TY - JOUR T1 - Negative selection in humans and fruit flies involves synergistic epistasis JF - bioRxiv DO - 10.1101/066407 SP - 066407 AU - Mashaal Sohail AU - Olga A. Vakhrusheva AU - Jae Hoon Sul AU - Sara Pulit AU - Laurent Francioli AU - GoNL Consortium, Alzheimer’s Disease Neuroimaging Initiative AU - Leonard H. van den Berg AU - Jan H. Veldink AU - Paul de Bakker AU - Georgii A. Bazykin AU - Alexey S. Kondrashov AU - Shamil R. Sunyaev Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/07/29/066407.abstract N2 - Negative selection against deleterious alleles produced by mutation is the most common form of natural selection, which strongly influences within-population variation and interspecific divergence. However, some fundamental properties of negative selection remain obscure. In particular, it is still 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 must produce negative linkage disequilibrium between deleterious alleles, and therefore, underdispersed distribution of the number of deleterious alleles in the genome. Indeed, we detected underdispersion of the number of rare loss-of-function (LoF) alleles in eight independent datasets from modern human and Drosophila melanogaster populations. Thus, ongoing selection against deleterious alleles is characterized by synergistic epistasis, which can explain how human and fly populations persist despite very high genomic deleterious mutation rates. ER -