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

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. A catalogue of predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets from the Genome Aggregation Database (gnomAD) reveals the spectrum of mutational constraints that affect these human protein-coding genes.

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Affiliated Institutions

• Brigham and Women's Hospital US
• Columbia University Irving Medical Center US
• Harvard University US
• Assistance Publique – Hôpitaux de Paris FR
• Framingham Heart Study US
• Helsinki University Hospital FI
• Sorbonne Université FR
• University of Illinois Chicago US
• Yale University US
• University of Parma IT
• Colorado School of Public Health US
• Hadassah Medical Center IL
• Hôpital Saint-Antoine FR
• Hospital Del Mar ES
• Broad Institute US
• Barts Health NHS Trust GB
• Icahn School of Medicine at Mount Sinai US
• Wake Forest University US
• University of Haifa IL
• National Human Genome Research Institute US
• National Institutes of Health US
• Massachusetts General Hospital US
• Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán MX
• University of Leicester GB
• University of Mississippi Medical Center US
• Christian-Albrechts-Universität zu Kiel DE
• Institute for Molecular Medicine Finland FI
• William Harvey Research Institute GB
• Cleveland Clinic Lerner College of Medicine US
• Hospital del Mar Research Institute ES
• Queen Mary University of London GB
• University of Michigan US
• NIHR Leicester Biomedical Research Centre GB
• Jackson Memorial Hospital US
• University of Lübeck DE
• Peninsula College of Medicine and Dentistry GB
• Imperial College London GB
• University of Helsinki FI
• National Heart Lung and Blood Institute US
• Chinese University of Hong Kong HK
• Wellcome Sanger Institute GB
• University of Washington US
• Instituto Nacional de Salud Pública MX
• Texas Biomedical Research Institute US
• SUNY Upstate Medical University US

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