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Human genomics. Effect of predicted protein-truncating genetic variants on the human transcriptome.
Rivas, Manuel A; Pirinen, Matti; Conrad, Donald F; Lek, Monkol; Tsang, Emily K; Karczewski, Konrad J; Maller, Julian B; Kukurba, Kimberly R; DeLuca, David S; Fromer, Menachem; Ferreira, Pedro G; Smith, Kevin S; Zhang, Rui; Zhao, Fengmei; Banks, Eric; Poplin, Ryan; Ruderfer, Douglas M; Purcell, Shaun M; Tukiainen, Taru; Minikel, Eric V; Stenson, Peter D; Cooper, David N; Huang, Katharine H; Sullivan, Timothy J; Nedzel, Jared; Bustamante, Carlos D; Li, Jin Billy; Daly, Mark J; Guigo, Roderic; Donnelly, Peter; Ardlie, Kristin; Sammeth, Michael; Dermitzakis, Emmanouil T; McCarthy, Mark I; Montgomery, Stephen B; Lappalainen, Tuuli; MacArthur, Daniel G.
Afiliación
  • Rivas MA; Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. rivas@well.ox.ac.uk tlappalainen@nygenome.org macarthur@atgu.mgh.harvard.edu.
  • Pirinen M; FInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • Conrad DF; Washington University in St. Louis, St. Louis, MO, USA.
  • Lek M; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Tsang EK; Department of Genetics, Stanford University, Stanford, CA, USA. Department of Pathology, Stanford University, Stanford, CA, USA. Biomedical Informatics Program, Stanford University, Stanford, CA, USA.
  • Karczewski KJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Maller JB; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Kukurba KR; Department of Genetics, Stanford University, Stanford, CA, USA. Department of Pathology, Stanford University, Stanford, CA, USA.
  • DeLuca DS; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Fromer M; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. Department of Psychiatry, Mt. Sinai Hospital, NY, USA.
  • Ferreira PG; Department of Genetic Medicine and Development,University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland.
  • Smith KS; Department of Genetics, Stanford University, Stanford, CA, USA. Department of Pathology, Stanford University, Stanford, CA, USA.
  • Zhang R; Department of Genetics, Stanford University, Stanford, CA, USA.
  • Zhao F; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Banks E; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Poplin R; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ruderfer DM; Department of Psychiatry, Mt. Sinai Hospital, NY, USA. Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY, USA.
  • Purcell SM; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. Department of Psychiatry, Mt. Sinai Hospital, NY, USA. Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Si
  • Tukiainen T; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Minikel EV; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Stenson PD; Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
  • Cooper DN; Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
  • Huang KH; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Sullivan TJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Nedzel J; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Bustamante CD; Department of Genetics, Stanford University, Stanford, CA, USA.
  • Li JB; Department of Genetics, Stanford University, Stanford, CA, USA.
  • Daly MJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Guigo R; Center for Genomic Regulation (CRG), Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain.
  • Donnelly P; Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. Department of Statistics, University of Oxford, Oxford, UK.
  • Ardlie K; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Sammeth M; Center for Genomic Regulation (CRG), Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. National Institute for Scientific Computing (LNCC), Petropolis, Rio de Janeiro, Brazil.
  • Dermitzakis ET; Department of Genetic Medicine and Development,University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland.
  • McCarthy MI; Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. Oxford Center for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
  • Montgomery SB; Department of Genetics, Stanford University, Stanford, CA, USA. Department of Pathology, Stanford University, Stanford, CA, USA.
  • Lappalainen T; Department of Genetics, Stanford University, Stanford, CA, USA. Department of Genetic Medicine and Development,University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switze
  • MacArthur DG; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. Department of Medicine, Harvard Medical School, Boston, MA, USA. rivas@well.ox.ac.uk tlappalainen@nygenome.org macarthur@atgu.mgh.harvard.edu.
Science ; 348(6235): 666-9, 2015 May 08.
Article en En | MEDLINE | ID: mdl-25954003
ABSTRACT
Accurate prediction of the functional effect of genetic variation is critical for clinical genome interpretation. We systematically characterized the transcriptome effects of protein-truncating variants, a class of variants expected to have profound effects on gene function, using data from the Genotype-Tissue Expression (GTEx) and Geuvadis projects. We quantitated tissue-specific and positional effects on nonsense-mediated transcript decay and present an improved predictive model for this decay. We directly measured the effect of variants both proximal and distal to splice junctions. Furthermore, we found that robustness to heterozygous gene inactivation is not due to dosage compensation. Our results illustrate the value of transcriptome data in the functional interpretation of genetic variants.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Variación Genética / Proteínas / Genoma Humano / Regulación de la Expresión Génica / Transcriptoma Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Science Año: 2015 Tipo del documento: Article
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Variación Genética / Proteínas / Genoma Humano / Regulación de la Expresión Génica / Transcriptoma Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Science Año: 2015 Tipo del documento: Article