Shifts in mutation bias promote mutators by altering the distribution of fitness effects

Recent experimental evidence demonstrates that shifts in mutational biases, for example increases in transversion frequency, can change the distribution of fitness effects of mutations (DFE). In particular, reducing or reversing an existing bias can increase the probability that a de novo mutation is beneficial. It has also been shown that mutator bacteria are more likely to emerge if the beneficial mutations they generate have a larger effect size than observed in the wildtype. Here, we connect these two results, demonstrating that mutator strains that reduce or reverse an existing bias have a positively-shifted DFE, which in turn dramatically increases their emergence probability. Since changes in mutation rate and bias are often coupled through the gain and loss of DNA repair enzymes, our results demonstrate that shifts in mutation bias can facilitate the invasion of mutator strains due to their improved access to previously undersampled beneficial mutations.