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

Abstract

During meiotic recombination, homologue-templated repair of programmed DNA double-strand breaks (DSBs) produces relatively few crossovers and many difficult-to-detect non-crossovers. By intercrossing two diverged mouse subspecies over five generations and deep-sequencing 119 offspring, we detect thousands of crossover and non-crossover events genome-wide with unprecedented power and spatial resolution. We find that both crossovers and non-crossovers are strongly depleted at DSB hotspots where the DSB-positioning protein PRDM9 fails to bind to the unbroken homologous chromosome, revealing that PRDM9 also functions to promote homologue-templated repair. Our results show that complex non-crossovers are much rarer in mice than humans, consistent with complex events arising from accumulated non-programmed DNA damage. Unexpectedly, we also find that GC-biased gene conversion is restricted to non-crossover tracts containing only one mismatch. These results demonstrate that local genetic diversity profoundly alters meiotic repair pathway decisions via at least two distinct mechanisms, impacting genome evolution and Prdm9 -related hybrid infertility.

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

“…driven by expected WT ZCWPW1 recruitment levels at each hotspot (Supplementary Figure 15). ZCWPW1 therefore offers a (thus far) unique protein, linking PRDM9 binding with its downstream functions (Davies et al, 2016;Hinch et al, 2019;R. Li et al, 2019) in aiding rapid DSB processing/repair at hotspots whose homologue is bound by PRDM9.…”

“…This is thought to reflect a wider phenomenon of faster DSB repair occurring within those hotspots whose homologue is more strongly bound by PRDM9, i.e. those hotspots with a stronger H3K4me3 signal in the WT mouse (Davies et al, 2016;Hinch et al, 2019;R. Li et al, 2019).…”

“…The sister chromatid can also provide a repair substrate, e.g. for DSBs on the X chromosome in males, and there is evidence that this also occurs at some autosomal hotspots (Allen and Latt, 1976;R. Li et al, 2019;Lu and Yu, 2015).…”

“…From mid-zygotene to early pachytene, as part of the recombinational repair process, DMC1 dissociates from the ssDNA and counts decrease until all breaks (except those on the XY chromosomes) are repaired in late pachytene (Moens et al, 2002). At DSB sites where the homologous chromosome is not bound by PRDM9, DMC1 signal is strongly elevated (Davies et al, 2016), suggesting delayed DSB repair, while fewer homologous recombination events occur (Hinch et al, 2019;R. Li et al, 2019), suggesting that (eventual) DSB repair may sometimes use a sister chromosome pathway.…”

Dual Histone Methyl Reader ZCWPW1 Facilitates Repair of Meiotic Double Strand Breaks

“…However, these DSBs are not repaired efficiently, leading to meiotic arrest and partial asynapsis. In F1 hybrid mice, the presence of PRDM9 binding motifs on both the cut and uncut homolog improves recombination rates (Hinch et al, 2019;Li et al, 2019b), suggesting that PRDM9 itself, and perhaps its downstream factors, play important roles beyond merely initiating DSBs.…”