin %A Falchi, Mario %A Puig, Susana %K Adult %K Coculture Techniques %K Computational Biology %K gene expression %K Genetic Predisposition to Disease %K Genomics %K Hair Color %K Humans %K Keratinocytes %K Melanocytes %K Middle Aged %K Phenotype %K Receptor, Melanocortin, Type 1 %X

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.

%B Oncotarget %V 8 %P 11589-11599 %8 2017 Feb 14 %G eng %U http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=14140&path%5B%5D=45094 %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/28030792?dopt=Abstract %R 10.18632/oncotarget.14140 %0 Journal Article %J N Engl J Med %D 2017 %T GGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonates. %A Roca-Ayats, Neus %A Balcells, Susana %A Garcia-Giralt, Natàlia %A Falcó-Mascaró, Maite %A Martínez-Gil, Núria %A Abril, Josep F %A Urreizti, Roser %A Dopazo, Joaquin %A Quesada-Gómez, José M %A Nogués, Xavier %A Mellibovsky, Leonardo %A Prieto-Alhambra, Daniel %A Dunford, James E %A Javaid, Muhammad K %A Russell, R Graham %A Grinberg, Daniel %A Díez-Pérez, Adolfo %K Aged %K Amino Acid Sequence %K Bone Density Conservation Agents %K Dimethylallyltranstransferase %K Diphosphonates %K Exome %K Farnesyltranstransferase %K Female %K Femoral Fractures %K Geranyltranstransferase %K Humans %K Middle Aged %K mutation %B N Engl J Med %V 376 %P 1794-1795 %8 2017 05 04 %G eng %U http://www.nejm.org/doi/full/10.1056/NEJMc1612804 %N 18 %1 https://www.ncbi.nlm.nih.gov/pubmed/28467865?dopt=Abstract %R 10.1056/NEJMc1612804 %0 Journal Article %J Nucleic Acids Res %D 2017 %T HGVA: the Human Genome Variation Archive. %A Lopez, Javier %A Coll, Jacobo %A Haimel, Matthias %A Kandasamy, Swaathi %A Tárraga, Joaquín %A Furio-Tari, Pedro %A Bari, Wasim %A Bleda, Marta %A Rueda, Antonio %A Gräf, Stefan %A Rendon, Augusto %A Dopazo, Joaquin %A Medina, Ignacio %K Genetic Variation %K Genome, Human %K Humans %K Internet %K Software %K User-Computer Interface %X

High-profile genomic variation projects like the 1000 Genomes project or the Exome Aggregation Consortium, are generating a wealth of human genomic variation knowledge which can be used as an essential reference for identifying disease-causing genotypes. However, accessing these data, contrasting the various studies and integrating those data in downstream analyses remains cumbersome. The Human Genome Variation Archive (HGVA) tackles these challenges and facilitates access to genomic data for key reference projects in a clean, fast and integrated fashion. HGVA provides an efficient and intuitive web-interface for easy data mining, a comprehensive RESTful API and client libraries in Python, Java and JavaScript for fast programmatic access to its knowledge base. HGVA calculates population frequencies for these projects and enriches their data with variant annotation provided by CellBase, a rich and fast annotation solution. HGVA serves as a proof-of-concept of the genome analysis developments being carried out by the University of Cambridge together with UK's 100 000 genomes project and the National Institute for Health Research BioResource Rare-Diseases, in particular, deploying open-source for Computational Biology (OpenCB) software platform for storing and analyzing massive genomic datasets.

%B Nucleic Acids Res %V 45 %P W189-W194 %8 2017 07 03 %G eng %U https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkx445 %N W1 %1 https://www.ncbi.nlm.nih.gov/pubmed/28535294?dopt=Abstract %R 10.1093/nar/gkx445 %0 Journal Article %J Plant Mol Biol %D 2017 %T Integration of transcriptomic and metabolic data reveals hub transcription factors involved in drought stress response in sunflower (Helianthus annuus L.). %A Moschen, Sebastián %A Di Rienzo, Julio A %A Higgins, Janet %A Tohge, Takayuki %A Watanabe, Mutsumi %A Gonzalez, Sergio %A Rivarola, Máximo %A Garcia-Garcia, Francisco %A Dopazo, Joaquin %A Hopp, H Esteban %A Hoefgen, Rainer %A Fernie, Alisdair R %A Paniego, Norma %A Fernandez, Paula %A Heinz, Ruth A %K Chlorophyll %K Gene Expression Regulation, Plant %K Helianthus %K Plant Leaves %K Plant Proteins %K Protein Array Analysis %K RNA, Plant %K Stress, Physiological %K Transcription Factors %K Water %X

By integration of transcriptional and metabolic profiles we identified pathways and hubs transcription factors regulated during drought conditions in sunflower, useful for applications in molecular and/or biotechnological breeding. Drought is one of the most important environmental stresses that effects crop productivity in many agricultural regions. Sunflower is tolerant to drought conditions but the mechanisms involved in this tolerance remain unclear at the molecular level. The aim of this study was to characterize and integrate transcriptional and metabolic pathways related to drought stress in sunflower plants, by using a system biology approach. Our results showed a delay in plant senescence with an increase in the expression level of photosynthesis related genes as well as higher levels of sugars, osmoprotectant amino acids and ionic nutrients under drought conditions. In addition, we identified transcription factors that were upregulated during drought conditions and that may act as hubs in the transcriptional network. Many of these transcription factors belong to families implicated in the drought response in model species. The integration of transcriptomic and metabolomic data in this study, together with physiological measurements, has improved our understanding of the biological responses during droughts and contributes to elucidate the molecular mechanisms involved under this environmental condition. These findings will provide useful biotechnological tools to improve stress tolerance while maintaining crop yield under restricted water availability.

%B Plant Mol Biol %V 94 %P 549-564 %8 2017 Jul %G eng %N 4-5 %1 https://www.ncbi.nlm.nih.gov/pubmed/28639116?dopt=Abstract %R 10.1007/s11103-017-0625-5 %0 Journal Article %J Hum Mutat %D 2017 %T Mutations in TRAPPC11 are associated with a congenital disorder of glycosylation. %A Matalonga, Leslie %A Bravo, Miren %A Serra-Peinado, Carla %A García-Pelegrí, Elisabeth %A Ugarteburu, Olatz %A Vidal, Silvia %A Llambrich, Maria %A Quintana, Ester %A Fuster-Jorge, Pedro %A Gonzalez-Bravo, Maria Nieves %A Beltran, Sergi %A Dopazo, Joaquin %A Garcia-Garcia, Francisco %A Foulquier, François %A Matthijs, Gert %A Mills, Philippa %A Ribes, Antonia %A Egea, Gustavo %A Briones, Paz %A Tort, Frederic %A Girós, Marisa %K Abnormalities, Multiple %K Alleles %K Amino Acid Substitution %K Brain %K Congenital Disorders of Glycosylation %K Genotype %K Humans %K Magnetic Resonance Imaging %K Male %K mutation %K Phenotype %K Vesicular Transport Proteins %K Whole Genome Sequencing %X

Congenital disorders of glycosylation (CDG) are a heterogeneous and rapidly growing group of diseases caused by abnormal glycosylation of proteins and/or lipids. Mutations in genes involved in the homeostasis of the endoplasmic reticulum (ER), the Golgi apparatus (GA), and the vesicular trafficking from the ER to the ER-Golgi intermediate compartment (ERGIC) have been found to be associated with CDG. Here, we report a patient with defects in both N- and O-glycosylation combined with a delayed vesicular transport in the GA due to mutations in TRAPPC11, a subunit of the TRAPPIII complex. TRAPPIII is implicated in the anterograde transport from the ER to the ERGIC as well as in the vesicle export from the GA. This report expands the spectrum of genetic alterations associated with CDG, providing new insights for the diagnosis and the understanding of the physiopathological mechanisms underlying glycosylation disorders.

%B Hum Mutat %V 38 %P 148-151 %8 2017 02 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/27862579?dopt=Abstract %R 10.1002/humu.23145 %0 Journal Article %J Molecular biology and evolution %D 2016 %T 267 Spanish exomes reveal population-specific differences in disease-related genetic variation. %A Joaquín Dopazo %A Amadoz, Alicia %A Bleda, Marta %A García-Alonso, Luz %A Alemán, Alejandro %A Garcia-Garcia, Francisco %A Rodriguez, Juan A %A Daub, Josephine T %A Muntané, Gerard %A Antonio Rueda %A Vela-Boza, Alicia %A López-Domingo, Francisco J %A Florido, Javier P %A Arce, Pablo %A Ruiz-Ferrer, Macarena %A Méndez-Vidal, Cristina %A Arnold, Todd E %A Spleiss, Olivia %A Alvarez-Tejado, Miguel %A Navarro, Arcadi %A Bhattacharya, Shomi S %A Borrego, Salud %A Santoyo-López, Javier %A Antiňolo, Guillermo %K disease %K NGS %K polymorphisms %K Population genomics %K prioritization %K SNP %X 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. %B Molecular biology and evolution %8 2016 Jan 13 %G eng %U https://mbe.oxfordjournals.org/content/early/2016/02/17/molbev.msw005.full %R 10.1093/molbev/msw005 %0 Journal Article %J Transl Psychiatry %D 2016 %T Human DNA methylomes of neurodegenerative diseases show common epigenomic patterns. %A Sanchez-Mut, J V %A Heyn, H %A Vidal, E %A Moran, S %A Sayols, S %A Delgado-Morales, R %A Schultz, M D %A Ansoleaga, B %A Garcia-Esparcia, P %A Pons-Espinal, M %A de Lagran, M M %A Dopazo, J %A Rabano, A %A Avila, J %A Dierssen, M %A Lott, I %A Ferrer, I %A Ecker, J R %A Esteller, M %K Adult %K Aged %K Aged, 80 and over %K DNA Methylation %K Epigenomics %K Female %K Humans %K Male %K Middle Aged %K neurodegenerative diseases %K Prefrontal Cortex %K Tissue Array Analysis %X

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

%B Transl Psychiatry %V 6 %P e718 %8 2016 Jan 19 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/26784972?dopt=Abstract %R 10.1038/tp.2015.214 %0 Journal Article %J Sci Rep %D 2016 %T Identification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa. %A Corton, M %A Avila-Fernández, A %A Campello, L %A Sánchez, M %A Benavides, B %A López-Molina, M I %A Fernández-Sánchez, L %A Sánchez-Alcudia, R %A da Silva, L R J %A Reyes, N %A Martín-Garrido, E %A Zurita, O %A Fernández-San José, P %A Pérez-Carro, R %A García-García, F %A Dopazo, J %A García-Sandoval, B %A Cuenca, N %A Ayuso, C %K Aged %K Animals %K Co-Repressor Proteins %K Codon, Nonsense %K Cohort Studies %K Comparative Genomic Hybridization %K Consanguinity %K DNA Mutational Analysis %K Exome %K Eye Proteins %K Female %K Gene Expression Regulation %K Genes, Recessive %K Homeodomain Proteins %K Homozygote %K Humans %K Male %K Mice %K Middle Aged %K Polymorphism, Single Nucleotide %K Protein Interaction Mapping %K Retina %K Retinal Dystrophies %K Retinal Rod Photoreceptor Cells %K Retinitis pigmentosa %K Spain %K Trans-Activators %K Transcription Factors %X

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

%B Sci Rep %V 6 %P 35370 %8 2016 10 13 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/27734943?dopt=Abstract %R 10.1038/srep35370 %0 Journal Article %J Plant Biotechnol J %D 2016 %T Integrating transcriptomic and metabolomic analysis to understand natural leaf senescence in sunflower. %A Moschen, Sebastián %A Bengoa Luoni, Sofía %A Di Rienzo, Julio A %A Caro, María Del Pilar %A Tohge, Takayuki %A Watanabe, Mutsumi %A Hollmann, Julien %A Gonzalez, Sergio %A Rivarola, Máximo %A Garcia-Garcia, Francisco %A Dopazo, Joaquin %A Hopp, Horacio Esteban %A Hoefgen, Rainer %A Fernie, Alisdair R %A Paniego, Norma %A Fernandez, Paula %A Heinz, Ruth A %K Gas Chromatography-Mass Spectrometry %K Gene Expression Profiling %K Gene Expression Regulation, Plant %K Gene ontology %K Genes, Plant %K Helianthus %K Ions %K metabolomics %K Oligonucleotide Array Sequence Analysis %K Plant Leaves %K Principal Component Analysis %K RNA, Messenger %K Transcription Factors %X

Leaf senescence is a complex process, which has dramatic consequences on crop yield. In sunflower, gap between potential and actual yields reveals the economic impact of senescence. Indeed, sunflower plants are incapable of maintaining their green leaf area over sustained periods. This study characterizes the leaf senescence process in sunflower through a systems biology approach integrating transcriptomic and metabolomic analyses: plants being grown under both glasshouse and field conditions. Our results revealed a correspondence between profile changes detected at the molecular, biochemical and physiological level throughout the progression of leaf senescence measured at different plant developmental stages. Early metabolic changes were detected prior to anthesis and before the onset of the first senescence symptoms, with more pronounced changes observed when physiological and molecular variables were assessed under field conditions. During leaf development, photosynthetic activity and cell growth processes decreased, whereas sucrose, fatty acid, nucleotide and amino acid metabolisms increased. Pathways related to nutrient recycling processes were also up-regulated. Members of the NAC, AP2-EREBP, HB, bZIP and MYB transcription factor families showed high expression levels, and their expression level was highly correlated, suggesting their involvement in sunflower senescence. The results of this study thus contribute to the elucidation of the molecular mechanisms involved in the onset and progression of leaf senescence in sunflower leaves as well as to the identification of candidate genes involved in this process.

%B Plant Biotechnol J %V 14 %P 719-34 %8 2016 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/26132509?dopt=Abstract %R 10.1111/pbi.12422 %0 Journal Article %J Scientific reports %D 2016 %T The pan-cancer pathological regulatory landscape. %A Falco, Matias M %A Bleda, Marta %A Carbonell-Caballero, José %A Joaquín Dopazo %X Dysregulation of the normal gene expression program is the cause of a broad range of diseases, including cancer. Detecting the specific perturbed regulators that have an effect on the generation and the development of the disease is crucial for understanding the disease mechanism and for taking decisions on efficient preventive and curative therapies. Moreover, detecting such perturbations at the patient level is even more important from the perspective of personalized medicine. We applied the Transcription Factor Target Enrichment Analysis, a method that detects the activity of transcription factors based on the quantification of the collective transcriptional activation of their targets, to a large collection of 5607 cancer samples covering eleven cancer types. We produced for the first time a comprehensive catalogue of altered transcription factor activities in cancer, a considerable number of them significantly associated to patient’s survival. Moreover, we described several interesting TFs whose activity do not change substantially in the cancer with respect to the normal tissue but ultimately play an important role in patient prognostic determination, which suggest they might be promising therapeutic targets. An additional advantage of this method is that it allows obtaining personalized TF activity estimations for individual patients. %B Scientific reports %V 6 %P 39709 %8 2016 Dec 21 %G eng %U http://www.nature.com/articles/srep39709 %R 10.1038/srep39709 %0 Journal Article %J Scientific Reports %D 2016 %T The pan-cancer pathological regulatory landscape %A Falco, Matias M. %A Bleda, Marta %A Carbonell-Caballero, José %A Dopazo, Joaquin %B Scientific Reports %V 6 %8 Jan-12-2016 %G eng %U http://www.nature.com/articles/srep39709http://www.nature.com/articles/srep39709.pdfhttp://www.nature.com/articles/srep39709.pdfhttp://www.nature.com/articles/srep39709 %N 1 %! Sci Rep %R 10.1038/srep39709 %0 Journal Article %J Mol Metab %D 2016 %T Stress-induced activation of brown adipose tissue prevents obesity in conditions of low adaptive thermogenesis. %A Razzoli, Maria %A Frontini, Andrea %A Gurney, Allison %A Mondini, Eleonora %A Cubuk, Cankut %A Katz, Liora S %A Cero, Cheryl %A Bolan, Patrick J %A Dopazo, Joaquin %A Vidal-Puig, Antonio %A Cinti, Saverio %A Bartolomucci, Alessandro %X

BACKGROUND: Stress-associated conditions such as psychoemotional reactivity and depression have been paradoxically linked to either weight gain or weight loss. This bi-directional effect of stress is not understood at the functional level. Here we tested the hypothesis that pre-stress level of adaptive thermogenesis and brown adipose tissue (BAT) functions explain the vulnerability or resilience to stress-induced obesity.

METHODS: We used wt and triple β1,β2,β3-Adrenergic Receptors knockout (β-less) mice exposed to a model of chronic subordination stress (CSS) at either room temperature (22 °C) or murine thermoneutrality (30 °C). A combined behavioral, physiological, molecular, and immunohistochemical analysis was conducted to determine stress-induced modulation of energy balance and BAT structure and function. Immortalized brown adipocytes were used for in vitro assays.

RESULTS: Departing from our initial observation that βARs are dispensable for cold-induced BAT browning, we demonstrated that under physiological conditions promoting low adaptive thermogenesis and BAT activity (e.g. thermoneutrality or genetic deletion of the βARs), exposure to CSS acted as a stimulus for BAT activation and thermogenesis, resulting in resistance to diet-induced obesity despite the presence of hyperphagia. Conversely, in wt mice acclimatized to room temperature, and therefore characterized by sustained BAT function, exposure to CSS increased vulnerability to obesity. Exposure to CSS enhanced the sympathetic innervation of BAT in wt acclimatized to thermoneutrality and in β-less mice. Despite increased sympathetic innervation suggesting adrenergic-mediated browning, norepinephrine did not promote browning in βARs knockout brown adipocytes, which led us to identify an alternative sympathetic/brown adipocytes purinergic pathway in the BAT. This pathway is downregulated under conditions of low adaptive thermogenesis requirements, is induced by stress, and elicits activation of UCP1 in wt and β-less brown adipocytes. Importantly, this purinergic pathway is conserved in human BAT.

CONCLUSION: Our findings demonstrate that thermogenesis and BAT function are determinant of the resilience or vulnerability to stress-induced obesity. Our data support a model in which adrenergic and purinergic pathways exert complementary/synergistic functions in BAT, thus suggesting an alternative to βARs agonists for the activation of human BAT.

%B Mol Metab %V 5 %P 19-33 %8 2016 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/26844204?dopt=Abstract %R 10.1016/j.molmet.2015.10.005 %0 Journal Article %J Nature methods %D 2015 %T Combining tumor genome simulation with crowdsourcing to benchmark somatic single-nucleotide-variant detection. %A Ewing, Adam D %A Houlahan, Kathleen E %A Hu, Yin %A Ellrott, Kyle %A Caloian, Cristian %A Yamaguchi, Takafumi N %A Bare, J Christopher %A P’ng, Christine %A Waggott, Daryl %A Sabelnykova, Veronica Y %A Kellen, Michael R %A Norman, Thea C %A Haussler, David %A Friend, Stephen H %A Stolovitzky, Gustavo %A Margolin, Adam A %A Stuart, Joshua M %A Boutros, Paul C %E ICGC-TCGA DREAM Somatic Mutation Calling Challenge participants %E Liu Xi %E Ninad Dewal %E Yu Fan %E Wenyi Wang %E David Wheeler %E Andreas Wilm %E Grace Hui Ting %E Chenhao Li %E Denis Bertrand %E Niranjan Nagarajan %E Qing-Rong Chen %E Chih-Hao Hsu %E Ying Hu %E Chunhua Yan %E Warren Kibbe %E Daoud Meerzaman %E Kristian Cibulskis %E Mara Rosenberg %E Louis Bergelson %E Adam Kiezun %E Amie Radenbaugh %E Anne-Sophie Sertier %E Anthony Ferrari %E Laurie Tonton %E Kunal Bhutani %E Nancy F Hansen %E Difei Wang %E Lei Song %E Zhongwu Lai %E Liao, Yang %E Shi, Wei %E Carbonell-Caballero, José %E Joaquín Dopazo %E Cheryl C K Lau %E Justin Guinney %K cancer %K NGS %K variant calling %X 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/. %B Nature methods %8 2015 May 18 %G eng %U http://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth.3407.html %R 10.1038/nmeth.3407 %0 Journal Article %J Hearing research %D 2015 %T Comparative gene expression study of the vestibular organ of the Igf1 deficient mouse using whole-transcript arrays. %A Rodríguez-de la Rosa, Lourdes %A Sánchez-Calderón, Hortensia %A Contreras, Julio %A Murillo-Cuesta, Silvia %A Falagan, Sandra %A Avendaño, Carlos %A Joaquín Dopazo %A Varela-Nieto, Isabel %A Milo, Marta %X The auditory and vestibular organs form the inner ear and have a common developmental origin. Insulin like growth factor 1 (IGF-1) has a central role in the development of the cochlea and maintenance of hearing. Its deficiency causes sensorineural hearing loss in man and mice. During chicken early development, IGF-1 modulates neurogenesis of the cochleovestibular ganglion but no further studies have been conducted to explore the potential role of IGF-1 in the vestibular system. In this study we have compared the whole transcriptome of the vestibular organ from wild type and Igf1(-/-) mice at different developmental and postnatal times. RNA was prepared from E18.5, P15 and P90 vestibular organs of Igf1(-/-) and Igf1(+/+) mice and the transcriptome analysed in triplicates using Affymetrix® Mouse Gene 1.1 ST Array Plates. These plates are whole-transcript arrays that include probes to measure both messenger (mRNA) and long intergenic non-coding RNA transcripts (lincRNA), with a coverage of over 28 thousand coding transcripts and over 7 thousands non-coding transcripts. Given the complexity of the data we used two different methods VSN-RMA and mmBGX to analyse and compare the data. This is to better evaluate the number of false positives and to quantify uncertainty of low signals. We identified a number of differentially expressed genes that we described using functional analysis and validated using RT-qPCR. The morphology of the vestibular organ did not show differences between genotypes and no evident alterations were observed in the vestibular sensory areas of the null mice. However, well-defined cellular alterations were found in the vestibular neurons with respect their number and size. Although these mice did not show a dramatic vestibular phenotype, we conducted a functional analysis on differentially expressed genes between genotypes and across time. This was with the aim to identify new pathways that are involved in the development of the vestibular organ as well as pathways that maybe affected by the lack of IGF-1 and be associated to the morphological changes of the vestibular neurons that we observed in the Igf1(-/-) mice. %B Hearing research %8 2015 Sep 1 %G eng %U http://www.sciencedirect.com/science/article/pii/S0378595515001835 %R 10.1016/j.heares.2015.08.016 %0 Journal Article %J Scientific reports %D 2015 %T Exome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease. %A Luzón-Toro, Berta %A Gui, Hongsheng %A Ruiz-Ferrer, Macarena %A Sze-Man Tang, Clara %A Fernández, Raquel M %A Sham, Pak-Chung %A Torroglosa, Ana %A Kwong-Hang Tam, Paul %A Espino-Paisán, Laura %A Cherny, Stacey S %A Bleda, Marta %A Enguix-Riego, María Del Valle %A Joaquín Dopazo %A Antiňolo, Guillermo %A Garcia-Barceló, Maria-Mercè %A Borrego, Salud %K babelomics %K Hirschprung %K NGS %K prioritization %X Hirschsprung disease (HSCR; OMIM 142623) is a developmental disorder characterized by aganglionosis along variable lengths of the distal gastrointestinal tract, which results in intestinal obstruction. Interactions among known HSCR genes and/or unknown disease susceptibility loci lead to variable severity of phenotype. Neither linkage nor genome-wide association studies have efficiently contributed to completely dissect the genetic pathways underlying this complex genetic disorder. We have performed whole exome sequencing of 16 HSCR patients from 8 unrelated families with SOLID platform. Variants shared by affected relatives were validated by Sanger sequencing. We searched for genes recurrently mutated across families. Only variations in the FAT3 gene were significantly enriched in five families. Within-family analysis identified compound heterozygotes for AHNAK and several genes (N = 23) with heterozygous variants that co-segregated with the phenotype. Network and pathway analyses facilitated the discovery of polygenic inheritance involving FAT3, HSCR known genes and their gene partners. Altogether, our approach has facilitated the detection of more than one damaging variant in biologically plausible genes that could jointly contribute to the phenotype. Our data may contribute to the understanding of the complex interactions that occur during enteric nervous system development and the etiopathology of familial HSCR. %B Scientific reports %V 5 %P 16473 %8 2015 %G eng %U http://www.nature.com/articles/srep16473 %R 10.1038/srep16473 %0 Journal Article %J Scientific Reports %D 2015 %T Exome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease %A Luzón-Toro, Berta %A Gui, Hongsheng %A Ruiz-Ferrer, Macarena %A Sze-Man Tang, Clara %A Fernández, Raquel M. %A Sham, Pak-Chung %A Torroglosa, Ana %A Kwong-Hang Tam, Paul %A Espino-Paisán, Laura %A Cherny, Stacey S. %A Bleda, Marta %A Enguix-Riego, María Del Valle %A Dopazo, Joaquin %A Antiňolo, Guillermo %A Garcia-Barceló, Maria-Mercè %A Borrego, Salud %B Scientific Reports %V 5 %8 Jan-12-2015 %G eng %U http://www.nature.com/articles/srep16473http://www.nature.com/articles/srep16473.pdfhttp://www.nature.com/articles/srep16473.pdfhttp://www.nature.com/articles/srep16473 %N 1 %! Sci Rep %R 10.1038/srep16473 %0 Journal Article %J Eur J Oral Sci %D 2015 %T Family-based genome-wide association study in Patagonia confirms the association of the DMD locus and cleft lip and palate. %A Fonseca, Renata F %A de Carvalho, Flávia M %A Poletta, Fernando A %A Montaner, David %A Dopazo, Joaquin %A Mereb, Juan C %A Moreira, Miguel A M %A Seuanez, Hector N %A Vieira, Alexandre R %A Castilla, Eduardo E %A Orioli, Iêda M %X

The etiology of cleft lip with or without cleft palate (CL±P) is complex and heterogeneous, and multiple genetic and environmental factors are involved. Some candidate genes reported to be associated with oral clefts are located on the X chromosome. At least three genes causing X-linked syndromes [midline 1 (MID1), oral-facial-digital syndrome 1 (OFD1), and dystrophin (DMD)] were previously found to be associated with isolated CL±P. We attempted to confirm the role of X-linked genes in the etiology of isolated CL±P in a South American population through a family-based genome-wide scan. We studied 27 affected children and their mothers, from 26 families, in a Patagonian population with a high prevalence of CL±P. We conducted an exploratory analysis of the X chromosome to identify candidate regions associated with CL±P. Four genomic segments were identified, two of which showed a statistically significant association with CL±P. One is an 11-kb region of Xp21.1 containing the DMD gene, and the other is an intergenic region (8.7 kb; Xp11.4). Our results are consistent with recent data on the involvement of the DMD gene in the etiology of CL±P. The MID1 and OFD1 genes were not included in the four potential CL±P-associated X-chromosome genomic segments.

%B Eur J Oral Sci %V 123 %P 381-384 %8 2015 Oct %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/26331285?dopt=Abstract %R 10.1111/eos.12212 %0 Journal Article %J BMC Medical Genomics %D 2015 %T Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas %A Luzón-Toro, Berta %A Bleda, Marta %A Navarro, Elena %A García-Alonso, Luz %A Ruiz-Ferrer, Macarena %A Medina, Ignacio %A Martín-Sánchez, Marta %A Gonzalez, Cristina Y. %A Fernández, Raquel M. %A Torroglosa, Ana %A Antiňolo, Guillermo %A Dopazo, Joaquin %A Borrego, Salud %X 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. %B BMC Medical Genomics %V 8 %P 83 %8 Dec %G eng %U https://doi.org/10.1186/s12920-015-0160-7 %R 10.1186/s12920-015-0160-7 %0 Journal Article %J BMC medical genomics %D 2015 %T Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas. %A Luzón-Toro, Berta %A Bleda, Marta %A Navarro, Elena %A García-Alonso, Luz %A Ruiz-Ferrer, Macarena %A Medina, Ignacio %A Martín-Sánchez, Marta %A Gonzalez, Cristina Y %A Fernández, Raquel M %A Torroglosa, Ana %A Antiňolo, Guillermo %A Dopazo, Joaquin %A Borrego, Salud %K epistasis %K GWAS %K Thyroid cancer %X 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. %B BMC medical genomics %V 8 %P 83 %8 2015 %G eng %U http://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-015-0160-7 %R 10.1186/s12920-015-0160-7 %0 Journal Article %J Molecular immunology %D 2015 %T Therapeutic targets for olive pollen allergy defined by gene markers modulated by Ole e 1-derived peptides. %A Calzada, David %A Aguerri, Miriam %A Baos, Selene %A Montaner, David %A Mata, Manuel %A Joaquín Dopazo %A Quiralte, Joaquín %A Florido, Fernando %A Lahoz, Carlos %A Cárdaba, Blanca %X Two regions of Ole e 1, the major olive-pollen allergen, have been characterized as T-cell epitopes, one as immunodominant region (aa91-130) and the other, as mainly recognized by non-allergic subjects (aa10-31). This report tries to characterize the specific relevance of these epitopes in the allergic response to olive pollen by analyzing the secreted cytokines and the gene expression profiles induced after specific stimulation of peripheral blood mononuclear cells (PBMCs). PBMCs from olive pollen-allergic and non-allergic control subjects were stimulated with olive-pollen extract and Ole e 1 dodecapeptides containing relevant T-cell epitopes. Levels of cytokines were measured in cellular supernatants and gene expression was determined by microarrays, on the RNAs extracted from PBMCs. One hundred eighty-nine differential genes (fold change >2 or <-2, P<0.05) were validated by qRT-PCR in a large population. It was not possible to define a pattern of response according the overall cytokine results but interesting differences were observed, mainly in the regulatory cytokines. Principal component (PCA) gene-expression analysis defined clusters that correlated with the experimental conditions in the group of allergic subjects. Gene expression and functional analyses revealed differential genes and pathways among the experimental conditions. A set of 51 genes (many essential to T-cell tolerance and homeostasis) correlated with the response to aa10-31 of Ole e 1. In conclusion, two peptides derived from Ole e 1 could regulate the immune response in allergic patients, by gene-expression modification of several regulation-related genes. These results open new research ways to the regulation of allergy by Oleaceae family members. %B Molecular immunology %V 64 %P 252-61 %8 2015 Apr %G eng %U http://www.sciencedirect.com/science/article/pii/S0161589014003356 %R 10.1016/j.molimm.2014.12.002 %0 Journal Article %J Human molecular genetics %D 2015 %T Whole Exome Sequencing Reveals ZNF408 as a New Gene Associated With Autosomal Recessive Retinitis Pigmentosa with Vitreal Alterations. %A Avila-Fernandez, Almudena %A Perez-Carro, Raquel %A Corton, Marta %A Lopez-Molina, Maria Isabel %A Campello, Laura %A Garanto, Alex %A Fernadez-Sanchez, Laura %A Duijkers, Lonneke %A Lopez-Martinez, Miguel Angel %A Riveiro-Alvarez, Rosa %A da Silva, Luciana Rodrigues Jacy %A Sanchez-Alcudia, Rocío %A Martin-Garrido, Esther %A Reyes, Noelia %A Garcia-Garcia, Francisco %A Dopazo, Joaquin %A Garcia-Sandoval, Blanca %A Collin, Rob W %A Cuenca, Nicolas %A Ayuso, Carmen %X Retinitis Pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors ten predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina. %B Human molecular genetics %V 24 %P 4037-4048 %8 2015 Apr 16 %G eng %U http://hmg.oxfordjournals.org/content/early/2015/04/16/hmg.ddv140.abstract %R 10.1093/hmg/ddv140 %0 Journal Article %J Hum Mol Genet %D 2015 %T Whole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations. %A Avila-Fernandez, Almudena %A Perez-Carro, Raquel %A Corton, Marta %A Lopez-Molina, Maria Isabel %A Campello, Laura %A Garanto, Alejandro %A Fernandez-Sanchez, Laura %A Duijkers, Lonneke %A Lopez-Martinez, Miguel Angel %A Riveiro-Alvarez, Rosa %A da Silva, Luciana Rodrigues Jacy %A Sanchez-Alcudia, Rocío %A Martin-Garrido, Esther %A Reyes, Noelia %A Garcia-Garcia, Francisco %A Dopazo, Joaquin %A Garcia-Sandoval, Blanca %A Collin, Rob W J %A Cuenca, Nicolas %A Ayuso, Carmen %K Amino Acid Sequence %K Animals %K Chlorocebus aethiops %K Chromosome Mapping %K COS Cells %K DNA-Binding Proteins %K Exome %K Genome-Wide Association Study %K High-Throughput Nucleotide Sequencing %K Homozygote %K Humans %K Molecular Sequence Data %K Mutant Proteins %K Pedigree %K Retina %K Retinal Cone Photoreceptor Cells %K Retinal Rod Photoreceptor Cells %K Retinitis pigmentosa %K Transcription Factors %X

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

%B Hum Mol Genet %V 24 %P 4037-48 %8 2015 Jul 15 %G eng %N 14 %1 https://www.ncbi.nlm.nih.gov/pubmed/25882705?dopt=Abstract %R 10.1093/hmg/ddv140 %0 Journal Article %J Nature communications %D 2014 %T Assessing technical performance in differential gene expression experiments with external spike-in RNA control ratio mixtures. %A Munro, Sarah A %A Lund, Steven P %A Pine, P Scott %A Binder, Hans %A Clevert, Djork-Arné %A Ana Conesa %A Dopazo, Joaquin %A Fasold, Mario %A Hochreiter, Sepp %A Hong, Huixiao %A Jafari, Nadereh %A Kreil, David P %A Labaj, Paweł P %A Li, Sheng %A Liao, Yang %A Lin, Simon M %A Meehan, Joseph %A Mason, Christopher E %A Santoyo-López, Javier %A Setterquist, Robert A %A Shi, Leming %A Shi, Wei %A Smyth, Gordon K %A Stralis-Pavese, Nancy %A Su, Zhenqiang %A Tong, Weida %A Wang, Charles %A Wang, Jian %A Xu, Joshua %A Ye, Zhan %A Yang, Yong %A Yu, Ying %A Salit, Marc %K RNA-seq %X There is a critical need for standard approaches to assess, report and compare the technical performance of genome-scale differential gene expression experiments. Here we assess technical performance with a proposed standard ’dashboard’ of metrics derived from analysis of external spike-in RNA control ratio mixtures. These control ratio mixtures with defined abundance ratios enable assessment of diagnostic performance of differentially expressed transcript lists, limit of detection of ratio (LODR) estimates and expression ratio variability and measurement bias. The performance metrics suite is applicable to analysis of a typical experiment, and here we also apply these metrics to evaluate technical performance among laboratories. An interlaboratory study using identical samples shared among 12 laboratories with three different measurement processes demonstrates generally consistent diagnostic power across 11 laboratories. Ratio measurement variability and bias are also comparable among laboratories for the same measurement process. We observe different biases for measurement processes using different mRNA-enrichment protocols. %B Nature communications %V 5 %P 5125 %8 2014 %G eng %U http://www.nature.com/ncomms/2014/140925/ncomms6125/full/ncomms6125.html %R 10.1038/ncomms6125 %0 Journal Article %J Cancer research %D 2014 %T A Comprehensive DNA Methylation Profile of Epithelial-to-Mesenchymal Transition. %A Carmona, F Javier %A Davalos, Veronica %A Vidal, Enrique %A Gomez, Antonio %A Heyn, Holger %A Hashimoto, Yutaka %A Vizoso, Miguel %A Martinez-Cardus, Anna %A Sayols, Sergi %A Ferreira, Humberto %A Sanchez-Mut, Jose %A Moran, Sebastian %A Margeli, Mireia %A Castella, Eva %A Berdasco, Maria %A Stefansson, Olafur Andri %A Eyfjord, Jorunn E %A Gonzalez-Suarez, Eva %A Dopazo, Joaquin %A Orozco, Modesto %A Gut, Ivo %A Esteller, Manel %K Methyl-Seq %K Methylomics %K Next Generation Sequencing %X Epithelial-to-mesenchymal transition (EMT) is a plastic process in which fully differentiated epithelial cells are converted into poorly differentiated, migratory and invasive mesenchymal cells and it has been related to the metastasis potential of tumors. This is a reversible process and cells can also eventually undergo mesenchymal-to-epithelial transition (MET). The existence of a dynamic EMT process suggests the involvement of epigenetic shifts in the phenotype. Herein, we obtained the DNA methylomes at single-base resolution of MDCK cells undergoing epithelial-to-mesenchymal transition (EMT) and translated the identified differentially methylated regions (DMRs) to human breast cancer cells undergoing a gain of migratory and invasive capabilities associated with the EMT phenotype. We noticed dynamic and reversible changes of DNA methylation, both on promoter sequences and gene-bodies in association with transcription regulation of EMT-related genes. Most importantly, the identified DNA methylation markers of EMT were present in primary mammary tumors in association with the epithelial or the mesenchymal phenotype of the studied breast cancer samples. %B Cancer research %V 74 %P 5608–19 %8 2014 Aug 8 %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/25106427 %R 10.1158/0008-5472.CAN-13-3659 %0 Journal Article %J Human mutation %D 2014 %T A New Overgrowth Syndrome is Due to Mutations in RNF125. %A Tenorio, Jair %A Mansilla, Alicia %A Valencia, María %A Martínez-Glez, Víctor %A Romanelli, Valeria %A Arias, Pedro %A Castrejón, Nerea %A Poletta, Fernando %A Guillén-Navarro, Encarna %A Gordo, Gema %A Mansilla, Elena %A García-Santiago, Fé %A González-Casado, Isabel %A Vallespín, Elena %A Palomares, María %A Mori, María A %A Santos-Simarro, Fernando %A García-Miñaur, Sixto %A Fernández, Luis %A Mena, Rocío %A Benito-Sanz, Sara %A Del Pozo, Angela %A Silla, Juan Carlos %A Ibañez, Kristina %A López-Granados, Eduardo %A Martín-Trujillo, Alex %A Montaner, David %A Heath, Karen E %A Campos-Barros, Angel %A Joaquín Dopazo %A Nevado, Julián %A Monk, David %A Ruiz-Pérez, Víctor L %A Lapunzina, Pablo %K NGS %K prioritization %K Rare Disease %X 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 Sjögren 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. %B Human mutation %V 35 %P 1436–1441 %8 2014 Sep 5 %G eng %U http://onlinelibrary.wiley.com/doi/10.1002/humu.22689/abstract %R 10.1002/humu.22689 %0 Journal Article %J Bioinformatics %D 2014 %T ngsCAT: a tool to assess the efficiency of targeted enrichment sequencing. %A López-Domingo, Francisco J %A Florido, Javier P %A Rueda, Antonio %A Dopazo, Joaquin %A Santoyo-López, Javier %K Exome %K Genome, Human %K High-Throughput Nucleotide Sequencing %K Humans %K Sequence Analysis, DNA %K Software %X

MOTIVATION: Targeted enrichment sequencing by next-generation sequencing is a common approach to interrogate specific loci or the whole exome in the human genome. The efficiency and the lack of bias in the enrichment process need to be assessed as a quality control step before performing downstream analysis of the sequence data. Tools that can report on the sensitivity, specificity, uniformity and other enrichment-specific features are needed.

RESULTS: We have implemented the next-generation sequencing data Capture Assessment Tool (ngsCAT), a tool that takes the information of the mapped reads and the coordinates of the targeted regions as input files, and generates a report with metrics and figures that allows the evaluation of the efficiency of the enrichment process. The tool can also take as input the information of two samples allowing the comparison of two different experiments.

AVAILABILITY AND IMPLEMENTATION: Documentation and downloads for ngsCAT can be found at http://www.bioinfomgp.org/ngscat.

%B Bioinformatics %V 30 %P 1767-8 %8 2014 Jun 15 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/24578402?dopt=Abstract %R 10.1093/bioinformatics/btu108 %0 Journal Article %J Hum Mutat %D 2014 %T Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients. %A García-Cazorla, Angels %A Oyarzabal, Alfonso %A Fort, Joana %A Robles, Concepción %A Castejón, Esperanza %A Ruiz-Sala, Pedro %A Bodoy, Susanna %A Merinero, Begoña %A Lopez-Sala, Anna %A Dopazo, Joaquin %A Nunes, Virginia %A Ugarte, Magdalena %A Artuch, Rafael %A Palacín, Manuel %A Rodríguez-Pombo, Pilar %A Alcaide, Patricia %A Navarrete, Rosa %A Sanz, Paloma %A Font-Llitjós, Mariona %A Vilaseca, Ma Antonia %A Ormaizabal, Aida %A Pristoupilova, Anna %A Agulló, Sergi Beltran %K Amino Acids, Branched-Chain %K Developmental Disabilities %K Fibroblasts %K Humans %K Male %K Mutation, Missense %K Nervous System Diseases %K Pediatrics %K Protein Kinases %X

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' 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.

%B Hum Mutat %V 35 %P 470-7 %8 2014 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/24449431?dopt=Abstract %R 10.1002/humu.22513 %0 Journal Article %J Human mutation %D 2014 %T Two Novel Mutations in the BCKDK Gene (Branched-Chain Keto-Acid Dehydrogenase Kinase) are Responsible of a Neurobehavioral Deficit in two Pediatric Unrelated Patients. %A García-Cazorla, Angels %A Oyarzabal, Alfonso %A Fort, Joana %A Robles, Concepción %A Castejón, Esperanza %A Ruiz-Sala, Pedro %A Bodoy, Susanna %A Merinero, Begoña %A Lopez-Sala, Anna %A Joaquín Dopazo %A Nunes, Virginia %A Ugarte, Magdalena %A Artuch, Rafael %A Palacín, Manuel %A Rodríguez-Pombo, Pilar %X 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’ 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. %B Human mutation %V 35 %P 470-7 %8 2014 Jan 21 %G eng %U http://onlinelibrary.wiley.com/doi/10.1002/humu.22513/abstract %R 10.1002/humu.22513 %0 Journal Article %J Oncotarget %D 2013 %T Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer. %A Puig-Butille, Joan Anton %A Escamez, Maria José %A Garcia-Garcia, Francisco %A Tell-Marti, Gemma %A Fabra, Angels %A Martínez-Santamaría, Lucía %A Badenas, Celia %A Aguilera, Paula %A Pevida, Marta %A Joaquín Dopazo %A Del Rio, Marcela %A Puig, Susana %X Germline mutations in CDKN2A and/or red hair color variants in MC1R genes are associated with an increased susceptibility to develop cutaneous melanoma or non melanoma skin cancer. We studied the impact of the CDKN2A germinal mutation p.G101W and MC1R variants on gene expression and transcription profiles associated with skin cancer. To this end we set-up primary skin cell co-cultures from siblings of melanoma prone-families that were later analyzed using the expression array approach. As a result, we found that 1535 transcripts were deregulated in CDKN2A mutated cells, with over-expression of immunity-related genes (HLA-DPB1, CLEC2B, IFI44, IFI44L, IFI27, IFIT1, IFIT2, SP110 and IFNK) and down-regulation of genes playing a role in the Notch signaling pathway. 3570 transcripts were deregulated in MC1R variant carriers. In particular, genes related to oxidative stress and DNA damage pathways were up-regulated as well as genes associated with neurodegenerative diseases such as Parkinson’s, Alzheimer and Huntington. Finally, we observed that the expression signatures indentified in phenotypically normal cells carrying CDKN2A mutations or MC1R variants are maintained in skin cancer tumors (melanoma and squamous cell carcinoma). These results indicate that transcriptome deregulation represents an early event critical for skin cancer development. %B Oncotarget %8 2013 Dec 16 %G eng %U http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=1444&path%5B%5D=1824 %0 Journal Article %J J Biol Regul Homeost Agents %D 2013 %T Differential gene-expression analysis defines a molecular pattern related to olive pollen allergy. %A Aguerri, M %A Calzada, D %A Montaner, D %A Mata, M %A Florido, F %A Quiralte, J %A Dopazo, J %A Lahoz, C %A Cardaba, B %K Adult %K Female %K Gene Expression Profiling %K Humans %K Male %K Middle Aged %K Olea %K Principal Component Analysis %K Rhinitis, Allergic, Seasonal %X

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

%B J Biol Regul Homeost Agents %V 27 %P 337-50 %8 2013 Apr-Jun %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/23830385?dopt=Abstract %0 Journal Article %J Mol Genet Metab %D 2013 %T Exome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria. %A Tort, Frederic %A García-Silva, María Teresa %A Ferrer-Cortès, Xènia %A Navarro-Sastre, Aleix %A Garcia-Villoria, Judith %A Coll, Maria Josep %A Vidal, Enrique %A Jiménez-Almazán, Jorge %A Dopazo, Joaquin %A Briones, Paz %A Elpeleg, Orly %A Ribes, Antonia %K Adolescent %K Adult %K Carboxylic Ester Hydrolases %K Child %K Exome %K Female %K High-Throughput Nucleotide Sequencing %K Humans %K Infant %K Male %K Metabolism, Inborn Errors %K mutation %X

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'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.

%B Mol Genet Metab %V 110 %P 73-7 %8 2013 Sep-Oct %G eng %N 1-2 %1 https://www.ncbi.nlm.nih.gov/pubmed/23707711?dopt=Abstract %R 10.1016/j.ymgme.2013.04.021 %0 Journal Article %J Orphanet journal of rare diseases %D 2013 %T Pathways systematically associated to Hirschsprung’s disease. %A Fernández, Raquel M %A Bleda, Marta %A Luzón-Toro, Berta %A García-Alonso, Luz %A Arnold, Stacey %A Sribudiani, Yunia %A Besmond, Claude %A Lantieri, Francesca %A Doan, Betty %A Ceccherini, Isabella %A Lyonnet, Stanislas %A Hofstra, Robert Mw %A Chakravarti, Aravinda %A Antiňolo, Guillermo %A Joaquín Dopazo %A Borrego, Salud %K GWAS %K Hirschprung %K network analysis %K Pathway Based Analysis %X Despite it has been reported that several loci are involved in Hirschsprung’s disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung’s disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations. %B Orphanet journal of rare diseases %V 8 %P 187 %8 2013 Dec 2 %G eng %U http://www.ojrd.com/content/8/1/187/abstract %R 10.1186/1750-1172-8-187 %0 Journal Article %J Orphanet J Rare Dis %D 2013 %T Pathways systematically associated to Hirschsprung's disease. %A Fernández, Raquel M %A Bleda, Marta %A Luzón-Toro, Berta %A García-Alonso, Luz %A Arnold, Stacey %A Sribudiani, Yunia %A Besmond, Claude %A Lantieri, Francesca %A Doan, Betty %A Ceccherini, Isabella %A Lyonnet, Stanislas %A Hofstra, Robert Mw %A Chakravarti, Aravinda %A Antiňolo, Guillermo %A Dopazo, Joaquin %A Borrego, Salud %K Female %K Genetic Predisposition to Disease %K Genotype %K Hirschsprung Disease %K Humans %K Male %K Polymorphism, Single Nucleotide %X

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

%B Orphanet J Rare Dis %V 8 %P 187 %8 2013 Dec 02 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/24289864?dopt=Abstract %R 10.1186/1750-1172-8-187 %0 Journal Article %J PloS one %D 2012 %T Development, Characterization and Experimental Validation of a Cultivated Sunflower (Helianthus annuus L.) Gene Expression Oligonucleotide Microarray. %A Fernandez, Paula %A Soria, Marcelo %A Blesa, David %A Dirienzo, Julio %A Moschen, Sebastián %A Rivarola, Máximo %A Clavijo, Bernardo Jose %A Gonzalez, Sergio %A Peluffo, Lucila %A Príncipi, Dario %A Dosio, Guillermo %A Aguirrezabal, Luis %A Garcia-Garcia, Francisco %A Ana Conesa %A Hopp, Esteban %A Joaquín Dopazo %A Heinz, Ruth Amelia %A Paniego, Norma %X Oligonucleotide-based microarrays with accurate gene coverage represent a key strategy for transcriptional studies in orphan species such as sunflower, H. annuus L., which lacks full genome sequences. The goal of this study was the development and functional annotation of a comprehensive sunflower unigene collection and the design and validation of a custom sunflower oligonucleotide-based microarray. A large scale EST (>130,000 ESTs) curation, assembly and sequence annotation was performed using Blast2GO (www.blast2go.de). The EST assembly comprises 41,013 putative transcripts (12,924 contigs and 28,089 singletons). The resulting Sunflower Unigen Resource (SUR version 1.0) was used to design an oligonucleotide-based Agilent microarray for cultivated sunflower. This microarray includes a total of 42,326 features: 1,417 Agilent controls, 74 control probes for sunflower replicated 10 times (740 controls) and 40,169 different non-control probes. Microarray performance was validated using a model experiment examining the induction of senescence by water deficit. Pre-processing and differential expression analysis of Agilent microarrays was performed using the Bioconductor limma package. The analyses based on p-values calculated by eBayes (p<0.01) allowed the detection of 558 differentially expressed genes between water stress and control conditions; from these, ten genes were further validated by qPCR. Over-represented ontologies were identified using FatiScan in the Babelomics suite. This work generated a curated and trustable sunflower unigene collection, and a custom, validated sunflower oligonucleotide-based microarray using Agilent technology. Both the curated unigene collection and the validated oligonucleotide microarray provide key resources for sunflower genome analysis, transcriptional studies, and molecular breeding for crop improvement. %B PloS one %V 7 %P e45899 %8 2012 %G eng %U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0045899 %R 10.1371/journal.pone.0045899 %0 Journal Article %J BMC Evol Biol %D 2012 %T Diversification of the expanded teleost-specific toll-like receptor family in Atlantic cod, Gadus morhua. %A Sundaram, Arvind Y M %A Kiron, Viswanath %A Dopazo, Joaquin %A Fernandes, Jorge M O %K Amino Acid Sequence %K Animals %K Binding Sites %K Evolution, Molecular %K Fish Diseases %K Fish Proteins %K Gadus morhua %K Gene Expression Profiling %K Genetic Variation %K Gills %K Head Kidney %K Host-Pathogen Interactions %K Models, Molecular %K Molecular Sequence Data %K Multigene Family %K Phylogeny %K Protein Structure, Tertiary %K Reverse Transcriptase Polymerase Chain Reaction %K Selection, Genetic %K Sequence Analysis, DNA %K Sequence Homology, Amino Acid %K Temperature %K Toll-Like Receptors %K Vibrio %X

BACKGROUND: Toll-like receptors (Tlrs) are major molecular pattern recognition receptors of the innate immune system. Atlantic cod (Gadus morhua) is the first vertebrate known to have lost most of the mammalian Tlr orthologues, particularly all bacterial recognising and other cell surface Tlrs. On the other hand, its genome encodes a unique repertoire of teleost-specific Tlrs. The aim of this study was to investigate if these duplicate Tlrs have been retained through adaptive evolution to compensate for the lack of other cell surface Tlrs in the cod genome.

RESULTS: In this study, one tlr21, 12 tlr22 and two tlr23 genes representing the teleost-specific Tlr family have been cloned and characterised in cod. Phylogenetic analysis grouped all tlr22 genes under a single clade, indicating that the multiple cod paralogues have arisen through lineage-specific duplications. All tlrs examined were transcribed in immune-related tissues as well as in stomach, gut and gonads of adult cod and were differentially expressed during early development. These tlrs were also differentially regulated following immune challenge by immersion with Vibrio anguillarum, indicating their role in the immune response. An increase in water temperature from 4 to 12°C was associated with a 5.5-fold down-regulation of tlr22d transcript levels in spleen. Maximum likelihood analysis with different evolution models revealed that tlr22 genes are under positive selection. A total of 24 codons were found to be positively selected, of which 19 are in the ligand binding region of ectodomain.

CONCLUSION: Positive selection pressure coupled with experimental evidence of differential expression strongly support the hypothesis that teleost-specific tlr paralogues in cod are undergoing neofunctionalisation and can recognise bacterial pathogen-associated molecular patterns to compensate for the lack of other cell surface Tlrs.

%B BMC Evol Biol %V 12 %P 256 %8 2012 Dec 29 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/23273344?dopt=Abstract %R 10.1186/1471-2148-12-256 %0 Journal Article %J Orphanet J Rare Dis %D 2012 %T Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung's disease. %A Fernández, Raquel Ma %A Bleda, Marta %A Núñez-Torres, Rocío %A Medina, Ignacio %A Luzón-Toro, Berta %A García-Alonso, Luz %A Torroglosa, Ana %A Marbà, Martina %A Enguix-Riego, Ma Valle %A Montaner, David %A Antiňolo, Guillermo %A Dopazo, Joaquin %A Borrego, Salud %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Hirschsprung Disease %K Humans %K Male %X

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'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.

%B Orphanet J Rare Dis %V 7 %P 103 %8 2012 Dec 28 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/23270508?dopt=Abstract %R 10.1186/1750-1172-7-103 %0 Journal Article %J Orphanet journal of rare diseases %D 2012 %T Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung’s disease. %A Fernández, Raquel Ma %A Bleda, Marta %A Núñez-Torres, Rocío %A Medina, Ignacio %A Luzón-Toro, Berta %A García-Alonso, Luz %A Torroglosa, Ana %A Marbà, Martina %A Enguix-Riego, Ma Valle %A Montaner, David %A Antiňolo, Guillermo %A Joaquín Dopazo %A Borrego, Salud %X 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’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. %B Orphanet journal of rare diseases %V 7 %P 103 %8 2012 Dec 28 %G eng %U http://www.ojrd.com/content/7/1/103/abstract %R 10.1186/1750-1172-7-103 %0 Journal Article %J PloS one %D 2012 %T Transcriptome profiling of the intoxication response of Tenebrio molitor larvae to Bacillus thuringiensis Cry3Aa protoxin. %A Oppert, Brenda %A Dowd, Scot E %A Bouffard, Pascal %A Li, Lewyn %A Ana Conesa %A Lorenzen, Marcé D %A Toutges, Michelle %A Marshall, Jeremy %A Huestis, Diana L %A Fabrick, Jeff %A Oppert, Cris %A Jurat-Fuentes, Juan Luis %K Administration %K Animals %K Bacterial Proteins %K Base Sequence %K Biosynthetic Pathways %K Complementary %K DNA %K Endotoxins %K Energy Metabolism %K Gene Expression Profiling %K Hemolysin Proteins %K Larva %K Microarray Analysis %K Molecular Sequence Data %K Oral %K Sequence Analysis %K Tenebrio %K Time Factors %K Transcriptome %X Bacillus thuringiensis (Bt) crystal (Cry) proteins are effective against a select number of insect pests, but improvements are needed to increase efficacy and decrease time to mortality for coleopteran pests. To gain insight into the Bt intoxication process in Coleoptera, we performed RNA-Seq on cDNA generated from the guts of Tenebrio molitor larvae that consumed either a control diet or a diet containing Cry3Aa protoxin. Approximately 134,090 and 124,287 sequence reads from the control and Cry3Aa-treated groups were assembled into 1,318 and 1,140 contigs, respectively. Enrichment analyses indicated that functions associated with mitochondrial respiration, signalling, maintenance of cell structure, membrane integrity, protein recycling/synthesis, and glycosyl hydrolases were significantly increased in Cry3Aa-treated larvae, whereas functions associated with many metabolic processes were reduced, especially glycolysis, tricarboxylic acid cycle, and fatty acid synthesis. Microarray analysis was used to evaluate temporal changes in gene expression after 6, 12 or 24 h of Cry3Aa exposure. Overall, microarray analysis indicated that transcripts related to allergens, chitin-binding proteins, glycosyl hydrolases, and tubulins were induced, and those related to immunity and metabolism were repressed in Cry3Aa-intoxicated larvae. The 24 h microarray data validated most of the RNA-Seq data. Of the three intoxication intervals, larvae demonstrated more differential expression of transcripts after 12 h exposure to Cry3Aa. Gene expression examined by three different methods in control vs. Cry3Aa-treated larvae at the 24 h time point indicated that transcripts encoding proteins with chitin-binding domain 3 were the most differentially expressed in Cry3Aa-intoxicated larvae. Overall, the data suggest that T. molitor larvae mount a complex response to Cry3Aa during the initial 24 h of intoxication. Data from this study represent the largest genetic sequence dataset for T. molitor to date. Furthermore, the methods in this study are useful for comparative analyses in organisms lacking a sequenced genome. %B PloS one %V 7 %P e34624 %8 2012 %G eng %R 10.1371/journal.pone.0034624 %0 Journal Article %J PloS one %D 2011 %T Analysis of normal-tumour tissue interaction in tumours: prediction of prostate cancer features from the molecular profile of adjacent normal cells. %A Trevino, Victor %A Tadesse, Mahlet G %A Vannucci, Marina %A Fatima Al-Shahrour %A Antczak, Philipp %A Durant, Sarah %A Bikfalvi, Andreas %A Dopazo, Joaquin %A Campbell, Moray J %A Falciani, Francesco %X

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

%B PloS one %V 6 %P e16492 %8 2011 %G eng %0 Journal Article %J Biostatistics (Oxford, England) %D 2011 %T ARSyN: a method for the identification and removal of systematic noise in multifactorial time course microarray experiments. %A Nueda, Maria J %A Alberto Ferrer %A Ana Conesa %X 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. %B Biostatistics (Oxford, England) %8 2011 Nov 14 %G eng %0 Journal Article %J Genome Res %D 2011 %T Differential expression in RNA-seq: a matter of depth. %A Tarazona, Sonia %A García-Alcalde, Fernando %A Dopazo, Joaquin %A Ferrer, Alberto %A Conesa, Ana %K Algorithms %K Expressed Sequence Tags %K Gene Expression Profiling %K Gene Expression Regulation %K Humans %K Models, Genetic %K Oligonucleotide Array Sequence Analysis %X

Next-generation sequencing (NGS) technologies are revolutionizing genome research, and in particular, their application to transcriptomics (RNA-seq) is increasingly being used for gene expression profiling as a replacement for microarrays. However, the properties of RNA-seq data have not been yet fully established, and additional research is needed for understanding how these data respond to differential expression analysis. In this work, we set out to gain insights into the characteristics of RNA-seq data analysis by studying an important parameter of this technology: the sequencing depth. We have analyzed how sequencing depth affects the detection of transcripts and their identification as differentially expressed, looking at aspects such as transcript biotype, length, expression level, and fold-change. We have evaluated different algorithms available for the analysis of RNA-seq and proposed a novel approach--NOISeq--that differs from existing methods in that it is data-adaptive and nonparametric. Our results reveal that most existing methodologies suffer from a strong dependency on sequencing depth for their differential expression calls and that this results in a considerable number of false positives that increases as the number of reads grows. In contrast, our proposed method models the noise distribution from the actual data, can therefore better adapt to the size of the data set, and is more effective in controlling the rate of false discoveries. This work discusses the true potential of RNA-seq for studying regulation at low expression ranges, the noise within RNA-seq data, and the issue of replication.

%B Genome Res %V 21 %P 2213-23 %8 2011 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/21903743?dopt=Abstract %R 10.1101/gr.124321.111 %0 Journal Article %J Diabetes %D 2011 %T Differential Lipid Partitioning Between Adipocytes and Tissue Macrophages Modulates Macrophage Lipotoxicity and M2/M1 Polarization in Obese Mice. %A Prieur, Xavier %A Mok, Crystal Y L %A Velagapudi, Vidya R %A Núñez, Vanessa %A Fuentes, Lucía %A Montaner, David %A Ishikawa, Ko %A Camacho, Alberto %A Barbarroja, Nuria %A O’Rahilly, Stephen %A Sethi, Jaswinder %A Dopazo, Joaquin %A Oresic, Matej %A Ricote, Mercedes %A Vidal-Puig, Antonio %X

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.

%B Diabetes %V 60 %P 797-809 %8 2011 Jan 24 %G eng %0 Journal Article %J Environmental microbiology %D 2011 %T Evolution of the biosynthesis of di-myo-inositol phosphate, a marker of adaptation to hot marine environments. %A Gonçalves, Luís G %A Borges, Nuno %A Serra, François %A Fernandes, Pedro L %A Dopazo, Hernán %A Santos, Helena %X

The synthesis of di-myo-inositol phosphate (DIP), a common compatible solute in hyperthermophiles, involves the consecutive actions of inositol-1-phosphate cytidylyltransferase (IPCT) and di-myo-inositol phosphate phosphate synthase (DIPPS). In most cases, both activities are present in a single gene product, but separate genes are also found in a few organisms. Genes for IPCT and DIPPS were found in the genomes of 33 organisms, all with thermophilic/hyperthermophilic lifestyles. Phylogeny of IPCT/DIPPS revealed an incongruent topology with 16S RNA phylogeny, thus suggesting horizontal gene transfer. The phylogenetic tree of the DIPPS domain was rooted by using phosphatidylinositol phosphate synthase sequences as out-group. The root locates at the separation of genomes with fused and split genes. We propose that the gene encoding DIPPS was recruited from the biosynthesis of phosphatidylinositol. The last DIP-synthesizing ancestor harboured separated genes for IPCT and DIPPS and this architecture was maintained in a crenarchaeal lineage, and transferred by horizontal gene transfer to hyperthermophilic marine Thermotoga species. It is plausible that the driving force for the assembly of those two genes in the early ancestor is related to the acquired advantage of DIP producers to cope with high temperature. This work corroborates the view that Archaea were the first hyperthermophilic organisms.

%B Environmental microbiology %8 2011 Oct 26 %G eng %R 10.1111/j.1462-2920.2011.02621.x %0 Journal Article %J BMC genomics %D 2011 %T Profiling the venom gland transcriptomes of Costa Rican snakes by 454 pyrosequencing. %A Durban, Jordi %A Juárez, Paula %A Angulo, Yamileth %A Lomonte, Bruno %A Flores-Diaz, Marietta %A Alape-Girón, Alberto %A Sasa, Mahmood %A Sanz, Libia %A Gutiérrez, José M %A Joaquín Dopazo %A Ana Conesa %A Calvete, Juan J %X

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

%B BMC genomics %V 12 %P 259 %8 2011 %G eng %0 Journal Article %J BMC genomics %D 2011 %T Recent human evolution has shaped geographical differences in susceptibility to disease. %A Marigorta, Urko M %A Lao, Oscar %A Casals, Ferran %A Calafell, Francesc %A Morcillo-Suarez, Carlos %A Faria, Rui %A Bosch, Elena %A Serra, François %A Bertranpetit, Jaume %A Dopazo, Hernán %A Navarro, Arcadi %X

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.

%B BMC genomics %V 12 %P 55 %8 2011 %G eng %0 Journal Article %J Genome research %D 2010 %T Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. %A Javierre, Biola M %A Fernandez, Agustin F %A Richter, Julia %A Fatima Al-Shahrour %A Martin-Subero, J Ignacio %A Rodriguez-Ubreva, Javier %A Berdasco, Maria %A Fraga, Mario F %A O’Hanlon, Terrance P %A Rider, Lisa G %A Jacinto, Filipe V %A Lopez-Longo, F Javier %A Dopazo, Joaquin %A Forn, Marta %A Peinado, Miguel A %A Carreño, Luis %A Sawalha, Amr H %A Harley, John B %A Siebert, Reiner %A Esteller, Manel %A Miller, Frederick W %A Ballestar, Esteban %X

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

%B Genome research %V 20 %P 170-9 %8 2010 Feb %G eng %0 Journal Article %J Breast Cancer Res %D 2010 %T DNA methylation epigenotypes in breast cancer molecular subtypes. %A Bediaga, Naiara G %A Acha-Sagredo, Amelia %A Guerra, Isabel %A Viguri, Amparo %A Albaina, Carmen %A Ruiz Diaz, Irune %A Rezola, Ricardo %A Alberdi, Maria Jesus %A Dopazo, Joaquin %A Montaner, David %A Renobales, Mertxe %A Fernandez, Agustin F %A Field, John K %A Fraga, Mario F %A Liloglou, Triantafillos %A de Pancorbo, Marian M %K Aged %K Breast Neoplasms %K CpG Islands %K DNA Methylation %K Epigenesis, Genetic %K Female %K Gene Expression Profiling %K Genes, p53 %K Genotype %K Humans %K Ki-67 Antigen %K Middle Aged %K mutation %K Neoplasm Grading %K Oligonucleotide Array Sequence Analysis %K Receptor, ErbB-2 %K Tumor Suppressor Protein p53 %X

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

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

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

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

%B Breast Cancer Res %V 12 %P R77 %8 2010 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/20920229?dopt=Abstract %R 10.1186/bcr2721 %0 Journal Article %J The Journal of biological chemistry %D 2010 %T FM19G11, a new hypoxia-inducible factor (HIF) modulator, affects stem cell differentiation status. %A Moreno-Manzano, Victoria %A Rodríguez-Jiménez, Francisco J %A Aceña-Bonilla, Jose L %A Fustero-Lardíes, Santos %A Erceg, Slaven %A Dopazo, Joaquin %A Montaner, David %A Stojkovic, Miodrag %A Sánchez-Puelles, Jose M %X

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

%B The Journal of biological chemistry %V 285 %P 1333-42 %8 2010 Jan 8 %G eng %0 Journal Article %J Pharmacogenomics J %D 2010 %T Functional analysis of multiple genomic signatures demonstrates that classification algorithms choose phenotype-related genes. %A Shi, W %A Bessarabova, M %A Dosymbekov, D %A Dezso, Z %A Nikolskaya, T %A Dudoladova, M %A Serebryiskaya, T %A Bugrim, A %A Guryanov, A %A Brennan, R J %A Shah, R %A Dopazo, J %A Chen, M %A Deng, Y %A Shi, T %A Jurman, G %A Furlanello, C %A Thomas, R S %A Corton, J C %A Tong, W %A Shi, L %A Nikolsky, Y %K Algorithms %K Databases, Genetic %K Endpoint Determination %K Gene Expression Profiling %K Genomics %K Humans %K Neural Networks, Computer %K Oligonucleotide Array Sequence Analysis %K Phenotype %K Predictive Value of Tests %K Proteins %K Quality Control %X

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.

%B Pharmacogenomics J %V 10 %P 310-23 %8 2010 Aug %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/20676069?dopt=Abstract %R 10.1038/tpj.2010.35 %0 Journal Article %J Nature biotechnology %D 2010 %T The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models. %A Shi, Leming %A Campbell, Gregory %A Jones, Wendell D %A Campagne, Fabien %A Wen, Zhining %A Walker, Stephen J %A Su, Zhenqiang %A Chu, Tzu-Ming %A Goodsaid, Federico M %A Pusztai, Lajos %A Shaughnessy, John D %A Oberthuer, André %A Thomas, Russell S %A Paules, Richard S %A Fielden, Mark %A Barlogie, Bart %A Chen, Weijie %A Du, Pan %A Fischer, Matthias %A Furlanello, Cesare %A Gallas, Brandon D %A Ge, Xijin %A Megherbi, Dalila B %A Symmans, W Fraser %A Wang, May D %A Zhang, John %A Bitter, Hans %A Brors, Benedikt %A Bushel, Pierre R %A Bylesjo, Max %A Chen, Minjun %A Cheng, Jie %A Cheng, Jing %A Chou, Jeff %A Davison, Timothy S %A Delorenzi, Mauro %A Deng, Youping %A Devanarayan, Viswanath %A Dix, David J %A Dopazo, Joaquin %A Dorff, Kevin C %A Elloumi, Fathi %A Fan, Jianqing %A Fan, Shicai %A Fan, Xiaohui %A Fang, Hong %A Gonzaludo, Nina %A Hess, Kenneth R %A Hong, Huixiao %A Huan, Jun %A Irizarry, Rafael A %A Judson, Richard %A Juraeva, Dilafruz %A Lababidi, Samir %A Lambert, Christophe G %A Li, Li %A Li, Yanen %A Li, Zhen %A Lin, Simon M %A Liu, Guozhen %A Lobenhofer, Edward K %A Luo, Jun %A Luo, Wen %A McCall, Matthew N %A Nikolsky, Yuri %A Pennello, Gene A %A Perkins, Roger G %A Philip, Reena %A Popovici, Vlad %A Price, Nathan D %A Qian, Feng %A Scherer, Andreas %A Shi, Tieliu %A Shi, Weiwei %A Sung, Jaeyun %A Thierry-Mieg, Danielle %A Thierry-Mieg, Jean %A Thodima, Venkata %A Trygg, Johan %A Vishnuvajjala, Lakshmi %A Wang, Sue Jane %A Wu, Jianping %A Wu, Yichao %A Xie, Qian %A Yousef, Waleed A %A Zhang, Liang %A Zhang, Xuegong %A Zhong, Sheng %A Zhou, Yiming %A Zhu, Sheng %A Arasappan, Dhivya %A Bao, Wenjun %A Lucas, Anne Bergstrom %A Berthold, Frank %A Brennan, Richard J %A Buness, Andreas %A Catalano, Jennifer G %A Chang, Chang %A Chen, Rong %A Cheng, Yiyu %A Cui, Jian %A Czika, Wendy %A Demichelis, Francesca %A Deng, Xutao %A Dosymbekov, Damir %A Eils, Roland %A Feng, Yang %A Fostel, Jennifer %A Fulmer-Smentek, Stephanie %A Fuscoe, James C %A Gatto, Laurent %A Ge, Weigong %A Goldstein, Darlene R %A Guo, Li %A Halbert, Donald N %A Han, Jing %A Harris, Stephen C %A Hatzis, Christos %A Herman, Damir %A Huang, Jianping %A Jensen, Roderick V %A Jiang, Rui %A Johnson, Charles D %A Jurman, Giuseppe %A Kahlert, Yvonne %A Khuder, Sadik A %A Kohl, Matthias %A Li, Jianying %A Li, Li %A Li, Menglong %A Li, Quan-Zhen %A Li, Shao %A Li, Zhiguang %A Liu, Jie %A Liu, Ying %A Liu, Zhichao %A Meng, Lu %A Madera, Manuel %A Martinez-Murillo, Francisco %A Medina, Ignacio %A Meehan, Joseph %A Miclaus, Kelci %A Moffitt, Richard A %A Montaner, David %A Mukherjee, Piali %A Mulligan, George J %A Neville, Padraic %A Nikolskaya, Tatiana %A Ning, Baitang %A Page, Grier P %A Parker, Joel %A Parry, R Mitchell %A Peng, Xuejun %A Peterson, Ron L %A Phan, John H %A Quanz, Brian %A Ren, Yi %A Riccadonna, Samantha %A Roter, Alan H %A Samuelson, Frank W %A Schumacher, Martin M %A Shambaugh, Joseph D %A Shi, Qiang %A Shippy, Richard %A Si, Shengzhu %A Smalter, Aaron %A Sotiriou, Christos %A Soukup, Mat %A Staedtler, Frank %A Steiner, Guido %A Stokes, Todd H %A Sun, Qinglan %A Tan, Pei-Yi %A Tang, Rong %A Tezak, Zivana %A Thorn, Brett %A Tsyganova, Marina %A Turpaz, Yaron %A Vega, Silvia C %A Visintainer, Roberto %A von Frese, Juergen %A Wang, Charles %A Wang, Eric %A Wang, Junwei %A Wang, Wei %A Westermann, Frank %A Willey, James C %A Woods, Matthew %A Wu, Shujian %A Xiao, Nianqing %A Xu, Joshua %A Xu, Lei %A Yang, Lun %A Zeng, Xiao %A Zhang, Jialu %A Zhang, Li %A Zhang, Min %A Zhao, Chen %A Puri, Raj K %A Scherf, Uwe %A Tong, Weida %A Wolfinger, Russell D %X

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.

%B Nature biotechnology %V 28 %P 827-38 %8 2010 Aug %G eng %U http://www.nature.com/nbt/journal/v28/n8/full/nbt.1665.html %0 Journal Article %J Leuk Lymphoma %D 2009 %T Analysis of chronic lymphotic leukemia transcriptomic profile: differences between molecular subgroups %A Jantus Lewintre, E. %A Reinoso Martin, C. %A Montaner, D. %A Marin, M. %A Jose Terol, M. %A Farras, R. %A Benet, I. %A Calvete, J. J. %A Dopazo, J. %A Garcia-Conde, J. %K cancer %K microarray data analysis %X

B cell chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder with a variable clinical course. Patients with unmutated IgV(H) gene show a shorter progression-free and overall survival than patients with immunoglobulin heavy chain variable regions (IgV(H)) gene mutated. In addition, BCL6 mutations identify a subgroup of patients with high risk of progression. Gene expression was analysed in 36 early-stage patients using high-density microarrays. Around 150 genes differentially expressed were found according to IgV(H) mutations, whereas no difference was found according to BCL6 mutations. Functional profiling methods allowed us to distinguish KEGG and gene ontology terms showing coordinated gene expression changes across subgroups of CLL. We validated a set of differentially expressed genes according to IgV(H) status, scoring them as putative prognostic markers in CLL. Among them, CRY1, LPL, CD82 and DUSP22 are the ones with at least equal or superior performance to ZAP70 which is actually the most used surrogate marker of IgV(H) status.

%B Leuk Lymphoma %V 50 %P 68-79 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19127482 %0 Journal Article %J BMC Bioinformatics %D 2009 %T Functional assessment of time course microarray data. %A Nueda, Maria José %A Sebastián, Patricia %A Tarazona, Sonia %A Garcia-Garcia, Francisco %A Dopazo, Joaquin %A Ferrer, Alberto %A Conesa, Ana %K Computer Simulation %K Gene Expression Profiling %K Oligonucleotide Array Sequence Analysis %K Time Factors %X

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.

%B BMC Bioinformatics %V 10 Suppl 6 %P S9 %8 2009 Jun 16 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/19534758?dopt=Abstract %R 10.1186/1471-2105-10-S6-S9 %0 Journal Article %J Bioinformatics %D 2009 %T ModLink+: Improving fold recognition by using protein-protein interactions %A Fornes, O. %A Aragues, R. %A Espadaler, J. %A M. A. Marti-Renom %A Sali, A. %A Oliva, B. %K protein folding %X

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

%B Bioinformatics %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19357100 %0 Journal Article %J Nature Methods %D 2009 %T Statistical methods for analysis of high-throughput RNA interference screens %A Birmingham, Amanda %A Selfors, Laura M %A Forster, Thorsten %A Wrobel, David %A Kennedy, Caleb J %A Shanks, Emma %A Santoyo-López, Javier %A Dunican, Dara J %A Long, Aideen %A Kelleher, Dermot %A Smith, Queta %A Beijersbergen, Roderick L %A Ghazal, Peter %A Shamu, Caroline E %K gene silencing %K regulation %K siRNA %B Nature Methods %I Nature Publishing Group %V 6 %P 569 - 575 %8 2009/08//print %@ 1548-7091 %G eng %U http://dx.doi.org/10.1038/nmeth.1351 %0 Journal Article %J Brief Bioinform %D 2008 %T Interoperability with Moby 1.0--it's better than sharing your toothbrush! %A Wilkinson, Mark D %A Senger, Martin %A Kawas, Edward %A Bruskiewich, Richard %A Gouzy, Jerome %A Noirot, Celine %A Bardou, Philippe %A Ng, Ambrose %A Haase, Dirk %A Saiz, Enrique de Andres %A Wang, Dennis %A Gibbons, Frank %A Gordon, Paul M K %A Sensen, Christoph W %A Carrasco, Jose Manuel Rodriguez %A Fernández, José M %A Shen, Lixin %A Links, Matthew %A Ng, Michael %A Opushneva, Nina %A Neerincx, Pieter B T %A Leunissen, Jack A M %A Ernst, Rebecca %A Twigger, Simon %A Usadel, Bjorn %A Good, Benjamin %A Wong, Yan %A Stein, Lincoln %A Crosby, William %A Karlsson, Johan %A Royo, Romina %A Párraga, Iván %A Ramírez, Sergio %A Gelpi, Josep Lluis %A Trelles, Oswaldo %A Pisano, David G %A Jimenez, Natalia %A Kerhornou, Arnaud %A Rosset, Roman %A Zamacola, Leire %A Tárraga, Joaquín %A Huerta-Cepas, Jaime %A Carazo, Jose María %A Dopazo, Joaquin %A Guigó, Roderic %A Navarro, Arcadi %A Orozco, Modesto %A Valencia, Alfonso %A Claros, M Gonzalo %A Pérez, Antonio J %A Aldana, Jose %A Rojano, M Mar %A Fernandez-Santa Cruz, Raul %A Navas, Ismael %A Schiltz, Gary %A Farmer, Andrew %A Gessler, Damian %A Schoof, Heiko %A Groscurth, Andreas %K Computational Biology %K Database Management Systems %K Databases, Factual %K Information Storage and Retrieval %K Internet %K Programming Languages %K Systems Integration %X

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/.

%B Brief Bioinform %V 9 %P 220-31 %8 2008 May %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/18238804?dopt=Abstract %R 10.1093/bib/bbn003 %0 Journal Article %J Brief Bioinform %D 2008 %T Interoperability with Moby 1.0–it’s better than sharing your toothbrush! %A Wilkinson, M. D. %A Senger, M. %A Kawas, E. %A Bruskiewich, R. %A Gouzy, J. %A Noirot, C. %A Bardou, P. %A Ng, A. %A Haase, D. %A Saiz Ede, A. %A Wang, D. %A Gibbons, F. %A Gordon, P. M. %A Sensen, C. W. %A Carrasco, J. M. %A Fernandez, J. M. %A Shen, L. %A Links, M. %A Ng, M. %A Opushneva, N. %A Neerincx, P. B. %A Leunissen, J. A. %A Ernst, R. %A Twigger, S. %A Usadel, B. %A Good, B. %A Wong, Y. %A Stein, L. %A Crosby, W. %A Karlsson, J. %A Royo, R. %A Parraga, I. %A Ramirez, S. %A Gelpi, J. L. %A Trelles, O. %A Pisano, D. G. %A Jimenez, N. %A Kerhornou, A. %A Rosset, R. %A Zamacola, L. %A Tarraga, J. %A Huerta-Cepas, J. %A Carazo, J. M. %A Dopazo, J. %A R. Guigo %A Navarro, A. %A Orozco, M. %A Valencia, A. %A Claros, M. G. %A Perez, A. J. %A Aldana, J. %A Rojano, M. M. %A Fernandez-Santa Cruz, R. %A Navas, I. %A Schiltz, G. %A Farmer, A. %A Gessler, D. %A Schoof, H. %A Groscurth, A. %K Computational Biology/*methods *Database Management Systems *Databases %K Factual Information Storage and Retrieval/*methods *Internet *Programming Languages Systems Integration %X

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/.

%B Brief Bioinform %V 9 %P 220-31 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18238804 %0 Journal Article %J Nat Genet %D 2008 %T SNP and haplotype mapping for genetic analysis in the rat %A K. Saar %A A. Beck %A M. T. Bihoreau %A E. Birney %A D. Brocklebank %A Y. Chen %A E. Cuppen %A S. Demonchy %A Dopazo, J. %A P. Flicek %A M. Foglio %A A. Fujiyama %A I. G. Gut %A D. Gauguier %A R. Guigo %A V. Guryev %A M. Heinig %A O. Hummel %A N. Jahn %A S. Klages %A V. Kren %A M. Kube %A H. Kuhl %A Kuramoto, T. %A Kuroki, Y. %A Lechner, D. %A Lee, Y. A. %A Lopez-Bigas, N. %A Lathrop, G. M. %A Mashimo, T. %A Medina, Ignacio %A Mott, R. %A Patone, G. %A Perrier-Cornet, J. A. %A Platzer, M. %A Pravenec, M. %A Reinhardt, R. %A Sakaki, Y. %A Schilhabel, M. %A Schulz, H. %A Serikawa, T. %A Shikhagaie, M. %A Tatsumoto, S. %A Taudien, S. %A Toyoda, A. %A Voigt, B. %A Zelenika, D. %A Zimdahl, H. %A Hubner, N. %K Animals Chromosome Mapping *Databases %K Genetic %K Genetic Genome *Haplotypes Linkage Disequilibrium Phylogeny *Polymorphism %K Inbred Strains/*genetics Recombination %K Single Nucleotide *Quantitative Trait Loci Rats/*genetics Rats %X

The laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies.

%B Nat Genet %V 40 %P 560-6 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18443594 %0 Journal Article %J Nat Genet %D 2008 %T SNP and haplotype mapping for genetic analysis in the rat. %A Saar, Kathrin %A Beck, Alfred %A Bihoreau, Marie-Thérèse %A Birney, Ewan %A Brocklebank, Denise %A Chen, Yuan %A Cuppen, Edwin %A Demonchy, Stephanie %A Dopazo, Joaquin %A Flicek, Paul %A Foglio, Mario %A Fujiyama, Asao %A Gut, Ivo G %A Gauguier, Dominique %A Guigó, Roderic %A Guryev, Victor %A Heinig, Matthias %A Hummel, Oliver %A Jahn, Niels %A Klages, Sven %A Kren, Vladimir %A Kube, Michael %A Kuhl, Heiner %A Kuramoto, Takashi %A Kuroki, Yoko %A Lechner, Doris %A Lee, Young-Ae %A Lopez-Bigas, Nuria %A Lathrop, G Mark %A Mashimo, Tomoji %A Medina, Ignacio %A Mott, Richard %A Patone, Giannino %A Perrier-Cornet, Jeanne-Antide %A Platzer, Matthias %A Pravenec, Michal %A Reinhardt, Richard %A Sakaki, Yoshiyuki %A Schilhabel, Markus %A Schulz, Herbert %A Serikawa, Tadao %A Shikhagaie, Medya %A Tatsumoto, Shouji %A Taudien, Stefan %A Toyoda, Atsushi %A Voigt, Birger %A Zelenika, Diana %A Zimdahl, Heike %A Hubner, Norbert %K Animals %K Chromosome Mapping %K Databases, Genetic %K Genome %K Haplotypes %K Linkage Disequilibrium %K Phylogeny %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Rats %K Rats, Inbred Strains %K Recombination, Genetic %X

The laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies.

%B Nat Genet %V 40 %P 560-6 %8 2008 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/18443594?dopt=Abstract %R 10.1038/ng.124 %0 Journal Article %J Bioinformatics %D 2007 %T Discovering gene expression patterns in time course microarray experiments by ANOVA-SCA %A Nueda, M. J. %A A. Conesa %A Westerhuis, J. A. %A Hoefsloot, H. C. %A Smilde, A. K. %A Talon, M. %A Ferrer, A. %K Algorithms *Analysis of Variance Computational Biology/*methods Computer Simulation Data Interpretation %K Genetic %K Genetic Models %K Statistical Gene Expression Profiling/*methods Models %K Statistical Oligonucleotide Array Sequence Analysis/*methods Principal Component Analysis Time Factors Transcription %X 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. %B Bioinformatics %V 23 %P 1792-800 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17519250 %0 Book Section %B Microarray Technology Through Applications %D 2007 %T Microarray Technology in Agricultural Research %A A. Conesa %A J. Forment %A J. Gadea %A van Dijk, J. %K babelomics %B Microarray Technology Through Applications %I F. Falciani. Publisher: Taylor and Francis Group %P 173-209 %G eng %0 Journal Article %J Nucleic Acids Res %D 2007 %T PeroxisomeDB: a database for the peroxisomal proteome, functional genomics and disease %A Schluter, A. %A Fourcade, S. %A Domenech-Estevez, E. %A Gabaldón, T. %A Huerta-Cepas, J. %A Berthommier, G. %A Ripp, R. %A Wanders, R. J. %A Poch, O. %A Pujol, A. %K Animals *Databases %K Protein Genomics Humans Internet Mice Peroxisomal Disorders/*genetics Peroxisomes/*metabolism Protein Sorting Signals Proteome/chemistry/*genetics/*physiology Rats Saccharomyces cerevisiae Proteins/genetics/physiology Software User-Computer Interface %X Peroxisomes are essential organelles of eukaryotic origin, ubiquitously distributed in cells and organisms, playing key roles in lipid and antioxidant metabolism. Loss or malfunction of peroxisomes causes more than 20 fatal inherited conditions. We have created a peroxisomal database (http://www.peroxisomeDB.org) that includes the complete peroxisomal proteome of Homo sapiens and Saccharomyces cerevisiae, by gathering, updating and integrating the available genetic and functional information on peroxisomal genes. PeroxisomeDB is structured in interrelated sections ’Genes’, ’Functions’, ’Metabolic pathways’ and ’Diseases’, that include hyperlinks to selected features of NCBI, ENSEMBL and UCSC databases. We have designed graphical depictions of the main peroxisomal metabolic routes and have included updated flow charts for diagnosis. Precomputed BLAST, PSI-BLAST, multiple sequence alignment (MUSCLE) and phylogenetic trees are provided to assist in direct multispecies comparison to study evolutionary conserved functions and pathways. Highlights of the PeroxisomeDB include new tools developed for facilitating (i) identification of novel peroxisomal proteins, by means of identifying proteins carrying peroxisome targeting signal (PTS) motifs, (ii) detection of peroxisomes in silico, particularly useful for screening the deluge of newly sequenced genomes. PeroxisomeDB should contribute to the systematic characterization of the peroxisomal proteome and facilitate system biology approaches on the organelle. %B Nucleic Acids Res %V 35 %P D815-22 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17135190 %0 Journal Article %J FEBS Lett %D 2007 %T Protein translocation into peroxisomes by ring-shaped import receptors %A Stanley, W. A. %A Fodor, K. %A M. A. Marti-Renom %A Schliebs, W. %A Wilmanns, M. %K Amino Acid Sequence Binding Sites Humans Molecular Sequence Data Peroxisomes/*metabolism Protein Structure %K Cytoplasmic and Nuclear/*chemistry %K Tertiary Protein Transport Receptors %X Folded and functional proteins destined for translocation from the cytosol into the peroxisomal matrix are recognized by two different peroxisomal import receptors, Pex5p and Pex7p. Both cargo-loaded receptors dock on the same translocon components, followed by cargo release and receptor recycling, as part of the complete translocation process. Recent structural and functional evidence on the Pex5p receptor has provided insight on the molecular requirements of specific cargo recognition, while the remaining processes still remain largely elusive. Comparison of experimental structures of Pex5p and a structural model of Pex7p reveal that both receptors are built by ring-like arrangements with cargo binding sites, central to the respective structures. Although, molecular insight into the complete peroxisomal translocon still remains to be determined, emerging data allow to deduce common molecular principles that may hold for other translocation systems as well. %B FEBS Lett %V 581 %P 4795-802 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17884042 %0 Journal Article %J Virology %D 2007 %T Transcriptional response of Citrus aurantifolia to infection by Citrus tristeza virus %A Gandia, M. %A A. Conesa %A Ancillo, G. %A J. Gadea %A J. Forment %A Pallas, V. %A Flores, R. %A Duran-Vila, N. %A Moreno, P. %A Guerri, J. %K Citrus/*genetics/physiology/virology Closterovirus/genetics/*physiology Genes %K Genetic %K Plant Oligonucleotide Array Sequence Analysis Reverse Transcriptase Polymerase Chain Reaction *Transcription %X Changes in gene expression of Mexican lime plants in response to infection with a severe (T305) or a mild (T385) isolate of Citrus tristeza virus (CTV) were analyzed using a cDNA microarray containing 12,672 probes to 6875 different citrus genes. Statistically significant (P<0.01) expression changes of 334 genes were detected in response to infection with isolate T305, whereas infection with T385 induced no significant change. Induced genes included 145 without significant similarity with known sequences and 189 that were classified in seven functional categories. Genes related with response to stress and defense were the main category and included 28% of the genes induced. Selected transcription changes detected by microarray analysis were confirmed by quantitative real-time RT-PCR. Changes detected in the transcriptome upon infecting lime with T305 may be associated either with symptom expression, with a strain-specific defense mechanism, or with a general response to stress. %B Virology %V 367 %P 298-306 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17617431 %0 Journal Article %J Cancer Res %D 2006 %T ERCC4 associated with breast cancer risk: a two-stage case-control study using high-throughput genotyping %A Milne, R. L. %A Ribas, G. %A Gonzalez-Neira, A. %A Fagerholm, R. %A Salas, A. %A Gonzalez, E. %A Dopazo, J. %A Nevanlinna, H. %A M. Robledo %A Benitez, J. %K 80 and over Breast Neoplasms/epidemiology/*genetics/pathology Case-Control Studies DNA-Binding Proteins/genetics/*physiology Female Finland/epidemiology Genes %K Adult Aged Aged %K Recessive Genetic Predisposition to Disease Genotype Humans Introns/genetics Linkage Disequilibrium Middle Aged Neoplasm Proteins/genetics/*physiology Neoplasm Staging *Polymorphism %K Single Nucleotide Risk Spain/epidemiology %X 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. %B Cancer Res %V 66 %P 9420-7 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17018596 %0 Journal Article %J Bioinformatics %D 2006 %T maSigPro: a method to identify significantly differential expression profiles in time-course microarray experiments %A A. Conesa %A Nueda, M. J. %A Ferrer, A. %A Talon, M. %K *Algorithms Computer Simulation Gene Expression/*physiology Gene Expression Profiling/*methods *Models %K Genetic Models %K Statistical Oligonucleotide Array Sequence Analysis/*methods *Software Time Factors %X 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. %B Bioinformatics %V 22 %P 1096-102 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16481333 %0 Journal Article %J Nature %D 2005 %T An anaerobic mitochondrion that produces hydrogen %A Boxma, B. %A de Graaf, R. M. %A van der Staay, G. W. %A van Alen, T. A. %A Ricard, G. %A Gabaldón, T. %A van Hoek, A. H. %A Moon-van der Staay, S. Y. %A Koopman, W. J. %A van Hellemond, J. J. %A Tielens, A. G. %A Friedrich, T. %A Veenhuis, M. %A M. A. Huynen %A Hackstein, J. H. %K *Anaerobiosis Animals Ciliophora/*cytology/genetics/*metabolism/ultrastructure Cockroaches/parasitology DNA %K Mitochondrial/genetics Electron Transport Electron Transport Complex I/antagonists & inhibitors/metabolism Genome Glucose/metabolism Hydrogen/*metabolism Mitochondria/enzymology/genetics/*metabolism/ultrastructure Molecular Sequence Data Open Reading Fra %X Hydrogenosomes are organelles that produce ATP and hydrogen, and are found in various unrelated eukaryotes, such as anaerobic flagellates, chytridiomycete fungi and ciliates. Although all of these organelles generate hydrogen, the hydrogenosomes from these organisms are structurally and metabolically quite different, just like mitochondria where large differences also exist. These differences have led to a continuing debate about the evolutionary origin of hydrogenosomes. Here we show that the hydrogenosomes of the anaerobic ciliate Nyctotherus ovalis, which thrives in the hindgut of cockroaches, have retained a rudimentary genome encoding components of a mitochondrial electron transport chain. Phylogenetic analyses reveal that those proteins cluster with their homologues from aerobic ciliates. In addition, several nucleus-encoded components of the mitochondrial proteome, such as pyruvate dehydrogenase and complex II, were identified. The N. ovalis hydrogenosome is sensitive to inhibitors of mitochondrial complex I and produces succinate as a major metabolic end product–biochemical traits typical of anaerobic mitochondria. The production of hydrogen, together with the presence of a genome encoding respiratory chain components, and biochemical features characteristic of anaerobic mitochondria, identify the N. ovalis organelle as a missing link between mitochondria and hydrogenosomes. %B Nature %V 434 %P 74-9 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15744302 %0 Journal Article %J Plant Mol Biol %D 2005 %T Development of a citrus genome-wide EST collection and cDNA microarray as resources for genomic studies %A J. Forment %A J. Gadea %A Huerta, L. %A Abizanda, L. %A Agusti, J. %A Alamar, S. %A Alos, E. %A Andres, F. %A Arribas, R. %A Beltran, J. P. %A Berbel, A. %A Blazquez, M. A. %A Brumos, J. %A Canas, L. A. %A Cercos, M. %A Colmenero-Flores, J. M. %A A. Conesa %A Estables, B. %A Gandia, M. %A Garcia-Martinez, J. L. %A Gimeno, J. %A Gisbert, A. %A Gomez, G. %A Gonzalez-Candelas, L. %A Granell, A. %A Guerri, J. %A Lafuente, M. T. %A Madueno, F. %A Marcos, J. F. %A Marques, M. C. %A Martinez, F. %A Martinez-Godoy, M. A. %A Miralles, S. %A Moreno, P. %A Navarro, L. %A Pallas, V. %A Perez-Amador, M. A. %A Perez-Valle, J. %A Pons, C. %A Rodrigo, I. %A Rodriguez, P. L. %A Royo, C. %A Serrano, R. %A Soler, G. %A Tadeo, F. %A Talon, M. %A Terol, J. %A Trenor, M. %A Vaello, L. %A Vicente, O. %A Vidal, Ch %A Zacarias, L. %A Conejero, V. %K Citrus/*genetics DNA %K Complementary/chemistry/genetics *Expressed Sequence Tags Gene Expression Profiling Gene Library *Genome %K DNA %K Plant Genomics/*methods Molecular Sequence Data Oligonucleotide Array Sequence Analysis/*methods RNA %K Plant/genetics/metabolism Reproducibility of Results Sequence Analysis %X 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. %B Plant Mol Biol %V 57 %P 375-91 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15830128 %0 Journal Article %J Nucleic Acids Res %D 2005 %T PupasView: a visual tool for selecting suitable SNPs, with putative pathological effect in genes, for genotyping purposes %A L. Conde %A Vaquerizas, J. M. %A Ferrer-Costa, C. %A de la Cruz, X. %A Orozco, M. %A Dopazo, J. %K Computer Graphics Genes *Genetic Predisposition to Disease Genotype Internet Phenotype *Polymorphism %K Single Nucleotide *Software User-Computer Interface %X We have developed a web tool, PupasView, for the selection of single nucleotide polymorphisms (SNPs) with potential phenotypic effect. PupasView constitutes an interactive environment in which functional information and population frequency data can be used as sequential filters over linkage disequilibrium parameters to obtain a final list of SNPs optimal for genotyping purposes. PupasView is the first resource that integrates phenotypic effects caused by SNPs at both the translational and the transcriptional level. PupasView retrieves SNPs that could affect conserved regions that the cellular machinery uses for the correct processing of genes (intron/exon boundaries or exonic splicing enhancers), predicted transcription factor binding sites and changes in amino acids in the proteins for which a putative pathological effect is calculated. The program uses the mapping of SNPs in the genome provided by Ensembl. PupasView will be of much help in studies of multifactorial disorders, where the use of functional SNPs will increase the sensitivity of the identification of the genes responsible for the disease. The PupasView web interface is accessible through http://pupasview.ochoa.fib.es and through http://www.pupasnp.org. %B Nucleic Acids Res %V 33 %P W501-5 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15980522 %0 Journal Article %J Genes Chromosomes Cancer %D 2004 %T Gene expression analysis of chromosomal regions with gain or loss of genetic material detected by comparative genomic hybridization %A Melendez, B. %A Diaz-Uriarte, R. %A Cuadros, M. %A Martinez-Ramirez, A. %A Fernandez-Piqueras, J. %A Dopazo, A. %A Cigudosa, J. C. %A Rivas, C. %A Dopazo, J. %A Martinez-Delgado, B. %A Benitez, J. %K Chromosomes %K Fluorescence Lymphoma %K Human %K Pair 13/*genetics Chromosomes %K Pair 19/*genetics Chromosomes %K Pair 6/*genetics Expressed Sequence Tags *Gene Dosage Gene Expression Profiling Humans In Situ Hybridization %K T-Cell/*genetics Nucleic Acid Hybridization Oligonucleotide Array Sequence Analysis %X Comparative genomic hybridization (CGH) has been widely used to detect copy number alterations in cancer and to identify regions containing candidate tumor-responsible genes; however, gene expression changes have been described only in highly amplified regions (amplicons). To study the overall impact of slight copy number changes on gene expression, we analyzed 16 T-cell lymphomas by using CGH and a custom-designed cDNA microarray containing 7,657 genes and expressed sequence tags related to tumorigenesis. We evaluated mean gene expression and variability within CGH-altered regions and explored the relationship between the effects of the gene and its position within these regions. Minimally overlapping CGH candidate areas (6q25, 13q21-q22, and 19q13.1) revealed a weak relationship between altered genomic content and gene expression. However, some candidate genes showed modified expression within these regions in the majority of tumors; these candidate genes were evaluated and confirmed in another independent series of 23 T-cell lymphomas by use of the same cDNA microarray and by FISH on a tissue microarray. When all the CGH regions detected for each tumor were considered, we found a significant increase or decrease in the mean expression of the genes contained in gained or lost regions, respectively. In addition, we found that the expression of a gene was dependent not only on its position within an altered region but also on its own mechanism of regulation: genes in the same altered region responded very differently to the gain or loss of genetic material. Supplementary material for this article can be found on the Genes, Chromosomes, and Cancer website at http://www.interscience.wiley.com/jpages/1045-2257/suppmat/index.html. %B Genes Chromosomes Cancer %V 41 %P 353-65 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15382261 %0 Journal Article %J Nucleic Acids Res %D 2004 %T MODBASE, a database of annotated comparative protein structure models, and associated resources %A Pieper, U. %A Eswar, N. %A Braberg, H. %A Madhusudhan, M. S. %A Davis, F. P. %A Stuart, A. C. %A Mirkovic, N. %A Rossi, A. %A M. A. Marti-Renom %A Fiser, A. %A Webb, B. %A Greenblatt, D. %A Huang, C. C. %A Ferrin, T. E. %A Sali, A. %K Amino Acid Sequence Animals Binding Sites *Computational Biology *Databases %K Molecular Molecular Sequence Data Polymorphism %K Protein Genomics Humans Internet Ligands Models %K Single Nucleotide Protein Binding Protein Conformation Proteins/*chemistry/genetics Sequence Alignment Software User-Computer Interface %X MODBASE (http://salilab.org/modbase) is a relational database of annotated comparative protein structure models for all available protein sequences matched to at least one known protein structure. The models are calculated by MODPIPE, an automated modeling pipeline that relies on the MODELLER package for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE uses the MySQL relational database management system for flexible querying and CHIMERA for viewing the sequences and structures (http://www.cgl.ucsf.edu/chimera/). MODBASE is updated regularly to reflect the growth in protein sequence and structure databases, as well as improvements in the software for calculating the models. For ease of access, MODBASE is organized into different data sets. The largest data set contains 1,26,629 models for domains in 659,495 out of 1,182,126 unique protein sequences in the complete Swiss-Prot/TrEMBL database (August 25, 2003); only models based on alignments with significant similarity scores and models assessed to have the correct fold despite insignificant alignments are included. Another model data set supports target selection and structure-based annotation by the New York Structural Genomics Research Consortium; e.g. the 53 new structures produced by the consortium allowed us to characterize structurally 24,113 sequences. MODBASE also contains binding site predictions for small ligands and a set of predicted interactions between pairs of modeled sequences from the same genome. Our other resources associated with MODBASE include a comprehensive database of multiple protein structure alignments (DBALI, http://salilab.org/dbali) as well as web servers for automated comparative modeling with MODPIPE (MODWEB, http://salilab. org/modweb), modeling of loops in protein structures (MODLOOP, http://salilab.org/modloop) and predicting functional consequences of single nucleotide polymorphisms (SNPWEB, http://salilab. org/snpweb). %B Nucleic Acids Res %V 32 %P D217-22 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14681398 %0 Journal Article %J Nucleic Acids Res %D 2003 %T Tools for comparative protein structure modeling and analysis %A Eswar, N. %A John, B. %A Mirkovic, N. %A Fiser, A. %A Ilyin, V. A. %A Pieper, U. %A Stuart, A. C. %A M. A. Marti-Renom %A Madhusudhan, M. S. %A Yerkovich, B. %A Sali, A. %K Amino Acid *Software *Structural Homology %K Internet Models %K Molecular Protein Folding Proteins/chemistry Reproducibility of Results Sequence Alignment Sequence Homology %K Protein Systems Integration %X The following resources for comparative protein structure modeling and analysis are described (http://salilab.org): MODELLER, a program for comparative modeling by satisfaction of spatial restraints; MODWEB, a web server for automated comparative modeling that relies on PSI-BLAST, IMPALA and MODELLER; MODLOOP, a web server for automated loop modeling that relies on MODELLER; MOULDER, a CPU intensive protocol of MODWEB for building comparative models based on distant known structures; MODBASE, a comprehensive database of annotated comparative models for all sequences detectably related to a known structure; MODVIEW, a Netscape plugin for Linux that integrates viewing of multiple sequences and structures; and SNPWEB, a web server for structure-based prediction of the functional impact of a single amino acid substitution. %B Nucleic Acids Res %V 31 %P 3375-80 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12824331 %0 Journal Article %J J Biotechnol %D 2002 %T Bioinformatics methods for the analysis of expression arrays: data clustering and information extraction %A J. Tamames %A Clark, D. %A Herrero, J. %A Dopazo, J. %A Blaschke, C. %A Fernandez, J. M. %A Oliveros, J. C. %A Valencia, A. %K Abstracting and Indexing as Topic/methods *Cluster Analysis *Database Management Systems Databases %K Computer-Assisted/methods Information Storage and Retrieval/*methods Internet Medline National Library of Medicine (U.S.) Oligonucleotide Array Sequence Analysis/*methods United States %K Genetic Gene Expression Gene Expression Profiling/*methods Image Processing %X Expression arrays facilitate the monitoring of changes in the expression patterns of large collections of genes. The analysis of expression array data has become a computationally-intensive task that requires the development of bioinformatics technology for a number of key stages in the process, such as image analysis, database storage, gene clustering and information extraction. Here, we review the current trends in each of these areas, with particular emphasis on the development of the related technology being carried out within our groups. %B J Biotechnol %V 98 %P 269-83 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12141992 %0 Journal Article %J Am J Pathol %D 2002 %T Identification of genes involved in resistance to interferon-alpha in cutaneous T-cell lymphoma %A Tracey, L. %A Villuendas, R. %A Ortiz, P. %A Dopazo, A. %A Spiteri, I. %A Lombardia, L. %A Rodriguez-Peralto, J. L. %A Fernandez-Herrera, J. %A Hernandez, A. %A Fraga, J. %A Dominguez, O. %A Herrero, J. %A Alonso, M. A. %A Dopazo, J. %A Piris, M. A. %K Antineoplastic Agents/*pharmacology/therapeutic use Carrier Proteins/biosynthesis/genetics DNA-Binding Proteins/biosynthesis/genetics Drug Resistance %K Biological Oligonucleotide Array Sequence Analysis RNA %K Cultured %K Cutaneous/diagnosis/drug therapy/*genetics/metabolism *Membrane Glycoproteins Models %K Interleukin-1 Reproducibility of Results STAT1 Transcription Factor STAT3 Transcription Factor Trans-Activators/biosynthesis/genetics Tumor Cells %K Neoplasm Gene Expression Profiling *Gene Expression Regulation %K Neoplasm/biosynthesis *Receptors %K Neoplastic Humans Interferon-alpha/*pharmacology/therapeutic use Kinetics Lymphoma %K T-Cell %X Interferon-alpha therapy has been shown to be active in the treatment of mycosis fungoides although the individual response to this therapy is unpredictable and dependent on essentially unknown factors. In an effort to better understand the molecular mechanisms of interferon-alpha resistance we have developed an interferon-alpha resistant variant from a sensitive cutaneous T-cell lymphoma cell line. We have performed expression analysis to detect genes differentially expressed between both variants using a cDNA microarray including 6386 cancer-implicated genes. The experiments showed that resistance to interferon-alpha is consistently associated with changes in the expression of a set of 39 genes, involved in signal transduction, apoptosis, transcription regulation, and cell growth. Additional studies performed confirm that STAT1 and STAT3 expression and interferon-alpha induction and activation are not altered between both variants. The gene MAL, highly overexpressed by resistant cells, was also found to be expressed by tumoral cells in a series of cutaneous T-cell lymphoma patients treated with interferon-alpha and/or photochemotherapy. MAL expression was associated with longer time to complete remission. Time-course experiments of the sensitive and resistant cells showed a differential expression of a subset of genes involved in interferon-response (1 to 4 hours), cell growth and apoptosis (24 to 48 hours.), and signal transduction. %B Am J Pathol %V 161 %P 1825-37 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12414529 %0 Journal Article %J Structure %D 2002 %T Reliability of assessment of protein structure prediction methods %A M. A. Marti-Renom %A Madhusudhan, M. S. %A Fiser, A. %A Rost, B. %A Sali, A. %K *Computer Simulation Humans *Models %K Molecular *Protein Conformation Proteins/*chemistry Reproducibility of Results %X

The reliability of ranking of protein structure modeling methods is assessed. The assessment is based on the parametric Student’s t test and the nonparametric Wilcox signed rank test of statistical significance of the difference between paired samples. The approach is applied to the ranking of the comparative modeling methods tested at the fourth meeting on Critical Assessment of Techniques for Protein Structure Prediction (CASP). It is shown that the 14 CASP4 test sequences may not be sufficient to reliably distinguish between the top eight methods, given the model quality differences and their standard deviations. We suggest that CASP needs to be supplemented by an assessment of protein structure prediction methods that is automated, continuous in time, based on several criteria applied to a large number of models, and with quantitative statistical reliability assigned to each characterization.

%B Structure %V 10 %P 435-40 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12005441 %0 Journal Article %J Microb Drug Resist %D 2001 %T Annotated draft genomic sequence from a Streptococcus pneumoniae type 19F clinical isolate %A Dopazo, J. %A Mendoza, A. %A Herrero, J. %A Caldara, F. %A Humbert, Y. %A Friedli, L. %A Guerrier, M. %A Grand-Schenk, E. %A Gandin, C. %A de Francesco, M. %A Polissi, A. %A Buell, G. %A Feger, G. %A Garcia, E. %A Peitsch, M. %A Garcia-Bustos, J. F. %K Bacterial Molecular Sequence Data Pneumococcal Infections/*microbiology Prokaryotic Cells RNA %K Bacterial/chemistry/genetics Genes %K Bacterial/genetics *Genome %K DNA %K Transfer/metabolism Streptococcus pneumoniae/*genetics %X The public availability of numerous microbial genomes is enabling the analysis of bacterial biology in great detail and with an unprecedented, organism-wide and taxon-wide, broad scope. Streptococcus pneumoniae is one of the most important bacterial pathogens throughout the world. We present here sequences and functional annotations for 2.1-Mbp of pneumococcal DNA, covering more than 90% of the total estimated size of the genome. The sequenced strain is a clinical isolate resistant to macrolides and tetracycline. It carries a type 19F capsular locus, but multilocus sequence typing for several conserved genetic loci suggests that the strain sequenced belongs to a pneumococcal lineage that most often expresses a serotype 15 capsular polysaccharide. A total of 2,046 putative open reading frames (ORFs) longer than 100 amino acids were identified (average of 1,009 bp per ORF), including all described two-component systems and aminoacyl tRNA synthetases. Comparisons to other complete, or nearly complete, bacterial genomes were made and are presented in a graphical form for all the predicted proteins. %B Microb Drug Resist %V 7 %P 99-125 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11442348 %0 Journal Article %J Bioinformatics %D 2001 %T EVA: continuous automatic evaluation of protein structure prediction servers %A Eyrich, V. A. %A M. A. Marti-Renom %A Przybylski, D. %A Madhusudhan, M. S. %A Fiser, A. %A Pazos, F. %A Valencia, A. %A Sali, A. %A Rost, B. %K Automation Internet *Protein Conformation Proteins/*analysis *Software %X Evaluation of protein structure prediction methods is difficult and time-consuming. Here, we describe EVA, a web server for assessing protein structure prediction methods, in an automated, continuous and large-scale fashion. Currently, EVA evaluates the performance of a variety of prediction methods available through the internet. Every week, the sequences of the latest experimentally determined protein structures are sent to prediction servers, results are collected, performance is evaluated, and a summary is published on the web. EVA has so far collected data for more than 3000 protein chains. These results may provide valuable insight to both developers and users of prediction methods. AVAILABILITY: http://cubic.bioc.columbia.edu/eva. CONTACT: eva@cubic.bioc.columbia.edu %B Bioinformatics %V 17 %P 1242-3 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11751240 %0 Journal Article %J J Immunol Methods %D 2001 %T Methods and approaches in the analysis of gene expression data %A Dopazo, J. %A Zanders, E. %A Dragoni, I. %A Amphlett, G. %A Falciani, F. %X

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

%B J Immunol Methods %V 250 %P 93-112 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11251224 %0 Journal Article %J J Mol Evol %D 2001 %T Phylogenetic analysis of viroid and viroid-like satellite RNAs from plants: a reassessment %A Elena, S. F. %A Dopazo, J. %A de la Pena, M. %A Flores, R. %A Diener, T. O. %A Moya, A. %K Evolution %K Molecular *Phylogeny Plant Viruses/*genetics RNA %K Satellite/*genetics RNA %K Viral/genetics Viroids/*genetics %X The proposed monophyletic origin of a group of subviral plant pathogens (viroids and viroid-like satellite RNAs), as well as the phylogenetic relationships and the resulting taxonomy of these entities, has been recently questioned. The criticism comes from the (apparent) lack of sequence similarity among these RNAs necessary to reliably infer a phylogeny. Here we show that, despite their low overall sequence similarity, a sequence alignment manually adjusted to take into account all the local similarities and the insertions/deletions and duplications/rearrangements described in the literature for viroids and viroid-like satellite RNA, along with the use of an appropriate estimator of genetic distances, constitutes a data set suitable for a phylogenetic reconstruction. When the likelihood-mapping method was applied to this data set, the tree-likeness obtained was higher than that corresponding to a sequence alignment that does not take into consideration the local similarities. In addition, bootstrap analysis also supports the major groups previously proposed and the reconstruction is consistent with the biological properties of this RNAs. %B J Mol Evol %V 53 %P 155-9 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11479686