The fitness cost of mismatch repair mutators in Saccharomyces cerevisiae: partitioning the mutational load.

Mutational load is the depression in a population's mean fitness that results from the continual influx of deleterious mutations. Here, we directly estimate the mutational load in a population of haploid Saccharomyces cerevisiae that are deficient for mismatch repair. We partition the load in haploids into two components. To estimate the load due to nonlethal mutations, we measure the competitive fitness of hundreds of randomly selected clones from both mismatch-repair-deficient and -proficient populations. Computation of the mean clone fitness for the mismatch-repair-deficient strain permits an estimation of the nonlethal load, and the histogram of fitness provides an interesting visualization of a loaded population. In a separate experiment, in order to estimate the load due to lethal mutations (i.e. the lethal mutation rate), we manipulate thousands of individual pairs of mother and daughter cells and track their fates. These two approaches yield point estimates for the two contributors to load, and the addition of these estimates is nearly equal to the separately measured short-term competitive fitness deficit for the mismatch-repair-deficient strain. This correspondence suggests that there is no need to invoke direct fitness effects to explain the fitness difference between mismatch-repair-deficient and -proficient strains. Assays in diploids are consistent with deleterious mutations in diploids tending towards recessivity. These results enhance our understanding of mutational load, a central population genetics concept, and we discuss their implications for the evolution of mutation rates.