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

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

doi:10.1101/531210

preprintbioRxiv (Cold Spring Harbor Laboratory)Jan 28, 2019GREEN OA

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

KJKonrad J. Karczewski LCLaurent C. Francioli GTGrace Tiao BBBeryl B. Cummings JAJessica Alföldi

Broad Institute · Massachusetts General Hospital · +15 more institutions

Indexed incrossref

Abstract

Summary Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes critical for an organism’s function will be depleted for such variants in natural populations, while non-essential genes will tolerate their accumulation. However, predicted loss-of-function (pLoF) 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 sizes 1 . 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…

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Topics

Keywords

Gene
Annotation
Genome
Biology
Computational biology
Exome sequencing
Human genome
Genetics

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