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Analysis of protein-coding genetic variation in 60,706 humans

Author

Listed:
  • Monkol Lek

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    School of Paediatrics and Child Health, University of Sydney
    Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead)

  • Konrad J. Karczewski

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Eric V. Minikel

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Program in Biological and Biomedical Sciences, Harvard Medical School)

  • Kaitlin E. Samocha

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Program in Biological and Biomedical Sciences, Harvard Medical School
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Eric Banks

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Timothy Fennell

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Anne H. O’Donnell-Luria

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Boston Children’s Hospital)

  • James S. Ware

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Harvard Medical School
    National Heart and Lung Institute, Imperial College London
    NIHR Royal Brompton Cardiovascular Biomedical Research Unit, Royal Brompton Hospital)

  • Andrew J. Hill

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Genome Sciences, University of Washington)

  • Beryl B. Cummings

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Program in Biological and Biomedical Sciences, Harvard Medical School)

  • Taru Tukiainen

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Daniel P. Birnbaum

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Jack A. Kosmicki

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Program in Bioinformatics and Integrative Genomics, Harvard Medical School)

  • Laramie E. Duncan

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Karol Estrada

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Fengmei Zhao

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • James Zou

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Emma Pierce-Hoffman

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Joanne Berghout

    (Mouse Genome Informatics, Jackson Laboratory
    Center for Biomedical Informatics and Biostatistics, University of Arizona)

  • David N. Cooper

    (Institute of Medical Genetics, Cardiff University)

  • Nicole Deflaux

    (Google, Mountain View)

  • Mark DePristo

    (Broad Institute of MIT and Harvard)

  • Ron Do

    (Icahn School of Medicine at Mount Sinai
    Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
    The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
    The Center for Statistical Genetics, Icahn School of Medicine at Mount Sinai)

  • Jason Flannick

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Menachem Fromer

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Icahn School of Medicine at Mount Sinai
    Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai)

  • Laura Gauthier

    (Broad Institute of MIT and Harvard)

  • Jackie Goldstein

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Namrata Gupta

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Daniel Howrigan

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Adam Kiezun

    (Broad Institute of MIT and Harvard)

  • Mitja I. Kurki

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital)

  • Ami Levy Moonshine

    (Broad Institute of MIT and Harvard)

  • Pradeep Natarajan

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Harvard Medical School
    Center for Human Genetic Research, Massachusetts General Hospital
    Cardiovascular Research Center, Massachusetts General Hospital)

  • Lorena Orozco

    (Immunogenomics and Metabolic Disease Laboratory, Instituto Nacional de Medicina Genómica)

  • Gina M. Peloso

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Center for Human Genetic Research, Massachusetts General Hospital
    Cardiovascular Research Center, Massachusetts General Hospital)

  • Ryan Poplin

    (Broad Institute of MIT and Harvard)

  • Manuel A. Rivas

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Valentin Ruano-Rubio

    (Broad Institute of MIT and Harvard)

  • Samuel A. Rose

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Douglas M. Ruderfer

    (Icahn School of Medicine at Mount Sinai
    Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Khalid Shakir

    (Broad Institute of MIT and Harvard)

  • Peter D. Stenson

    (Institute of Medical Genetics, Cardiff University)

  • Christine Stevens

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Brett P. Thomas

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Grace Tiao

    (Broad Institute of MIT and Harvard)

  • Maria T. Tusie-Luna

    (Molecular Biology and Genomic Medicine Unit, Instituto Nacional de Ciencias Médicas y Nutrición)

  • Ben Weisburd

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Hong-Hee Won

    (Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University)

  • Dongmei Yu

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital
    Center for Human Genetic Research, Massachusetts General Hospital
    Massachusetts General Hospital)

  • David M. Altshuler

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Vertex Pharmaceuticals)

  • Diego Ardissino

    (University Hospital)

  • Michael Boehnke

    (University of Michigan)

  • John Danesh

    (Strangeways Research Laboratory)

  • Stacey Donnelly

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Roberto Elosua

    (Cardiovascular Epidemiology and Genetics, Hospital del Mar Medical Research Institute)

  • Jose C. Florez

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Harvard Medical School
    Center for Human Genetic Research, Massachusetts General Hospital)

  • Stacey B. Gabriel

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

  • Gad Getz

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Massachusetts General Hospital)

  • Stephen J. Glatt

    (Psychiatric Genetic Epidemiology & Neurobiology Laboratory, State University of New York, Upstate Medical University
    State University of New York, Upstate Medical University
    State University of New York, Upstate Medical University)

  • Christina M. Hultman

    (Karolinska Institutet)

  • Sekar Kathiresan

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Harvard Medical School
    Center for Human Genetic Research, Massachusetts General Hospital
    Cardiovascular Research Center, Massachusetts General Hospital)

  • Markku Laakso

    (University of Eastern Finland and Kuopio University Hospital)

  • Steven McCarroll

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Mark I. McCarthy

    (Wellcome Trust Centre for Human Genetics, University of Oxford
    Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford
    Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Foundation Trust)

  • Dermot McGovern

    (Inflammatory Bowel Disease and Immunobiology Research Institute, Cedars-Sinai Medical Center)

  • Ruth McPherson

    (Atherogenomics Laboratory, University of Ottawa Heart Institute)

  • Benjamin M. Neale

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Aarno Palotie

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Program in Biological and Biomedical Sciences, Harvard Medical School
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki)

  • Shaun M. Purcell

    (Icahn School of Medicine at Mount Sinai
    Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Danish Saleheen

    (Perelman School of Medicine at the University of Pennsylvania
    Perelman School of Medicine at the University of Pennsylvania
    Center for Non-Communicable Diseases)

  • Jeremiah M. Scharf

    (Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital
    Center for Human Genetic Research, Massachusetts General Hospital)

  • Pamela Sklar

    (Icahn School of Medicine at Mount Sinai
    Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Friedman Brain Institute, Icahn School of Medicine at Mount Sinai)

  • Patrick F. Sullivan

    (University of North Carolina
    Karolinska Institutet)

  • Jaakko Tuomilehto

    (University of Helsinki)

  • Ming T. Tsuang

    (University of California)

  • Hugh C. Watkins

    (Wellcome Trust Centre for Human Genetics, University of Oxford
    University of Oxford)

  • James G. Wilson

    (University of Mississippi Medical Center)

  • Mark J. Daly

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Daniel G. MacArthur

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard)

Abstract

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.

Suggested Citation

  • Monkol Lek & Konrad J. Karczewski & Eric V. Minikel & Kaitlin E. Samocha & Eric Banks & Timothy Fennell & Anne H. O’Donnell-Luria & James S. Ware & Andrew J. Hill & Beryl B. Cummings & Taru Tukiainen , 2016. "Analysis of protein-coding genetic variation in 60,706 humans," Nature, Nature, vol. 536(7616), pages 285-291, August.
    • Handle: RePEc:nat:nature:v:536:y:2016:i:7616:d:10.1038_nature19057
    DOI: 10.1038/nature19057
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