PRDM9 is a Major Determinant of Meiotic Recombination Hotspots in humans and mice

By F. Baudat, J. Buard, C. Grey, A. Fledel-Alon, Carole Ober, Molly Przeworski, Graham Coop, B. Massy. Science, 2009

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Homing in on Hotspots The clustering of recombination in the genome, around locations known as hotspots, is associated with specific DNA motifs. Now, using a variety of techniques, three studies implicate a chromatin-modifying protein, the histone-methyltransferase PRDM9, as a major factor involved in human hotspots (see the Perspective by Cheung et al.). Parvanov et al. (p. 835, published online 31 December) mapped the locus in mice, and analyzed allelic variation in mice and humans, whereas Myers et al. (p. 876, published online 31 December) used a comparative analysis between human and chimpanzees to show that the recombination process leads to a self-destructive drive in which the very motifs that recruit hotspots are eliminated from our genome. Baudat et al. (p. 836, published online 31 December) took this analysis a step further to identify human allelic variants within Prdm9 that differed in the frequency at which they used hotspots. Furthermore, differential binding of this protein to different human alleles suggests that this protein interacts with specific DNA sequences. Thus, PDRM9 functions in the determination of recombination loci within the genome and may be a significant factor in the genomic differences between closely related species. A chromatin-modifying enzyme is implicated in the determination of recombination loci within the genome. Meiotic recombination events cluster into narrow segments of the genome, defined as hotspots. Here, we demonstrate that a major player for hotspot specification is the Prdm9 gene. First, two mouse strains that differ in hotspot usage are polymorphic for the zinc finger DNA binding array of PRDM9. Second, the human consensus PRDM9 allele is predicted to recognize the 13-mer motif enriched at human hotspots; this DNA binding specificity is verified by in vitro studies. Third, allelic variants of PRDM9 zinc fingers are significantly associated with variability in genome-wide hotspot usage among humans. Our results provide a molecular basis for the distribution of meiotic recombination in mammals, in which the binding of PRDM9 to specific DNA sequences targets the initiation of recombination at specific locations in the genome.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/67c6440347038208f1a48e32751713076b45322d

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Citations in the corpus

Interpreting differentiation landscapes in the light of long-term linked selection (2017, background): “2015), diversity reductions through linked selection in low-recombination regions will be particularly strong, and diversity and differentiation landscapes will be correlated over longer timescales than in taxa with more dynamically evolving recombination landscapes, such as most mammals (e.g. Olive”
A map of human genome variation from population scale sequencing (2010, background): “We found a much smaller number of variants likely to have greater functional impact: in frame indels (190-210), premature stop codons (80-100), splice site disrupting variants (40-50), and deletions that shift reading frame (220-250), in each individual.”