Estimating the Rate of Mutation to a Mutator Phenotype

A mutator is a variant in a population of organisms whose mutation rate is higher than the average mutation rate in the population. For genetic and population dynamics reasons, mutators are produced and survive with much greater frequency than anti-mutators (variants with a lower-than-average mutation rate). This strong asymmetry is a consequence of both fundamental genetics and natural selection; it can lead to a ratchet-like increase in the mutation rate. The rate at which mutators appear is, therefore, a parameter that should be of great interest to evolutionary biologists generally; for example, it can influence: (1) the survival duration of a species, especially asexual species (which are known to be short-lived), (2) the evolution of recombination, a process that can ameliorate the deleterious effects of mutator abundance, (3) the rate at which cancer appears, (4) the ability of pathogens to escape immune surveillance in their hosts, (5) the long-term fate of mitochondria, etc. In spite of its great relevance to basic and applied science, the rate of mutation to a mutator phenotype continues to be essentially unknown. The reasons for this gap in our knowledge are largely methodological; in general, a mutator phenotype cannot be observed directly, but must instead be inferred from the numbers of some neutral "marker" mutation that can be observed directly: different mutation-rate variants will produce this marker mutation at different rates. Here, we derive the expected distribution of the numbers of the marker mutants observed, accounting for the fact that some of the mutants will have been produced by a mutator phenotype that itself arose by mutation during the growth of the culture. These developments, together with previous enhancements of the Luria-Delbruck assay (by one of us, dubbed the "Jones protocol"), make possible a novel experimental protocol for estimating the rate of mutation to a mutator phenotype. Simulated experiments using biologically reasonable parameters that employ this protocol show that such experiments in the lab can give us fairly accurate estimates of the rate of mutation to a mutator phenotype. Although our ability to estimate mutation-to-mutator rates from simulated experiments is promising, we view this study as a proof-of-concept study and an important first step towards practical empirical estimation.