Abstract
Despite substantial attention from theoreticians, the evolutionary mechanisms that drive intra- and interspecific variation in the mutation rate remain unclear. It has often been argued that mutation rates associated with the major replicative polymerases have been driven down to their physiological limits, defined as the point at which further enhancement in replication fidelity incurs a cost in terms of reproductive output, but no evidence in support of this argument has emerged for cellular organisms. Here, it is suggested that the lower barrier to mutation rate evolution may ultimately be defined not by molecular limitations but by the power of random genetic drift. As the mutation rate is reduced to a very low level, a point will eventually be reached at which the small advantage of any further reduction is overwhelmed by the power of drift. This hypothesis is consistent with a number of observations, including the inverse relationship between the per-site mutation rate and genome size in microbes, the negative scaling between the per-site mutation rate and effective population size in eukaryotes, and the elevated error rates associated with less frequently deployed polymerases and repair pathways.