Abstract
PRDM9 has recently been identified as a likely trans-regulator of meiotic recombination hot spots in humans and mice1-3. The protein contains a zinc finger array that in humans can recognise a short sequence motif associated with hot spots4, with binding to this motif possibly triggering hot-spot activity via chromatin remodelling5. We now show that variation in the zinc finger array in humans has a profound effect on sperm hot-spot activity, even at hot spots lacking the sequence motif. Very subtle changes within the array can create hot-spot non-activating and enhancing alleles, and even trigger the appearance of a new hot spot. PRDM9 thus appears to be the preeminent global regulator of hot spots in humans. Variation at this locus also influences aspects of genome instability, specifically a megabase-scale rearrangement underlying two genomic disorders6 as well as minisatellite instability7, implicating PRDM9 as a risk factor for some pathological genome rearrangements.
Highlights
PR domain–containing 9 (PRDM9) is a meiosis-specific histone H3 methyltransferase with a C-terminal tandem-repeat C2H2 zinc finger (ZnF) domain encoded by a minisatellite[8]
Diversity in Africans was high[3] (Fig. 1b), and classification of alleles according to the predicted ability of the resulting protein variants to recognize the hot-spot motif (Fig. 1a and Supplementary Fig. 1) showed that nearly half of these variants should result in impaired binding relative to the common A allele (Fig. 1b), providing a key resource for analyzing PRDM9 effects
Ranking of 112 men by recombination frequency over all hot spots tested (Online Methods) showed that the 17 lowest-ranked individuals included 14 of the 15 men with non-A alleles (N/N) genotypes (Supplementary Table 1) (P = 5 × 10−16). This association remained in a subgroup of men of Southern East-African descent (11 N/N men from this population all ranked lowest in the 38 men tested; P = 2 × 10−9), ruling out differences between populations at other loci as significant confounding variables
Summary
L QT men were 41% ± 16% of those in A/A men, which is consistent with a simple additive model whereby hot-spot activity is proportional to the number of activating alleles present. PRDM9 clearly regulates minisatellite instability, though it DNA binding[15] This inability to activate hot spots might be due to is unclear whether this occurs by interaction of the ZnF array with allele L13 carrying an additional alteration that inactivates the gene, hot-spot motifs present within the minisatellites themselves (Fig. 4a)[4] though such null alleles should be rare given that Prdm[9] disruption or by interaction with a flanking recombination hot spot that in turn in mice causes sterility[8]. The neighboring hot spot MSTM1a was active in only 3 of the 25 tions map within a short palindromic AT-rich repeat (PATRR), men surveyed[16] These three men carried the non-A alleles L9 or L24 allowing de novo translocations to be detected by PCR24. Translocation frequencies in sperm varied widely between the L9/L24 alleles and hot-spot activity was significant between men (Fig. 6b), reflecting the sensitivity of the process to a b
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