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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.

Original publication

DOI

10.1038/s41586-020-2308-7

Type

Journal article

Journal

Nature

Publication Date

27/05/2020

Volume

581

Pages

434 - 443

Addresses

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. konradk@broadinstitute.org.

Keywords

Genome Aggregation Database Consortium, Brain, Humans, Cardiovascular Diseases, Genetic Predisposition to Disease, RNA, Messenger, Cohort Studies, Reproducibility of Results, Genes, Essential, Genome, Human, Databases, Genetic, Adult, Female, Male, Genetic Variation, Genome-Wide Association Study, Mutation Rate, Exome, Proprotein Convertase 9, Whole Genome Sequencing, Whole Exome Sequencing, Loss of Function Mutation