Mismatch repair disturbs meiotic class I crossover control

Abstract

Sequence divergence, mediated by the anti-recombinogenic activity of mismatch repair (MMR), forms a barrier to meiotic recombination and in turn the formation of viable gametes. However, rather than MMR acting as a non-specific impediment to meiotic recombination, here we provide evidence that at regions of greater sequence divergence MMR preferentially suppresses interfering (class I) crossovers (COs). Specifically, as measured in two Saccharomyces cerevisiae hybrids containing thousands of DNA-sequence polymorphisms, removal of MMR components increases both the frequency of CO formation and the uniformity of the observed CO distribution. At fine scale, CO positions are skewed away from polymorphic regions in MMR-proficient cells, but, critically, not when members of the class I CO pathway, MSH4 or ZIP3, are inactivated. These findings suggest that class I COs are more sensitive to heteroduplex DNA arising during recombination. Simulations and analysis of Zip3 foci on meiotic chromosomes support roles for Msh2 both early and late in the class I CO maturation process. Collectively, our observations highlight an unexpected interaction between DNA sequence divergence, MMR, and meiotic class I CO control, thereby intimately linking the regulation of CO numbers and their distribution to pathways contributing to reproductive isolation and eventual speciation.