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Originally published as Genetics Published Articles Ahead of Print on March 17, 2006.
Genetics, Vol. 173, 891-900, June 2006, Copyright © 2006
doi:10.1534/genetics.106.057570
The Distribution of Fitness Effects of New Deleterious Amino Acid Mutations in Humans
Adam Eyre-Walker*,
,1,
Megan Woolfit*,2 and
Ted Phelps
* School of Life Sciences and Department of Informatics, University of Sussex, Brighton, BN1 9QG, United Kingdom and National Evolutionary Synthesis Center, Durham, North Carolina 27705
1 Corresponding author: School of Biological Sciences, University of Sussex, Brighton, BN1 9QG, United Kingdom.
E-mail: a.c.eyre-walker{at}sussex.ac.uk
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 x 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.
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