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Title: Negative selection in humans and fruit flies involves synergistic epistasis
Author(s): M. Sohail, O.A. Vakhrusheva, J. Hoon Sul, S.L. Pulit, L.C. Francioli, Genome of the Netherlands Consortium, A. Abdellaoui, J.J. Hottenga, G. Willemsen, D.I. Boomsma, Alzheimer’s Disease Neuroimaging Initiative, L.H. van den Berg, J.H. Veldink, P.I.W. de Bakker, G.A. Bazykin, A.S. Kondrashov, S.R. Sunyaev and many others
Journal: Science
Year: 2017
Month: May
Day: 5
Volume: 356
Issue: 6337
Pages: 539-542
DOI: 10.1126/science.aah5238
File URL: http://science.sciencemag.org/content/356/6337/539.long
Web URL: http://science.sciencemag.org/content/356/6337/539/tab-figures-data
Abstract: 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.

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