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 language | English |
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Pages (from-to) | 539-542 |
Number of pages | 4 |
Journal | Science |
Volume | 356 |
Issue number | 6337 |
Early online date | 5 May 2017 |
DOIs | |
Publication status | Published - 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.
Funders | Funder number |
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National Institutes of Health | R01GM078598, R01GM105857, U01HG009088 |
National Institute of Mental Health | R01MH101244 |
Alzheimer's Disease Neuroimaging Initiative | |
Russian Science Foundation | 14-50-00150 |
Keywords
- Journal Article
Cohort Studies
- Netherlands Twin Register (NTR)