title: Triallelic Population Genomics for Inferring Correlated Fitness Effects of Same Site Nonsynonymous Mutations.
abstract: The distribution of mutational effects on fitness is central to evolutionary genetics. Typical univariate distributions, however, cannot model the effects of multiple mutations at the same site, so we introduce a model in which mutations at the same site have correlated fitness effects. To infer the strength of that correlation, we developed a diffusion approximation to the triallelic frequency spectrum, which we applied to data from Drosophila melanogaster We found a moderate positive correlation between the fitness effects of nonsynonymous mutations at the same codon, suggesting that both mutation identity and location are important for determining fitness effects in proteins. We validated our approach by comparing it to biochemical mutational scanning experiments, finding strong quantitative agreement, even between different organisms. We also found that the correlation of mutational fitness effects was not affected by protein solvent exposure or structural disorder. Together, our results suggest that the correlation of fitness effects at the same site is a previously overlooked yet fundamental property of protein evolution.
authors.affiliation: Program in Applied Mathematics, University of Arizona, Tucson, Arizona 85721.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Ragsdale
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721.
authors.forename: Alec J
authors.initials: AJ
authors.lastname: Coffman
authors.affiliation: Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, Arizona 85721.
authors.forename: PingHsun
authors.initials: P
authors.lastname: Hsieh
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721.
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Struck
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721 rgutenk@email.arizona.edu.
authors.forename: Ryan N
authors.initials: RN
authors.lastname: Gutenkunst
mesh_terms: D000818:Animals; D003062:Codon / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics; D019143:Evolution, Molecular; D005787:Gene Frequency; D056084:Genetic Fitness; D049750:Genome, Insect; D008957:Models, Genetic; D009154:Mutation
chemical_list: D003062:Codon
keywords: Drosophila melanogaster; diffusion approximation; distribution of fitness effects; nonsynonymous mutations; triallelic sites