PRDM9 Drives Evolutionary Erosion of Hotspots in Mus musculus through Haplotype-Specific Initiation of Meiotic Recombination

Abstract

Meiotic recombination generates new genetic variation and assures the proper segregation of chromosomes in gametes. PRDM9, a zinc finger protein with histone methyltransferase activity, initiates meiotic recombination by binding DNA at recombination hotspots and directing the position of DNA double-strand breaks (DSB). The DSB repair mechanism suggests that hotspots should eventually self-destruct, yet genome-wide recombination levels remain constant, a conundrum known as the hotspot paradox. To test if PRDM9 drives this evolutionary erosion, we measured activity of the Prdm9 Cst allele in two Mus musculus subspecies, M.m. castaneus, in which Prdm9Cst arose, and M.m. domesticus, into which Prdm9Cst was introduced experimentally. Comparing these two strains, we find that haplotype differences at hotspots lead to qualitative and quantitative changes in PRDM9 binding and activity. Using Mus spretus as an outlier, we found most variants affecting PRDM9Cst binding arose and were fixed in M.m. castaneus, suppressing hotspot activity. Furthermore, M.m. castaneus×M.m. domesticus F1 hybrids exhibit novel hotspots, with large haplotype biases in both PRDM9 binding and chromatin modification. These novel hotspots represent sites of historic evolutionary erosion that become activated in hybrids due to crosstalk between one parent's Prdm9 allele and the opposite parent's chromosome. Together these data support a model where haplotype-specific PRDM9 binding directs biased gene conversion at hotspots, ultimately leading to hotspot erosion.

Re-engineering the zinc fingers of PRDM9 reverses hybrid sterility in mice

“…1). A feature of PRDM9 (explored further below) is the co-evolution of its ZF-array with the genomic background in which it sits 13,17 . Minisatellite mutational processes at PRDM9 can produce new alleles with duplications, deletions or rearrangements within the ZF-array, yielding an almost complete change in PRDM9 binding sites, and thus hotspot locations 14 .…”

In vivo binding of PRDM9 reveals interactions with noncanonical genomic sites

“…This effect could be caused by erosion of PRDM9 Dom2 motifs by gene conversion (Myers et al 2010;Baker et al 2015). As the PRDM9 Dom2 protein is produced in the M. m. domesticus C57BL/6 strain and PRDM9 Cst is a variant derived from M. m. castaneus and Figure 4.…”

Mammalian Meiotic Recombination: A Toolbox for Genome Evolution

“…Therefore, this biased gene conversion predicts that hotspots should undergo evolutionary erosion due to the mutagenic effect of meiotic recombination. Thus, if hotspots drive themselves to extinction, it is unlikely that recombination persists in the same region, leading to a phenomenon known as the 'hotspot paradox' [Boulton et al, 1997;Coop and Myers, 2007;Baker et al, 2015]. However, the PRDM9 function brings a solution to this paradox, as its rapid evolutionary change can overcome hotspot loss by undergoing mutations altering its ZnF array and, thus, changing the genome-wide distribution of hotpots.…”