Negative selection in humans and fruit flies involves synergistic epistasis

Mashaal Sohail, Olga A Vakhrusheva, Jae Hoon Sul, Sara L Pulit, Laurent C Francioli, Leonard H van den Berg, Jan H Veldink, Paul I W de Bakker, Georgii A Bazykin, Alexey S Kondrashov, Shamil R Sunyaev, Genome of the Netherlands Consortium, A. Abdellaoui, J.J. Hottenga, Gonneke Willemsen, D.I. Boomsma

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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.

Original languageEnglish
Pages (from-to)539-542
Number of pages4
JournalScience
Volume356
Issue number6337
Early online date5 May 2017
DOIs
Publication statusPublished - 5 May 2017

Funding

We are grateful to L. Mirny, G. McVean, and I. Adzhubey for scientific discussions; all members of the Sunyaev lab and two anonymous reviewers for comments that improved the manuscript; D. Jordan for providing SLiM 2.0 simulation runs; C. Cassa, D. Jordan, D. Weghorn, and D. Balick for providing genic selection estimates for humans; J. Fan for helping with analyses as a summer student; and J. Lack for help with D. melanogaster inversion data. This project was supported by NIH grants R01GM078598, R01GM105857, R01MH101244, and U01HG009088. Analysis of fruit fly data was performed at IITP RAS and supported by the Russian Science Foundation (grant no. 14-50-00150). Data sets used in this study can be accessed as follows: GoNL: www.nlgenome.nl/; ADNI: http://adni.loni.usc.edu/; Project MinE: www.projectmine.com; The 1000 Genomes Phase I Project: ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/; DGRP and DPGP3: www.johnpool.net/genomes.html.

FundersFunder number
National Institutes of HealthR01GM078598, R01GM105857, U01HG009088
National Institute of Mental HealthR01MH101244
Alzheimer's Disease Neuroimaging Initiative
Russian Science Foundation14-50-00150

    Keywords

    • Journal Article

    Cohort Studies

    • Netherlands Twin Register (NTR)

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