The distribution of fitness effects of new deleterious amino acid mutations in humans

Eyre-Walker, Adam, Woolfit, Megan and Phelps, Ted (2006) The distribution of fitness effects of new deleterious amino acid mutations in humans. Genetics, 173 (2). pp. 891-900. ISSN 0016-6731

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The distribution of fitness effects of new mutations is a fundamental parameter in genetics. Here we present a new method by which the distribution can be estimated. The method is fairly robust to changes in population size and admixture, and it can be corrected for any residual effects if a model of the demography is available. We apply the method to extensively sampled single-nucleotide polymorphism data from humans and estimate the distribution of fitness effects for amino acid changing mutations. We show that a gamma distribution with a shape parameter of 0.23 provides a good fit to the data and we estimate that >50% of mutations are likely to have mild effects, such that they reduce fitness by between one one-thousandth and one-tenth. We also infer that <15% of new mutations are likely to have strongly deleterious effects. We estimate that on average a nonsynonymous mutation reduces fitness by a few percent and that the average strength of selection acting against a nonsynonymous polymorphism is ~9 × 10-5. We argue that the relaxation of natural selection due to modern medicine and reduced variance in family size is not likely to lead to a rapid decline in genetic quality, but that it will be very difficult to locate most of the genes involved in complex genetic diseases.

Item Type: Article
Additional Information: AEW came up with the idea and did about 80% of the work. MW was a PhD student with Lindell Bromham and AEW at the time.
Schools and Departments: School of Life Sciences > Evolution, Behaviour and Environment
Depositing User: Adam Eyre-Walker
Date Deposited: 06 Feb 2012 18:13
Last Modified: 20 Mar 2012 09:40
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