Browsing by Keyword "PREDICTION"
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Publication A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families(Nature Publishing Group, 2015) Calvete, Oriol; Martinez, Paula; Garcia-Pavia, Pablo; Benitez-Buelga, Carlos; Paumard-Hernandez B; Fernandez, Victoria; Dominguez, Fernando; Salas, Clara; Romero-Laorden, Nuria; Garcia-Donas, Jesus; Carrillo, Jaime; Perona, Rosario; Carlos Trivino, Juan; Andrés, Raquel; Maria Cano, Juana; Rivera, Barbara; Alonso-Pulpon, Luis; Setien, Fernando; Esteller, Manel; Rodriguez Perales, Sandra; Bougeard, Gaelle; Frebourg, Tierry; Urioste, Miguel; Blasco, MA; Benitez, Javier; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Centro de Investigación Biomedica en Red - CIBER; Unión Europea. Comisión Europea; Unión Europea. Comisión Europea. European Research Council (ERC); Korber Foundation; Botín Foundation; Fundación Lilly; ICREACardiac angiosarcoma (CAS) is a rare malignant tumour whose genetic basis is unknown. Here we show, by whole-exome sequencing of a TP53-negative Li-Fraumeni-like (LFL) family including CAS cases, that a missense variant (p.R117C) in POT1 (protection of telomeres 1) gene is responsible for CAS. The same gene alteration is found in two other LFL families with CAS, supporting the causal effect of the identified mutation. We extend the analysis to TP53-negative LFL families with no CAS and find the same mutation in a breast AS family. The mutation is recently found once in 121,324 studied alleles in ExAC server but it is not described in any other database or found in 1,520 Spanish controls. In silico structural analysis suggests how the mutation disrupts POT1 structure. Functional and in vitro studies demonstrate that carriers of the mutation show reduced telomere-bound POT1 levels, abnormally long telomeres and increased telomere fragility.Publication APPRIS 2017: principal isoforms for multiple gene sets(Oxford University Press, 2018-01-04) Rodriguez, Jose Manuel; Rodriguez Rivas, Juan; Di Domenico, Tomás; Vazquez, Jesús; Valencia, Alfonso; Tress ML, Michael L; National Institutes of Health (Estados Unidos); Ministerio de Economía y Competitividad (España); Instituto Nacional de Bioinformatica (España); Instituto de Salud Carlos IIIThe APPRIS database (http://appris-tools.org) uses protein structural and functional features and information from cross-species conservation to annotate splice isoforms in protein-coding genes. APPRIS selects a single protein isoform, the 'principal' isoform, as the reference for each gene based on these annotations. A single main splice isoform reflects the biological reality for most protein coding genes and APPRIS principal isoforms are the best predictors of these main proteins isoforms. Here, we present the updates to the database, new developments that include the addition of three new species (chimpanzee, Drosophila melangaster and Caenorhabditis elegans), the expansion of APPRIS to cover the RefSeq gene set and the UniProtKB proteome for six species and refinements in the core methods that make up the annotation pipeline. In addition APPRIS now provides a measure of reliability for individual principal isoforms and updates with each release of the GENCODE/Ensembl and RefSeq reference sets. The individual GENCODE/Ensembl, RefSeq and UniProtKB reference gene sets for six organisms have been merged to produce common sets of splice variants.Publication C-reactive protein levels in patients at cardiovascular risk: EURIKA study(BioMed Central (BMC), 2014) Halcox, Julian P. J.; Roy, Carine; Tubach, Florence; Banegas, José Ramón; Dallongeville, Jean; De Backer, Guy; Guallar, Eliseo; Sazova, Oguen; Medina, Jesus; Perk, Joep; Steg, Philippe Gabriel; Rodríguez-Artalejo, Fernando; Borghi, Claudio; Oxford PharmaGenesisBackground: Elevated C-reactive protein (CRP) levels are associated with high cardiovascular risk, and might identify patients who could benefit from more carefully adapted risk factor management. We have assessed the prevalence of elevated CRP levels in patients with one or more traditional cardiovascular risk factors. Methods: Data were analysed from the European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice (EURIKA, ClinicalTrials. gov Identifier: NCT00882336), which included patients (aged = 50 years) from 12 European countries with at least one traditional cardiovascular risk factor but no history of cardiovascular disease. Analysis was also carried out on the subset of patients without diabetes mellitus who were not receiving statin therapy. Results: In the overall population, CRP levels were positively correlated with body mass index and glycated haemoglobin levels, and were negatively correlated with high- density lipoprotein cholesterol levels. CRP levels were also higher in women, those at higher traditionally estimated cardiovascular risk and those with greater numbers of metabolic syndrome markers. Among patients without diabetes mellitus who were not receiving statin therapy, approximately 30\% had CRP levels >= 3 mg/ L, and approximately 50\% had CRP levels = 2 mg/ L, including those at intermediate levels of traditionally estimated cardiovascular risk. Conclusions: CRP levels are elevated in a large proportion of patients with at least one cardiovascular risk factor, without diabetes mellitus who are not receiving statin therapy, suggesting a higher level of cardiovascular risk than predicted according to conventional risk estimation systems.Publication Loose ends: almost one in five human genes still have unresolved coding status(Oxford University Press, 2018) Abascal, Federico; Juan, David; Jungreis, Irwin; Martinez, Laura; Rigau, Maria; Rodriguez, Jose Manuel; Vazquez, Jesus; Tress, Michael L.; National Institutes of Health (Estados Unidos)Seventeen years after the sequencing of the human genome, the human proteome is still under revision. One in eight of the 22 210 coding genes listed by the Ensembl/GENCODE, RefSeq and UniProtKB reference databases are annotated differently across the three sets. We have carried out an in-depth investigation on the 2764 genes classified as coding by one or more sets of manual curators and not coding by others. Data from large-scale genetic variation analyses suggests that most are not under protein-like purifying selection and so are unlikely to code for functional proteins. A further 1470 genes annotated as coding in all three reference sets have characteristics that are typical of non-coding genes or pseudogenes. These potential non-coding genes also appear to be undergoing neutral evolution and have considerably less supporting transcript and protein evidence than other coding genes. We believe that the three reference databases currently overestimate the number of human coding genes by at least 2000, complicating and adding noise to large-scale biomedical experiments. Determining which potential non-coding genes do not code for proteins is a difficult but vitally important task since the human reference proteome is a fundamental pillar of most basic research and supports almost all large-scale biomedical projects.Publication miRNA profiling during antigen-dependent T cell activation: A role for miR-132-3p(Nature Publishing Group, 2017) Gutierrez-Vazquez, Cristina; Rodriguez-Galan, Ana; Fernandez-Alfara, Marcos; Mittelbrunn, Maria; Sanchez-Cabo, Fatima; Jorge Martinez-Herrera, Dannys; Ramirez-Huesca, Marta; Pascual-Montano, Alberto; Sanchez-Madrid, Francisco; Ministerio de Economía y Competitividad (España); Instituto de Salud Carlos III; Fundación ProCNICmicroRNAs (miRNAs) are tightly regulated during T lymphocyte activation to enable the establishment of precise immune responses. Here, we analyzed the changes of the miRNA profiles of T cells in response to activation by cognate interaction with dendritic cells. We also studied mRNA targets common to miRNAs regulated in T cell activation. pik3r1 gene, which encodes the regulatory subunits of PI3K p50, p55 and p85, was identified as target of miRNAs upregulated after T cell activation. Using 3'UTR luciferase reporter-based and biochemical assays, we showed the inhibitory relationship between miR-132-3p upregulation and expression of the pik3r1 gene. Our results indicate that specific miRNAs whose expression is modulated during T cell activation might regulate PI3K signaling in T cells.Publication Multiple evidence strands suggest that there may be as few as 19 000 human protein-coding genes(Oxford University Press, 2014) Ezkurdia, Iakes; Juan, David; Manuel Rodriguez, Jose; Frankish, Adam; Diekhans, Mark; Harrow, Jennifer; Vazquez, Jesus; Valencia, Alfonso; Tress, Michael L.; National Institutes of Health (Estados Unidos); Ministerio de Ciencia e Innovación (España)Determining the full complement of protein-coding genes is a key goal of genome annotation. The most powerful approach for confirming protein-coding potential is the detection of cellular protein expression through peptide massspectrometry(MS) experiments. Here, we mapped peptides detected in seven large-scale proteomics studies to almost 60\% of the protein-coding genes in the GENCODE annotation of the human genome. We found a strong relationship between detection in proteomics experiments and both gene family age and cross-species conservation. Most of the genes for which we detected peptides were highly conserved. We found peptides for >96\% of genes that evolved before bilateria. At the opposite end of the scale, we identified almost no peptides for genes that have appeared since primates, for genes that did not have any protein-like features or for genes with poor cross-species conservation. These results motivated us to describe a set of 2001 potential non-coding genes based on features such as weak conservation, a lack of protein features, or ambiguous annotations from major databases, all of which correlated with low peptide detection across the seven experiments. We identified peptides for just 3\% of these genes. We show that many of these genes behave more like non-coding genes than protein-coding genes and suggest that most are unlikely to code for proteins under normal circumstances. We believe that their inclusion in the human protein-coding gene catalogue should be revised as part of the ongoing human genome annotation effort.