Sunday, August 31, 2008

hot motif

A paper just out in Nature Genetics (Myers et al) extends what we know about how local sequence determines recombination hotspot activity (hotspots are 1-2kb regions where recombination happens far more frequently than in the surrounding region).
The location of recombination hotspots along the genome can be inferred from linkage disequilibrium (LD), as LD represents the joint action of genetic drift and recombination over thousands of generations (i.e. meioses). What came as a real surprise to (I think) everyone is how good these predictions have turned out to be (e.g. McVean et al, Crawford et al., See also my previous post). The good performance of these methods, combined with the large genotyping data sets such as Perlegen and the HapMap have allowed tens of thousands of putative hotspots to be identified from LD. These methods are not perfect and there will be many false positives and negatives, but this large set of hotspots allowed researchers to identify the relatively subtle signal of a recombination promoting motif (a 7mer, Myers et al. 2006). This new paper further extends this motif to a degenerate 13mer. I view the success of these LD based methods and the discovery of the motif as one of the real success stories of empirical population genetics. Population genetic analyses have really lead the way in giving a glimpse of something unknown about the mechanism of recombination. We don't know what sequence motifs promote recombination (or even if one exists) in mouse or S.cerevisiae where far more mechanistic work has be performed (we do know about a motif in S. pombe, Steiner and Smith).

Further, the authors sow that the motif is involved in non-allelic (ectopic) recombination events. This is not entirely surprising as the a motif that promotes recombination bound to get it wrong some of the time, but they are still really nice examples.

Myers et al. A common sequence motif associated with recombination hot spots and genome instability in humans.
Nat Genet. 2008 Aug 24

Crawford et al. Evidence for substantial fine-scale variation in recombination rates across the human genome. Nat Genet. 2004 Jul;36(7):700-6.

McVean et al. The fine-scale structure of recombination rate variation in the human genome. Science. 2004 Apr 23;304(5670):581-4

Myers et al. A fine-scale map of recombination rates and hotspots across the human genome. Science. 2005 Oct 14;310(5746):321-4

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