A high-resolution map of non-crossover events in mice reveals impacts of genetic diversity on meiotic recombination

In mice and humans, meiotic recombination begins with programmed DNA double-strand breaks at PRDM9-bound sites. These mainly resolve as difficult-to-detect non-crossovers, rather than crossovers. Here, we intercrossed two mouse subspecies over five generations and deep-sequenced 119 offspring, whose high heterozygosity allowed detection of 2,500 crossover and 1,575 non-crossover events with unprecedented power and spatial resolution. These events were strongly depleted at 9asymmetric9 sites where PRDM9 mainly binds one homologue, implying they instead repair from the sister chromatid. This proves that symmetric PRDM9 binding promotes inter-homologue interactions, illuminating the mechanism of PRDM9-related hybrid infertility. Non-crossovers were surprisingly short (mean 30-41 bp), and complex non-crossovers, seen commonly in humans, were extremely rare. Unexpectedly, GC-biased gene conversion disappeared at non-crossovers containing multiple mismatches. These results demonstrate that local genetic diversity can alter meiotic repair pathway decisions in mammals by changing PRDM9 binding symmetry and non-crossover resolution, which influence genome evolution, fertility, and speciation.