Mutational Bias Shifts and Severe Environmental Stress Promote Mutator Emergence

This thesis explores how elevations in mutation rates, also known as the rise of mutators, can be affected by two main factors: mutational biases and harsh environmental challenges. We show here that shifts in mutational biases -especially reductions or reversals- increase an organism's access to previously under-sampled mutations, resulting in higher frequencies of beneficial de novo mutations. Through a discrete-time mathematical model and simulations, we demonstrate that this enhanced access facilitates the rise of mutator strains with larger fitness effects. We also consider how evolutionary rescue can promote mutator lineages under abrupt or gradual environmental stress. Using branching processes and deterministic models, supported by simulations, we show that de novo mutators are likely to hitchhike due to evolutionary rescue events when the wildtype mutation rate is intermediate, while pre-existing mutators in the populations have a significant advantage when mutation costs are minimal due to low wildtype mutation rates. Unsurprisingly, the stronger a mutator is, the more effective it is if the wildtype mutation rate is low, while its relative advantage decreases in populations where the wildtype itself is a mutator. Finally, by analyzing cancer mutational data, we show that our theoretical predictions apply to human cancer. We find that non-hypermutated tumors exhibit a reversal of germline mutation biases such that a similar mutation spectrum across tissues shows signs of positive selection in cancer genes, whereas hypermutated tumors potentially access cancer-driver mutations through their high mutation rates without the need for bias shifts. Altogether, these findings underscore the important role that mutational biases and severe environmental stresses have on mutator emergence in asexual organisms, point to mechanisms of adaptive evolution and drug resistance development, and suggest possible therapeutical implications for the treatment of cancer.