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Sign of selection on mutation rate modifiers depends on population size

Y. Raynes,C. Wylie,P. Sniegowski,D. Weinreich

Published 2017 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance It has been known since the early days of population genetics that population size plays a critical role in natural selection. In small populations, selection on alleles that intrinsically affect fitness can be overwhelmed by genetic drift, rendering both beneficial and deleterious alleles selectively neutral. In contrast, alleles that increase the genomic mutation rate (mutators) experience indirect selection, which acts not on their fitness effects but on their genomic associations with fitness-affecting alleles. Here, we show that the sign of indirect selection on mutators can change depending on population size. This phenomenon of sign inversion in selective effect reflects a qualitatively distinct role of population size in evolution and may be broadly important in other instances of indirect selection. The influence of population size (N) on natural selection acting on alleles that affect fitness has been understood for almost a century. As N 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 Saccharomyces cerevisiae to examine the influence of N 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 N 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 N declines. This surprising phenomenon of sign inversion in selective effect demonstrates that indirect selection on mutators exhibits a profound and qualitatively distinct dependence on N.

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