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

Genome Aggregation Database Consortium

    Research output: Contribution to journalArticlepeer-review

    2887 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)434-443
    Number of pages10
    JournalNature
    Volume581
    Issue number7809
    DOIs
    StatePublished - May 28 2020

    ASJC Scopus subject areas

    • General

    Fingerprint

    Dive into the research topics of 'The mutational constraint spectrum quantified from variation in 141,456 humans'. Together they form a unique fingerprint.

    Cite this