Negative selection in humans and fruit flies involves synergistic epistasis.

TitleNegative selection in humans and fruit flies involves synergistic epistasis.
Publication TypeJournal Article
Year of Publication2017
AuthorsSohail, M, Vakhrusheva, OA, Sul, JHoon, Pulit, SL, Francioli, LC, van den Berg, LH, Veldink, JH, de Bakker, PIW, Bazykin, GA, Kondrashov, AS, Sunyaev, SR
Corporate AuthorsGenome of the Netherlands Consortium, Alzheimer’s Disease Neuroimaging Initiative
Date Published2017 05 05
KeywordsAlleles, Animals, Drosophila melanogaster, Epistasis, Genetic, Genetic Fitness, Genome, Human, Genome, Insect, Humans, Linkage Disequilibrium, Mutation Rate, Mutation, Missense, Selection, Genetic

Negative selection against deleterious alleles produced by mutation influences within-population variation as the most pervasive form of natural selection. However, it is not known whether deleterious alleles affect fitness independently, so that cumulative fitness loss depends exponentially on the number of deleterious alleles, or synergistically, so that each additional deleterious allele results in a larger decrease in relative fitness. Negative selection with synergistic epistasis should produce negative linkage disequilibrium between deleterious alleles and, therefore, an underdispersed distribution of the number of deleterious alleles in the genome. Indeed, we detected underdispersion of the number of rare loss-of-function alleles in eight independent data sets from human and fly populations. Thus, selection against rare protein-disrupting alleles is characterized by synergistic epistasis, which may explain how human and fly populations persist despite high genomic mutation rates.

Alternate JournalScience
PubMed ID28473589
PubMed Central IDPMC6200135
Grant ListR01 GM078598 / GM / NIGMS NIH HHS / United States
R01 GM105857 / GM / NIGMS NIH HHS / United States
R01 MH101244 / MH / NIMH NIH HHS / United States
U01 HG009088 / HG / NHGRI NIH HHS / United States