General antimutators are improbable

Abstract

Antimutator mutations reduce spontaneous mutation rates, at least at some sites and along some pathways. Antimutators have been found in several microbial systems since their initial discovery in bacteriophage T4, where they occur mainly among mutations of gene 43 (which encodes the viral DNA polymerase). The phage T4 antimutators are highly specific, often strongly reducing mutations rates but only along specific pathways, usually A.T-->G.C. They may fail to affect other pathways, such as G.C-->A.T, and may even accelerate mutation at yet other pathways, such as transversions (R.Y-->Y.R). Both enzymatic and evolutionary considerations suggest that it should be difficult to isolate strong, general antimutator mutations, that is, mutations that substantially lower the total spontaneous mutation rate over the entire genome without producing strongly deleterious side effects. This notion has been tested by measuring mutation rates over a target comprising several kilobases in a set of phage T4 antimutators. In each case, this rate was indistinguishable from or greater than the wild-type rate. A survey of reports describing antimutators in other microbes reveals that none are yet demonstrated to be general antimutators.