Sign of selection on mutation rate modifiers depends on population size.

Abstract

The influence of population size (<i>N</i>) on natural selection acting on alleles that affect fitness has been understood for almost a century. As <i>N</i> declines, genetic drift overwhelms selection and alleles with direct fitness effects are rendered neutral. Often, however, alleles experience so-called indirect selection, meaning they affect not the fitness of an individual but the fitness distribution of its offspring. Some of the best-studied examples of indirect selection include alleles that modify aspects of the genetic system such as recombination and mutation rates. Here, we use analytics, simulations, and experimental populations of <i>Saccharomyces cerevisiae</i> to examine the influence of <i>N</i> on indirect selection acting on alleles that increase the genomic mutation rate (mutators). Mutators experience indirect selection via genomic associations with beneficial and deleterious mutations they generate. We show that, as <i>N</i> declines, indirect selection driven by linked beneficial mutations is overpowered by drift before drift can neutralize the cost of the deleterious load. As a result, mutators transition from being favored by indirect selection in large populations to being disfavored as <i>N</i> declines. This surprising phenomenon of sign inversion in selective effect demonstrates that indirect selection on mutators exhibits a profound and qualitatively distinct dependence on <i>N</i>.