The Distribution of Fitness Effects of New Deleterious Amino Acid Mutations in Humans

Abstract

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 3 10 À5. 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.

Mutation–selection balance in mixed mating populations

“…The IHM can thus be used to rapidly provide a 'start point' for K85 that is very close to the true equilibrium. Second, K85 becomes numerically intractable for large U or small values of h and s. This is a serious difficulty if most deleterious mutations have very slight effects, as suggested by recent surveys of molecular data (Eyre-Walker et al, 2006;Loewe et al, 2006). Large U/s values are effectively accommodated by the IHM, although if s is sufficiently small (on the order of the reciprocal of the effective population size), then genetic drift must also be considered.…”

Positional conservation and amino acids shape the correct diagnosis and population frequencies of benign and damaging personal amino acid mutations

“…These in silico predictions are of great interest in detecting variants for Mendelian and complex diseases, in prioritizing polymorphisms for experimental research in humans and other species, and in analyzing data from genome-wide association studies (e.g., Rudd et al 2005;Bhatti et al 2006;Kryukov et al 2007;Doniger et al 2008). Using various prediction tools, up to one-fourth of nonsynonymous mutations have been diagnosed to be not strictly neutral and are thus thought to harbor signatures of negative or positive selection (Yampolsky et al 2005;Eyre-Walker et al 2006;Levy et al 2007;Shastry 2007;Bentley et al 2008;Boyko et al 2008;Wang et al 2008;Wheeler et al 2008).…”

A remark on rare variants

“…With these values, the numeric integration of Equation (25) .2) of g 1 (s) was chosen according to the analyses of Eyre-Walker and Keightley. 15,27 Choosing an average of sˆ1¼À0.001, only 40% of the mutations under g 1 (s) were neutral (s4À1/(2N e )) accounting for the fact that a large fraction of nonsynonymous mutations are mildly deleterious. 27,28 For g 2 (s) an even more leptokurtic shape parameter (b 2 ¼0.1) and an effectively neutral average (sˆ2¼À0.1/(2N e )) were chosen to account for the overwhelming part of the genome that does not appear to be relevant for fitness.…”