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

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. Gauthier, Harrison Brand, Matthew Solomonson, Nicholas A. Watts, Daniel Rhodes, Moriel Singer-Berk, Eleina M. England, Eleanor G. Seaby, Jack A. Kosmicki, Raymond K. Walters, Katherine Tashman, Yossi Farjoun, Eric Banks, Timothy Poterba, Arcturus Wang, Cotton Seed, Nicola Whiffin, Jessica X. Chong, Kaitlin E. Samocha, Emma Pierce-Hoffman, Zachary Zappala, Anne H. O’Donnell-Luria, Eric Vallabh Minikel, Ben Weisburd, Monkol Lek, James S. Ware, Christopher Vittal, Irina M. Armean, Louis Bergelson, Kristian Cibulskis, Kristen M. Connolly, Miguel Covarrubias, Stacey Donnelly, Steven Ferriera, Stacey Gabriel, Jeff Gentry, Namrata Gupta, Thibault Jeandet, Diane Kaplan, Christopher Llanwarne, Ruchi Munshi, Sam Novod, Nikelle Petrillo, David Roazen, Valentin Ruano-Rubio, Andrea Saltzman, Molly Schleicher, Jose Soto, Kathleen Tibbetts, Charlotte Tolonen, Gordon Wade, Michael E. Talkowski, Benjamin M. Neale, Mark J. Daly and Daniel G. MacArthur ()
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Konrad J. Karczewski: Broad Institute of MIT and Harvard
Laurent C. Francioli: Broad Institute of MIT and Harvard
Grace Tiao: Broad Institute of MIT and Harvard
Beryl B. Cummings: Broad Institute of MIT and Harvard
Jessica Alföldi: Broad Institute of MIT and Harvard
Qingbo Wang: Broad Institute of MIT and Harvard
Ryan L. Collins: Broad Institute of MIT and Harvard
Kristen M. Laricchia: Broad Institute of MIT and Harvard
Andrea Ganna: Broad Institute of MIT and Harvard
Daniel P. Birnbaum: Broad Institute of MIT and Harvard
Laura D. Gauthier: Broad Institute of MIT and Harvard
Harrison Brand: Broad Institute of MIT and Harvard
Matthew Solomonson: Broad Institute of MIT and Harvard
Nicholas A. Watts: Broad Institute of MIT and Harvard
Daniel Rhodes: Queen Mary University of London and Barts Health NHS Trust
Moriel Singer-Berk: Broad Institute of MIT and Harvard
Eleina M. England: Broad Institute of MIT and Harvard
Eleanor G. Seaby: Broad Institute of MIT and Harvard
Jack A. Kosmicki: Broad Institute of MIT and Harvard
Raymond K. Walters: Broad Institute of MIT and Harvard
Katherine Tashman: 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
Arcturus Wang: Broad Institute of MIT and Harvard
Cotton Seed: Broad Institute of MIT and Harvard
Nicola Whiffin: Broad Institute of MIT and Harvard
Jessica X. Chong: University of Washington
Kaitlin E. Samocha: Wellcome Genome Campus
Emma Pierce-Hoffman: Broad Institute of MIT and Harvard
Zachary Zappala: Broad Institute of MIT and Harvard
Anne H. O’Donnell-Luria: Broad Institute of MIT and Harvard
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
Christopher Vittal: Massachusetts General Hospital
Irina M. Armean: Broad Institute of MIT and Harvard
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
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
Benjamin M. Neale: Broad Institute of MIT and Harvard
Mark J. Daly: Broad Institute of MIT and Harvard
Daniel G. MacArthur: Broad Institute of MIT and Harvard

Nature, 2020, vol. 581, issue 7809, 434-443

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2308-7

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