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

TitleEstimating the selective effects of heterozygous protein-truncating variants from human exome data.
Publication TypeJournal Article
Year of Publication2017
AuthorsCassa, CA, Weghorn, D, Balick, DJ, Jordan, DM, Nusinow, D, Samocha, KE, O'Donnell-Luria, A, MacArthur, DG, Daly, MJ, Beier, DR, Sunyaev, SR
JournalNat Genet
Volume49
Issue5
Pagination806-810
Date Published2017 May
ISSN1546-1718
KeywordsAlgorithms, Animals, Bayes Theorem, Exome, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Heterozygote, Humans, Mice, Knockout, Models, Genetic, Mutation, Selection, Genetic, Sequence Analysis, DNA
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.

DOI10.1038/ng.3831
Alternate JournalNat. Genet.
PubMed ID28369035
PubMed Central IDPMC5618255
Grant ListR01 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
R01 GM104371 / GM / NIGMS NIH HHS / United States