Estimating the selective effects of heterozygous protein-truncating variants from human exome data.

Nat Genet
Authors
Keywords
Abstract

The evolutionary cost of gene loss is a central question in genetics and has been investigated in model organisms and human cell lines. In humans, tolerance of the loss of one or both functional copies of a gene is related to the gene's causal role in disease. However, estimates of the selection and dominance coefficients in humans have been elusive. Here we analyze exome sequence data from 60,706 individuals to make genome-wide estimates of selection against heterozygous loss of gene function. Using this distribution of selection coefficients for heterozygous protein-truncating variants (PTVs), we provide corresponding Bayesian estimates for individual genes. We find that genes under the strongest selection are enriched in embryonic lethal mouse knockouts, Mendelian disease-associated genes, and regulators of transcription. Screening by essentiality, we find a large set of genes under strong selection that are likely to have crucial functions but have not yet been thoroughly characterized.

Year of Publication
2017
Journal
Nat Genet
Volume
49
Issue
5
Pages
806-810
Date Published
2017 May
ISSN
1546-1718
DOI
10.1038/ng.3831
PubMed ID
28369035
PubMed Central ID
PMC5618255
Links
Grant list
R01 GM078598 / GM / NIGMS NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
K99 HG007229 / HG / NHGRI NIH HHS / United States
R00 HG007229 / HG / NHGRI NIH HHS / United States
R01 MH101244 / MH / NIMH NIH HHS / United States
U01 HG009088 / HG / NHGRI NIH HHS / United States