Nutrient-dependent growth defects and mutability of mutators in Escherichia coli.

So-called mutators emerge when mismatch repair and proofreading mechanisms are defective. Mutators not only accelerate the accumulation of mutations that are beneficial for adaptation but also cause a large number of deleterious mutations that are disadvantageous for cell growth. However, such growth defects may be compensated by nutrient availability. How the growth burden is associated with high mutability in relation to nutritional variation is an intriguing question. To address this question, we constructed a variety of Escherichia coli mutator strains through combinatorial deletions of mismatch repair and proofreading genes and quantitatively evaluated their growth and mutation rates under different nutritional conditions. Growth defects caused by high mutation rates were commonly observed in all mutators, and these defects were alleviated by nutrient supplementation in most mutators. In addition, the mutation rates of the mutators fluctuated greatly in response to nutritional conditions, in contrast to the nearly constant mutation rate of the wild-type strain under varying nutritional conditions. The results showed conditional growth defects and nutrition-sensitive mutability as general features of mutators. This study indicates the importance of modulating mutability in response to changing nutrient conditions to minimize the risk of extinction due to genetic load.