Evolution of the rate, spectrum, and fitness effects of mutation under minimal selection in Caenorhabditis elegans

The rate, molecular spectrum, and fitness effects of mutations vary at all levels of the biological hierarchy, from within individual genomes to among taxonomic domains. Understanding the evolutionary factors underpinning that variation is of fundamental importance to biology. Accurate quantification of the properties of mutations requires that other evolutionary forces, especially natural selection, be minimized as much as possible. To investigate the evolution of the mutational process in C. elegans, we propagated a set of 100 "first order" mutation accumulation (O1MA) lines under minimal selection for [~]150 generations, divided each O1MA line into two "second order" MA (O2MA) lines and propagated them for another [~]150 generations, at which time the genome of each O2MA line was sequenced, and a subset of 50 O1MA families was assayed for competitive fitness. Over the course of the experiment, the mean nucleotide substitution mutation rate did not change, but the variance increased. In contrast, the indel mutation rate increased significantly. The two types of mutations fulfill the predictions of different theoretical models for the evolution of mutation rate. These results reinforce previous findings that the rate of indels is more sensitive to endogenous stress than the rate of nucleotide substitutions. Several evolutionary quandaries could be resolved if deleterious mutations interact synergistically (negative epistasis). Evidence for synergistic epistasis is famously inconclusive, although there is reason to think it may be more detectable under competitive conditions. However, a model of constant mutational effects on competitive fitness explains the results significantly better than a model including epistasis.