Analysis of protein-coding genetic variation in 60,706 humans
Monkol LekAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USAKonrad J. KarczewskiAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USAEric Vallabh MinikelAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USAKaitlin E. SamochaAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USAEric BanksProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USATimothy R. FennellProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USAAnne O’Donnell‐LuriaAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, 02114, Massachusetts, USAJames S. WareDepartment of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USAAndrew HillAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USABeryl B. CummingsAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USATaru TukiainenAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USADaniel P. BirnbaumProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USAJack A. KosmickiAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USALaramie E. DuncanAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USAKarol EstradaAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USAFengmei ZhaoAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USAJames ZouProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USAEmma Pierce‐HoffmanAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USAJoanne BerghoutCenter for Biomedical Informatics and Biostatistics, University of Arizona, Tucson, Arizona 85721, USAD.N. CooperInstitute of Medical Genetics, Cardiff University, Cardiff CF10 3XQ, UKNicole DeflauxGoogle, Mountain View, California 94043, USAMark A. DePristoBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USARon DoDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USAJason FlannickDepartment of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USAMenachem FromerAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USALaura D. GauthierBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USAJackie GoldsteinAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USANamrata GuptaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USADaniel P. HowriganAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USAAdam KieżunBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USAMitja KurkiProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USAAmi Levy MoonshineBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USAPradeep NatarajanCardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USALorena OrozcoImmunogenomics and Metabolic Disease Laboratory, Instituto Nacional de Medicina Genómica, Mexico City 14610, MexicoGina M. PelosoCardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USARyan PoplinBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USAManuel A. RivasProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USAValentín Ruano-RubioBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USASamuel A. RoseStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USADouglas M. RuderferDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USAKhalid ShakirBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USAPeter D. StensonInstitute of Medical Genetics, Cardiff University, Cardiff CF10 3XQ, UKChristine StevensProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USABrett ThomasAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USAGrace TiaoBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USAMaria T. Tusie-LunaMolecular Biology and Genomic Medicine Unit, Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City 14080, MexicoBen WeisburdProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USAHong‐Hee WonSamsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, South KoreaDongmei YuCenter for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USADavid AltshulerProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USADiego ArdissinoDepartment of Cardiology, University Hospital, 43100 Parma, ItalyMichael BoehnkeDepartment of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USAJohn DaneshDepartment of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge CB1 8RN, UKStacey DonnellyProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USARoberto ElosúaCardiovascular Epidemiology and Genetics, Hospital del Mar Medical Research Institute, 08003 Barcelona, SpainJosé C. FlorezCenter for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USAStacey GabrielProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USAGad GetzBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USAStephen J. GlattDepartment of Neuroscience and Physiology, State University of New York, Upstate Medical University, Syracuse, New York 13210, USAChristina M. HultmanDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, SwedenSekar KathiresanCardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USAMarkku LaaksoDepartment of Medicine, University of Eastern Finland and Kuopio University Hospital, 70211 Kuopio, FinlandSteven A. McCarrollDepartment of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USAMark I. McCarthyOxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX1 2JD, UKDermot McGovernInflammatory Bowel Disease and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USARuth McPhersonAtherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, CanadaBenjamin M. NealeAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USAAarno PalotieAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USAShaun PurcellDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USADanish SaleheenCenter for Non-Communicable Diseases, Karachi, PakistanJeremiah M. ScharfCenter for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USAPamela SklarDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USAPatrick F. SullivanDepartment of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USAJaakko TuomilehtoDepartment of Public Health, University of Helsinki, 00100 Helsinki, FinlandMing T. TsuangDepartment of Psychiatry, University of California, San Diego, California 92093, USAHugh WatkinsRadcliffe Department of Medicine, University of Oxford, Oxford OX1 2JD, UKJames G. WilsonDepartment of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216, USAMark J. DalyAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USADaniel G. MacArthurAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
2016en
ABI
Аннотация
Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.
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