Regulating General Mutation Rates: Examination of the Hypermutable State Model for Cairnsian Adaptive Mutation

In the lac adaptive mutation system of Cairns, selected mutant colonies but not unselected mutant types appear to arise from a nongrowing population of Escherichia coli. The general mutagenesis suffered by the selected mutants has been interpreted as support for the idea that E. coli possesses an evolved (and therefore beneficial) mechanism that increases the mutation rate in response to stress (the hypermutable state model, HSM). This mechanism is proposed to allow faster genetic adaptation to stressful conditions and to explain why mutations appear directed to useful sites. Analysis of the HSM reveals that it requires implausibly intense mutagenesis (10^5 times the unselected rate) and even then cannot account for the behavior of the Cairns system. The assumptions of the HSM predict that selected revertants will carry an average of eight deleterious null mutations and thus seem unlikely to be successful in longterm evolution. The experimentally observed 35-fold increase in the level of general mutagenesis cannot account for even one Lac+ revertant from a mutagenized subpopulation of 10^5 cells (the number proposed to enter the hypermutable state). We conclude that temporary general mutagenesis during stress is unlikely to provide a long-term selective advantage in this or any similar genetic system.