NIH Research Festival
Meiotic recombination is a fundamental process to generate genetic variation in most eukaryotes. In humans and mice, the DNA double strand breaks (DSBs) that initiate recombination occur at hotspots determined by a H3K4 methyltransferase protein called PRDM9. In Prdm9-/- mice, recombination hotspots coincide with constitutive H3K4me3 sites and results in sterility of these mice. However, dogs contain an inactive, pseudogenized, Prdm9 gene yet remain fertile. Thus, to investigate the mechanism of recombination in the absence of PRDM9, we built high-resolution and genome-wide maps of meiotic DSBs in three individual dogs. We identified up to 15,823 recombination hotspots per individual, and consistent with the loss of Prdm9, all three dogs share a majority of DSB hotspots. Over 90% of dog hotspots are observed at constitutive H3K4 trimethylation marks including gene promoters, and DSB formation appears to be at CpG islands. Like in human males, dog DSB maps exhibit a strong bias toward subtelomeric regions, suggesting that a conserved mechanism may modulate DSB formation at chromosome ends in both species. In contrast to DSB maps in mice and humans, we detected multiple extended regions with elevated DSB formation outside of hotspots, and these “recombination domains” are primarily at the ends of chromosomes, are enriched in CpG islands, have a high GC content, are conserved among individuals and exhibited a significantly elevated recombination rate. Together, our genome-wide recombination maps in dog males provide new insights into the regulation of meiotic recombination without Prdm9.
Scientific Focus Area: Genetics and Genomics
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