The mutational constraint spectrum quantified from variation in 141,456 humans
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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 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 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.
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The record
- Venue
- Nature
- Topic
- Genomics and Rare Diseases
- Field
- Biochemistry, Genetics and Molecular Biology
- Canadian institutions
- Université de MontréalMontreal Heart InstituteUniversity of Ottawa
- Funders
- Common FundNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institute of General Medical SciencesNational Institute on AgingSanofi GenzymeNational Institute of Mental HealthNational Heart, Lung, and Blood InstituteNational Institutes of HealthSchweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungNational Cancer InstituteBritish Heart FoundationNational Center for Advancing Translational SciencesNational Human Genome Research InstituteWellcome TrustEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentSanofiRosetrees TrustBioMarin PharmaceuticalNational Science Foundation
- Keywords
- GeneGenomeBiologyComputational biologyAnnotationExome sequencingHuman genomeGeneticsExomeLoss functionPhenotypeFunction (biology)Mutation
- Has abstract in OpenAlex
- yes