RT Journal Article SR Electronic T1 Negative selection in humans and fruit flies involves synergistic epistasis JF bioRxiv FD Cold Spring Harbor Laboratory SP 066407 DO 10.1101/066407 A1 Mashaal Sohail A1 Olga A. Vakhrusheva A1 Jae Hoon Sul A1 Sara Pulit A1 Laurent Francioli A1 GoNL Consortium, Alzheimer’s Disease Neuroimaging Initiative A1 Leonard H. van den Berg A1 Jan H. Veldink A1 Paul de Bakker A1 Georgii A. Bazykin A1 Alexey S. Kondrashov A1 Shamil R. Sunyaev YR 2016 UL http://biorxiv.org/content/early/2016/07/29/066407.abstract AB 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.