Abstract
PRDM9 has recently been identified as a likely trans regulator of meiotic recombination hot spots in humans and mice1,2,3. PRDM9 contains a zinc finger array that, in humans, can recognize a short sequence motif associated with hot spots4, with binding to this motif possibly triggering hot-spot activity via chromatin remodeling5. 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 disorders6 as well as minisatellite instability7—implicating PRDM9 as a risk factor for some pathological genome rearrangements.
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Acknowledgements
We thank J. Blower and volunteers for providing semen samples, colleagues for helpful discussions and the Medical Research Council, the Wellcome Trust (ref. 081227/Z/06/Z), the Boehringer Ingelheim Fonds, the Royal Society and the Louis-Jeantet Foundation for funding support.
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I.L.B., R.N., K.-W.G.L., S.S., L.O.-H., C.A.M. and A.J.J. all contributed to designing aspects of the study. I.L.B., R.N. and A.J.J. characterized PRDM9 alleles, I.L.B., S.S., L.O.-H. and A.J.J. analyzed hot spots, R.N. surveyed minisatellite instability, K.-W.G.L. characterized genome rearrangements and A.J.J. analyzed translocations. A.J.J. wrote the paper.
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Berg, I., Neumann, R., Lam, KW. et al. PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans. Nat Genet 42, 859–863 (2010). https://doi.org/10.1038/ng.658
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DOI: https://doi.org/10.1038/ng.658
