The distribution of fitness effects of new deleterious amino acid mutations in humans.
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 approximately 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.
Eyre-Walker
Adam
A
School of Life Sciences, University of Sussex, Brighton, UK. a.c.eyre-walker@sussex.ac.uk
Woolfit
Megan
M
Phelps
Ted
T
D000483:Alleles; D019943:Amino Acid Substitution; D000596:Amino Acids / Q000235:genetics*; D001699:Biometry; D005787:Gene Frequency; D005828:Genetics, Population; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D012641:Selection, Genetic; D013997:Time Factors
D000596:Amino Acids