The mutational constraint spectrum quantified from variation in 141,456 humans
Спектр мутационных ограничений, количественно оценённый на основе вариаций у 141 456 человек
2020-05-27
SCID: 54.1/5zs668s7
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Genome Aggregation Databasegene discoveryhuman protein-coding genesmutational constraintpredicted loss-of-function variants
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Abstract (AI)
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.
Key Findings
1
After filtering sequencing and annotation artefacts, the cohort contains 443,769 high-confidence predicted loss-of-function variants.
2
An improved human mutation-rate model classifies protein-coding genes along a spectrum of tolerance to inactivation.
3
Gene intolerance classifications are validated using model-organism data and engineered human cells.
4
The constraint spectrum improves gene-discovery power for both common and rare diseases.
5
The study aggregates 125,748 exomes and 15,708 genomes into the Genome Aggregation Database (gnomAD).
Research Object
human protein-coding genes and their predicted loss-of-function variation in 141,456 sequenced humans
Research Subject
the spectrum of gene tolerance to inactivation, including depletion of loss-of-function variants and its implications for gene discovery
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2020-05-27
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