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 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.

Figure 1.

The allele frequency distribution of nonsynonymous (solid bars) and intron (shaded bars) SNPs relative to the values expected for neutral mutations in an equilibrium population (open bars). Alleles have been grouped into the classes used in the analysis. Singletons were treated by themselves and then SNPs that were present in 2–3, 4–7, 8–15, 16–31, and 32–85 alleles were grouped together.

Figure 2.

The distribution of fitness effects of deleterious mutations represented as either (a) a continuous or (b) a discrete function. The dashed lines in a and the solid lines in b represent the 95% credibility intervals. (a) A transformation of the gamma distribution to a log-scale. Note also the difference in the minimum values for a and b.

Figure 3.

The variance in a quantitative trait as a function of allele frequency and association of the trait with fitness. The distribution of trait effects is assumed to be a gamma distribution with a shape parameter of 0.23. The curves going from left to right show decreasing association with fitness: β = 1, 0.1, 0.01, and 0.001.