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Applicability of the mutation-selection balance model to population genetics of heterozygous protein-truncating variants in humans

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dc.contributor.author Weghorn, Donate
dc.contributor.author Balick, Daniel J.
dc.contributor.author Cassa, Christopher
dc.contributor.author Kosmicki, Jack A.
dc.contributor.author Daly, Mark J.
dc.contributor.author Beier, David R.
dc.contributor.author Sunyaev, Shamil R.
dc.date.accessioned 2019-09-12T11:15:28Z
dc.date.issued 2019
dc.identifier.citation Weghorn D, Balick DJ, Cassa C, Kosmicki JA, Daly MJ, Beier DR, Sunyaev SR. Applicability of the mutation-selection balance model to population genetics of heterozygous protein-truncating variants in humans. Mol Biol Evol. 2019; 36(8):1701-1710. DOI 10.1093/molbev/msz092
dc.identifier.issn 0737-4038
dc.identifier.uri http://hdl.handle.net/10230/42267
dc.description.abstract The fate of alleles in the human population is believed to be highly affected by the stochastic force of genetic drift. Estimation of the strength of natural selection in humans generally necessitates a careful modeling of drift including complex effects of the population history and structure. Protein-truncating variants (PTVs) are expected to evolve under strong purifying selection and to have a relatively high per-gene mutation rate. Thus, it is appealing to model the population genetics of PTVs under a simple deterministic mutation-selection balance, as has been proposed earlier (Cassa et al. 2017). Here, we investigated the limits of this approximation using both computer simulations and data-driven approaches. Our simulations rely on a model of demographic history estimated from 33,370 individual exomes of the Non-Finnish European subset of the ExAC data set (Lek et al. 2016). Additionally, we compared the African and European subset of the ExAC study and analyzed de novo PTVs. We show that the mutation-selection balance model is applicable to the majority of human genes, but not to genes under the weakest selection.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Oxford University Press
dc.relation.ispartof Mol Biol Evol. 2019; 36(8):1701-1710
dc.rights © Oxford University Press. This is a pre-copyedited, author-produced version of an article accepted for publication in Molecular biology and evolution following peer review. The version of record Weghorn D, Balick DJ, Cassa C, Kosmicki JA, Daly MJ, Beier DR, Sunyaev SR. Applicability of the mutation-selection balance model to population genetics of heterozygous protein-truncating variants in humans. Mol Biol Evol. 2019; 36(8):1701-1710 is available online at: https://doi.org/10.1093/molbev/msz092
dc.title Applicability of the mutation-selection balance model to population genetics of heterozygous protein-truncating variants in humans
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1093/molbev/msz092
dc.subject.keyword Protein-truncating variants
dc.subject.keyword Selection inference
dc.subject.keyword Genetic drift
dc.rights.accessRights info:eu-repo/semantics/embargoedAccess
dc.type.version info:eu-repo/semantics/acceptedVersion
dc.embargo.liftdate 2020-08-01
dc.date.embargoEnd info:eu-repo/date/embargoEnd/2020-08-01

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