Inferences about the distribution of dominance drawn from yeast gene knockout data

Abstract

Data from several thousand knockout mutations in yeast (Saccharomyces cerevisiae) were used to estimate the distribution of dominance coefficients. We propose a new unbiased likelihood approach to measuring dominance coefficients. On average, deleterious mutations are partially recessive, with a mean dominance coefficient ~0.2. Alleles with large homozygous effects are more likely to be more recessive than are alleles of weaker effect. Our approach allows us to quantify, for the first time, the substantial variance and skew in the distribution of dominance coefficients. This heterogeneity is so great that many population genetic processes analyses based on the mean dominance coefficient alone will be in substantial error. These results are applied to the debate about various mechanisms for the evolution of dominance, and we conclude that they are most consistent with models that depend on indirect selection on homeostatic gene expression or on the ability to perform well under periods of high demand for a protein.

Figure 1.—

The distribution of observed growth rates observed from the homozygote yeast knockout data. The solid thick line indicates the distribution of observed growth rates predicted by the model described in the text with the maximum-likelihood values of its parameters.

Figure 2.—

Prediction of distribution of dominance values, h, from model 7 as a function of selection, s. Negative values of s represent deleterious mutations. The two discrete approximations used in the likelihood model are shown. For deleterious mutations, the distribution of h is constant within short intervals of s, but varies among s intervals. Within each s interval, the distribution of h values is represented by 25 equally probable values of h, shown here as vertically stacked segments with light shading; the mean, μ_h, is shown with dark shading.

Figure 3.—

Inbreeding depression contributed by 1000 loci, with fixed selection and dominance parameters. The inbreeding depression expected by the equations in Whitlock (2002) is shown, in which inbreeding depression depends strongly on the dominance coefficient, but is not affected by the selection coefficient, provided s > 0 and h > 0. The inbreeding coefficient of the measured individuals is shown as , corresponding to full-sib mating. The solid line shows the inbreeding depression expected at mutation–selection balance in a panmictic population, and the dashed line shows inbreeding depression in a population that was previously at mutation–selection equilibrium with F_ST = 0.1. Inbreeding depression is strongly affected by the dominance coefficient, and purging by previous inbreeding is also greatest at low h.