Understanding how mutator strains emerge in bacterial populations is relevant both to evolutionary theory and to reduce the threat they pose in clinical settings. The rise of mutator alleles is understood as a result of their hitchhiking with linked beneficial mutations, although the factors that govern this process remain unclear. A prominent but underappreciated fact is that each mutator allele increases only a specific spectrum of mutational changes. This spectrum has been speculated to alter the distribution of fitness effects of beneficial mutations, potentially affecting hitchhiking. To study this possibility, we analyzed the fitness distribution of beneficial mutations generated from different mutator and wild-type Escherichia coli strains. Using antibiotic resistance as a model system, we show that mutational spectra can alter these distributions substantially, ultimately determining the competitive ability of each strain across environments. Computer simulation showed that the effect of mutational spectrum on hitchhiking dynamics follows a non-linear function, implying that even slight spectrum-dependent fitness differences are sufficient to alter mutator success frequency by several orders of magnitude. These results indicate an unanticipated central role for the mutational spectrum in the evolution of bacterial mutation rates. At a practical level, this study indicates that knowledge of the molecular details of resistance determinants is crucial for minimizing mutator evolution during antibiotic therapy. Author Summary Natural and laboratory populations of bacteria can readily give rise to strains with high mutation rates. The evolution of these mutator bacteria—of particular concern in clinical situations—has been understood exclusively in terms of their increased capacity to generate beneficial mutations, such as those that confer antibiotic resistance. Current models, however, have largely overlooked that each mutator allele increases only characteristic types of mutations, a prominent fact whose evolutionary consequences remain unexplored. Using laboratory Escherichia coli populations, we show that this mutational bias determines the competitiveness of different mutators across environments. Computer simulation showed that this effect can markedly influence the evolutionary fate of mutator alleles. These results indicate that this unrecognized factor can be a major determinant in the evolution of mutator bacteria and suggest future experimental approaches for improving antibiotic therapy design.
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