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The mutational constraint spectrum quantified from variation in 141,456 humans

Author

Listed:
  • Konrad J. Karczewski

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Laurent C. Francioli

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Grace Tiao

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Beryl B. Cummings

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

  • Jessica Alföldi

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Qingbo Wang

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

  • Ryan L. Collins

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

  • Kristen M. Laricchia

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Andrea Ganna

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Institute for Molecular Medicine Finland)

  • Daniel P. Birnbaum

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Laura D. Gauthier

    (Broad Institute of MIT and Harvard)

  • Harrison Brand

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Matthew Solomonson

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Nicholas A. Watts

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Daniel Rhodes

    (Queen Mary University of London and Barts Health NHS Trust)

  • Moriel Singer-Berk

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Eleina M. England

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Eleanor G. Seaby

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Jack A. Kosmicki

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

  • Raymond K. Walters

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

  • Katherine Tashman

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

  • Yossi Farjoun

    (Broad Institute of MIT and Harvard)

  • Eric Banks

    (Broad Institute of MIT and Harvard)

  • Timothy Poterba

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

  • Arcturus Wang

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

  • Cotton Seed

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

  • Nicola Whiffin

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Imperial College London
    Royal Brompton & Harefield Hospitals NHS Trust)

  • Jessica X. Chong

    (University of Washington)

  • Kaitlin E. Samocha

    (Wellcome Genome Campus)

  • Emma Pierce-Hoffman

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Zachary Zappala

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Vertex Pharmaceuticals Inc)

  • Anne H. O’Donnell-Luria

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Boston Children’s Hospital
    Harvard Medical School)

  • Eric Vallabh Minikel

    (Broad Institute of MIT and Harvard)

  • Ben Weisburd

    (Broad Institute of MIT and Harvard)

  • Monkol Lek

    (Yale School of Medicine)

  • James S. Ware

    (Broad Institute of MIT and Harvard
    Imperial College London
    Royal Brompton & Harefield Hospitals NHS Trust)

  • Christopher Vittal

    (Massachusetts General Hospital
    Broad Institute of MIT and Harvard)

  • Irina M. Armean

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Louis Bergelson

    (Broad Institute of MIT and Harvard)

  • Kristian Cibulskis

    (Broad Institute of MIT and Harvard)

  • Kristen M. Connolly

    (Broad Institute of MIT and Harvard)

  • Miguel Covarrubias

    (Broad Institute of MIT and Harvard)

  • Stacey Donnelly

    (Broad Institute of MIT and Harvard)

  • Steven Ferriera

    (Broad Institute of MIT and Harvard)

  • Stacey Gabriel

    (Broad Institute of MIT and Harvard)

  • Jeff Gentry

    (Broad Institute of MIT and Harvard)

  • Namrata Gupta

    (Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard)

  • Thibault Jeandet

    (Broad Institute of MIT and Harvard)

  • Diane Kaplan

    (Broad Institute of MIT and Harvard)

  • Christopher Llanwarne

    (Broad Institute of MIT and Harvard)

  • Ruchi Munshi

    (Broad Institute of MIT and Harvard)

  • Sam Novod

    (Broad Institute of MIT and Harvard)

  • Nikelle Petrillo

    (Broad Institute of MIT and Harvard)

  • David Roazen

    (Broad Institute of MIT and Harvard)

  • Valentin Ruano-Rubio

    (Broad Institute of MIT and Harvard)

  • Andrea Saltzman

    (Broad Institute of MIT and Harvard)

  • Molly Schleicher

    (Broad Institute of MIT and Harvard)

  • Jose Soto

    (Broad Institute of MIT and Harvard)

  • Kathleen Tibbetts

    (Broad Institute of MIT and Harvard)

  • Charlotte Tolonen

    (Broad Institute of MIT and Harvard)

  • Gordon Wade

    (Broad Institute of MIT and Harvard)

  • Michael E. Talkowski

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

  • Benjamin M. Neale

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

  • Mark J. Daly

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Institute for Molecular Medicine Finland
    Broad Institute of MIT and Harvard)

  • Daniel G. MacArthur

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Garvan Institute of Medical Research, and UNSW Sydney
    Murdoch Children’s Research Institute)

Abstract

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes1. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.

Suggested Citation

  • Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
    • Handle: RePEc:nat:nature:v:581:y:2020:i:7809:d:10.1038_s41586-020-2308-7
    DOI: 10.1038/s41586-020-2308-7
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