title: Estimating the selective effects of heterozygous protein-truncating variants from human exome data.
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.
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Cassa
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Donate
authors.initials: D
authors.lastname: Weghorn
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Balick
authors.affiliation: Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Jordan
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: David
authors.identifier: http://orcid.org/0000-0002-7819-5261
authors.initials: D
authors.lastname: Nusinow
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kaitlin E
authors.initials: KE
authors.lastname: Samocha
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: O'Donnell-Luria
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Mark J
authors.identifier: http://orcid.org/0000-0002-0949-8752
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington, USA.|Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Beier
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Shamil R
authors.initials: SR
authors.lastname: Sunyaev
mesh_terms: D000465:Algorithms; D000818:Animals; D001499:Bayes Theorem; D059472:Exome / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D018345:Mice, Knockout; D008957:Models, Genetic; D009154:Mutation; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA / Q000379:methods / Q000706:statistics & numerical data