Resolving the hotspot paradox, at least partly)

A while back I described our previous work on the paradoxical activity of meiotic recombination hotspots (their mode of action is self-destructive). A new paper by Simon Myers and coauthors (Drive Against Hotspot Motifs in Primates Implicates the PRDM9 Gene in Meiotic Recombination.) now goes a long way towards resolving the paradox, though it doesn't explain how our recombination system got itself into this mess.

This group had previously identified a 13-nt sequence motif typical of human hotspots (thought not all of them); it's thought to be the sequence motif recognized by the process that initiates recombination by creating a double-strand break in the hotspot DNA. Previous work had suggested that chimpanzee hotspots are in different places than human hotspots, so the authors looked at the chimpanzee homologs of the human hotspots and found that although the sites did have this sequence (or variants of it), they didn't function as hotspots. The chimpanzee genome also had this motif at other sites, more than the human genome does. They concluded that many of the human occurrences of the motif had been lost from the human genome because their hotspot activity was self-destructive. They hypothesized that the motif was not ancestrally a hotspot but had become one in the human lineage, 1-2 million years ago.

They then decided to look for the protein that recognizes these sites. Based on their earlier work they had already hypothesized that it would be a zinc-finger protein with ≥12 'fingers' to bind the motif. So they used structural predictions to examine candidate zinc-finger proteins encoded by the human genome, and found five candidates, of which the best was a protein called PRDM9.

If PRDM9 is indeed the protein that, in humans, binds the 13 nt hotspot motif to initiate recombination, its human version should recognize this motif but its chimpanzee version should not. Consistent with this, PRDM9 was the only one of the five candidates that was different in chimpanzees (the other four had identical sequences in both species). Furthermore, it's sequence didn't just have random differences, but had many of its differences in the zinc-fingers that recognize DNA sequence,with hallmarks of positive selection for the changes. And independent work on this protein in mice and genetic mapping, both implicate it as playing a role in the initiation of recombination.

So what are the implications for the hotspot paradox? My simple view is that active hotspots do self-destruct over evolutionary time, as we predicted, and because we need recombination to hold chromosomes together in meiosis, this creates selection on the protein that recognizes them. Variant proteins that recognize new sequences are favoured (that's the positive selection) because they can cause more recombination and thus better prevent chromosome errors. So over long evolutionary periods, genomes may progress through a series of different hotspot motifs and locations.

Researchers have sometimes proposed that different kinds of genes evolve best with different amounts of recombination, and that the chromosomal locations of genes and/or hotspots have evolved to that optimize the amount of recombination. This new paper throws cold water on that idea.

Added later: Turns out the Myers paper was published together with two other papers about PRDM9's role in recombination, confirming and extending the conclusions. And, the same gene was identified last year as a locus very important in speciation, so maybe changing your hotspot specificity changes who you can reproduce with.