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

Mutational load is the depression in a population9s mean fitness that results from the unceasing influx of deleterious mutations. Here, we directly estimate the mutational load in a population of mismatch repair-deficient *Saccharomyces cerevisiae*. We partition the load 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 (0.016 and 0.009 respectively) is approximately 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. These results enhance our understanding of mutational load, a classic population genetics concept, and we discuss their implications for the evolution of mutation rates.