Abstract
The dominant paradigm for the evolution of mutator alleles in bacterial populations is that they spread by indirect selection for linked beneficial mutations when bacteria are poorly adapted. In this paper, we challenge the ubiquity of this paradigm by demonstrating that a clinically important stressor, hydrogen peroxide, generates direct selection for an elevated mutation rate in the pathogenic bacterium Pseudomonas aeruginosa as a consequence of a trade-off between the fidelity of DNA repair and hydrogen peroxide resistance. We demonstrate that the biochemical mechanism underlying this trade-off in the case of mutS is the elevated secretion of catalase by the mutator strain. Our results provide, to our knowledge, the first experimental evidence that direct selection can favour mutator alleles in bacterial populations, and pave the way for future studies to understand how mutation and DNA repair are linked to stress responses and how this affects the evolution of bacterial mutation rates.
Highlights
A minority of bacteria isolated from natural and clinical environments have genetically elevated mutation rates, often as a result of mutations in genes involved in the highly conserved methyl-directed mismatch repair (MMR) pathway [1]
Computer simulations and experiments have shown that mutator alleles can spread in bacterial populations as a result of second-order selection [2,3,4,5,6]; that is, selection drives an increase in the frequency of beneficial mutations, and mutator alleles increase in frequency when they are linked to these beneficial mutations
We show that mutators can be favoured by direct selection as a result of oxidative stress resistance; a major advantage for an opportunistic pathogen such as P. aeruginosa
Summary
A minority of bacteria isolated from natural and clinical environments have genetically elevated mutation rates, often as a result of mutations in genes involved in the highly conserved methyl-directed mismatch repair (MMR) pathway [1]. Many stressors, including antibiotics, induce the expression of stress response pathways that are associated with an increase in the mutation rate, by inducing the expression of alternative, low-fidelity DNA polymerases [10]. This may constrain or promote the evolution of genetic mutators, depending on how the stress differentially affects phenotypic mutation rates of mutators and wildtype. Direct competition experiments between mutators and wild-type confirm the nature of ‘public good’ of the protective enzymes, as both strains share the benefits when exposed to the stress
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