PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans

PRDM9 has recently been identified as a likely trans regulator of meiotic recombination hot spots in humans and mice(1-3). PRDM9 contains a zinc finger array that, in humans, can recognize a short sequence motif associated with hot spots(4), with binding to this motif possibly triggering hot-spot activity via chromatin remodeling(5). We now report that human genetic variation at the PRDM9 locus has a strong effect on sperm hot-spot activity, even at hot spots lacking the sequence motif. Subtle changes within the zinc finger array can create hot-spot nonactivating or enhancing variants and can even trigger the appearance of a new hot spot, suggesting that PRDM9 is a major global regulator of hot spots in humans. Variation at the PRDM9 locus also influences aspects of genome instability-specifically, a megabase-scale rearrangement underlying two genomic disorders(6) as well as minisatellite instability(7)-implicating PRDM9 as a risk factor for some pathological genome rearrangements.