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

Nat Commun. 2019 Aug 29;10(1):3900. doi: 10.1038/s41467-019-11675-y.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cell Cycle Proteins / genetics
  • Chromosomes
  • Crossing Over, Genetic
  • DNA Breaks, Double-Stranded*
  • DNA Damage
  • DNA Mismatch Repair
  • Female
  • Gene Conversion
  • Genetic Variation*
  • Histone-Lysine N-Methyltransferase / genetics
  • Histones / genetics
  • Homologous Recombination*
  • Humans
  • Hybridization, Genetic
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Genetic
  • Phosphate-Binding Proteins / genetics
  • Polymorphism, Single Nucleotide
  • Recombinational DNA Repair

Substances

  • Cell Cycle Proteins
  • Dmc1 protein, mouse
  • Histones
  • Phosphate-Binding Proteins
  • histone H3 trimethyl Lys4
  • Histone-Lysine N-Methyltransferase
  • PRDM9 protein, human
  • prdm9 protein, mouse