NIH Research Festival
Genetic recombination generates genetic diversity in sexually reproducing species. In mice, humans and most other mammals, the DNA double strand breaks (DSBs) that initiate meiotic recombination are directed to a subset of genomic loci by sequence-specific DNA binding of the PRDM9 protein. This sequence specificity is conferred by a long array of C-terminal zinc fingers (ZFs) that each recognize a preferred DNA sequence. Genome-wide maps of DSB hotspots have been generated for a limited repertoire of Prdm9 alleles in congenic mice (Brick et al., Nature 2012), however to understand the interplay between Prdm9 and genetic background, we identified and analyzed DSB hotspots in mice with different Prdm9 alleles representing all four Mus musculus subspecies and in their F1 hybrids. In the six mice homozygous for Prdm9, almost all DSB hotspot loci differ and are defined by the Prdm9 allele. Alleles with common ZF combinations define some shared hotspot loci, however even a single extra ZF with little predicted effect on DNA binding can globally alter the hotspot landscape. Most hotspots in hybrids coincide with parental hotspots, with no evidence of imprinting, however up to 35% of hybrid hotspots are absent from the parental genomes. Recombination-mediated sequence variation destroys PRDM9 binding sites and can explain most such hotspots. This self-destructive drive also appears to govern the preferential usage of some Prdm9 alleles over others in hybrid mice and by this mechanism, Prdm9 may play a key evolutionary role in the origin of species.
Scientific Focus Area: Genetics and Genomics
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