Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination

Abstract

Although present in both humans and chimpanzees, recombination hotspots, at which meiotic crossover events cluster, differ markedly in their genomic location between the species. We report that a 13-base pair sequence motif previously associated with the activity of 40% of human hotspots does not function in chimpanzees and is being removed by self-destructive drive in the human lineage. Multiple lines of evidence suggest that the rapidly evolving zinc-finger protein PRDM9 binds to this motif and that sequence changes in the protein may be responsible for hotspot differences between species. The involvement of PRDM9, which causes histone H3 lysine 4 trimethylation, implies that there is a common mechanism for recombination hotspots in eukaryotes but raises questions about what forces have driven such rapid change.

Figure 1

Recombination rates and patterns of motif gain and loss in human and chimpanzee. For additional details, see (8). A Estimated HapMap Phase II recombination rate across the 40kb surrounding 16 human THE1 elements (red line) and 6 L2 elements (blue line) orthologous to the 22 regions analyzed in chimpanzee, and each containing a conserved exact match to the 13-bp core motif. Rates are smoothed using a 2kb sliding window slid in 50bp increments, averaged across elements. Horizontal dashed line: the human average recombination rate of 1.1cM/Mb. Vertical dotted line: the centre of the repeat. B Average estimated recombination rate for the western chimpanzee data across around the 16 THE1 elements (red line) and six L2 elements (blue line) containing the 13-bp core motif. Other details as for A. C Numbers of core motif gains (left hand bars) versus losses (right bars), inferred using macaque and orang-utan outgroup information (8), in humans (orange bars) and chimpanzees (cyan bars) on three backgrounds; THE1, L2 and non-repeat (NR). For each background, gains are shown as a fraction of motifs currently present in each species, losses as a fraction of motifs inferred in the human-chimpanzee ancestor. The intervals flanking the plot on each side show exact 1-sided 95% confidence intervals and associated p-values for testing equality of gain/loss rate between the species (8).

Figure 2

A Previously estimated degeneracy of the 13-bp hotspot motif (6) (logo plot; relative letter height proportional to estimated probability of hotspot activity, total letter height determined by degree of base specificity) as well as an extended ~39-bp motif (text below logo, with influential positions (p<0.01) shown in red). B In silico prediction of the binding consensus for PRDM9, aligned with the 13-mer, with more influential positions shown in red. Underlined in both A and B is an additional 8-bp matching sequence. The logo shows predicted degeneracy within this consensus (8). Below the text is the sequence of four predicted DNA-contacting amino acids for the 13 successive human PRDM9 zinc fingers (1 oval per finger, differing colors for differing fingers, separated finger is gapped N-terminal from others), and their predicted base contacts within the motif. C Sequence of four predicted DNA-contacting amino acids for the PRDM9 zinc fingers in 7 mammalian species, presented as in B. Distinct fingers given different colors; fingers present in at least two species have black border.