THE POPULATION-GENETICS OF SYNTHETIC LETHALS

Synthetic lethals are variants at different loci that have little or n o effect on viability singly but cause lethality in combination. The i mportance of synthetic lethals and, more generally, of synthetic delet erious loci (SDL) has been controversial. Here, we derive the expected frequencies for SDL under a mutation-selection balance for the comple te haploid model and selected cases of the diploid model. We have also obtained simple approximations that demonstrate good fit to exact sol utions based on numerical iterations. In the haploid case, equilibrium frequencies of carrier haplotypes (individuals with only a single mut ation) are comparable to analogous single-locus results, after allowin g for the effects of linkage. Frequencies in the diploid case, however , are much higher and more comparable to the square root of the single -locus results. In particular, when selection operates only on the dou ble-mutant homozygote and linkage is not too tight, the expected frequ ency of the carriers is approximately the quartic root of the ratio be tween the mutation rate and the selection coefficient of the synthetic s. For a reasonably wide set of models, the frequencies of carriers ca n be on the order of a few percent. The equilibrium frequencies of the se deleterious alleles can be relatively high because, with SDL, both dominance and epistasis act to shield carriers from exposure to select ion. We also discuss the possible role of SDL in maintaining genetic v ariation and in hybrid breakdown.