Sunday, October 08, 2006

The hotspot paradox   posted by JP @ 10/08/2006 09:55:00 PM

In the comments of a previous post, rikurzhen asks the following question:
do we know enough about recombination hot spots to say if they are heritable? if so, could the location of a hot spot itself be under selection?

I responded that it would be tough to tell whether or not hotspots are heritable or not, but this isn't entirely true-- I limited myself to thinking about humans. On a bit of further reading, I can now definitively say yes, certain DNA sequences are more likely than others to initiate recombination, and these sequences are (obviously) heritable.

The interesting thing is that the very existence of hotspots implies a paradox. I highly recommend the introduction to this article for those looking to understand why this is so. Here's a good summary of the problem:
Sexual recombination is one of the main forces shaping eukaryote evolution, but implicit in its mechanism is a serious paradox. The mechanism, called double-strand break repair, was first proposed for fungi in 1983. It has become increasingly well understood and well supported in a wide variety of organisms, and double-strand DNA breaks (DSBs) are now thought to be the primary initiators of meiotic recombination in eukaryotes. DSBs usually occur at chromosomal sites called recombination hotspots, whose evolutionary persistence is at the heart of the paradox. DSBs appear to frequently cause destruction of the DNA sequence specifying the hotspot and replacement of this sequence by the sequence of its homolog. Over many generations this self-destructive mechanism is expected to cause all active hotspot alleles to be replaced by alleles incapable of initiating DSBs. The paradox is that this has not happened.

However, the story may be more complicated, at least in humans. From here:
Haplotype analysis around both hotspots identified active and suppressed men sharing identical haplotypes, establishing that these major variations in the presence/absence of a hotspot and in quantitative activity are not caused by local DNA sequence variation

It seems likely, to me, that there must be some mechanism that maintains a certain number of recombination events on a chromosome (recall from your molecular biology class that at least one crossing-over must occur on each chromosome in meiosis I to guarantee proper segregation of the chromosomes). The actual location of the crossing-over may be determined by a number of factors, local sequence variation included. Perhaps this recombination-guaranteeing system, which itself is not part of the crossing-over, could resolve the paradox.