What drives accelerated molecular evolution?
In the paper describing the discovery of Human Accelerated Region 1 (HAR1), an RNA gene expressed in the brain and apparently under selection along the human lineage, the authors allude to the method they used to identify this region of the genome. The paper describing what they did in more detail is in revision at PLoS Genetics and is thus freely available.
Their basic approach was to find regions of the genome that were highly conserved throughout most of vertebrate evolution, but particulaly divergent in humans. To do this, they first aligned the chimp, mouse, and rat genomes to find highly conserved regions. They then looked at the genomes of 17 other species (including humans) and compare two phylogenetic models for each of the conserved blocks– a model where the substutution rate is held constant to a model where an additional parameter for the human substitution rate is added. If the two models are significantly different, then voila, humans have experienced faster molecular evolution in that area.
They eventually come up with 202 interesting regions of the genome this way. The most impressive one they follow up a bit, as described previously. The regions they find are primarily non-coding, and located near genes involved in transcription and DNA binding. As is warranted, they give a nod to King and Wilson.
But have these areas really been under natural selection? One thing they note is that the substitutions they find are disproportionately AT–>GC mutations, and are located predominantly in areas with high recombination. Could the these substitutions simply be a neutral byproduct of the amount of recombination in these areas?
It’s certainly possible, but one possibility, raised by a professor of mine, is that recombination hotspots aid the efficacy of natural selection. That is, in order for a number of benefecial mutations (which have arisen on different backgrounds) to sweep to selection with any efficiency, they must be on the same haplotype. The only way for two benefical mutations on different haplotypes to end up together? Recombination. So perhaps the presence of HARs in regions of high recombination is not an argument for their neutrality, but rather a hint as to the mechanisms that allow for strong positive selection on a region.
The first time I read your last paragraph, I thought Hill-Robertson meets epistasis. Then I realized you weren’t saying anything about epistasis. But the function of non-translated RNAs are heavily influenced by secondary structure, which is greatly determined by sequence. This could be something . . . or maybe I’m just talking out my ass.
good point, and something I hadn’t though of. for sequences that form watson-crick pairing, two substitutions would have to arise for the most stable new structure to arise. that sounds like epistasis to me, and increased recombination could promote that. I hadn’t seen this paper before, but it seems relevant:
http://www.genetics.org/cgi/content/abstract/173/3/1793
but here we’re talking about recombination on an extremely small scale
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?
do we know enough about recombination hot spots to say if they are heritable
hm. what are the chances that over the past hundreds of millions of years (nearly a billion right?) that diploid organisms haven’t found a way to rig mutational hotspots in way that might increase their fitness??? (if it could increase their fitness) i guess what i’m getting at is that is the propensity toward hotspots structurally fixed in a metabolically/biophysically manner…like presumably cellulose metabolization….
do we know enough about recombination hot spots to say if they are heritable?
hotspots aren’t conserved between humans and chimps, as far as one can tell. evidence suggests they evolve rapidly. is activity at a certain hotspot heritable to some degree? probably, but it’s impossible to tell (measuring the activity of a hotspot in men is plausible, as they make a ton of sperm to type, but in women you can’t really look at the meiotic products to measure recombination). so the closest thing to that is jefferies et al. and their sperm studies.
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. These findings suggest a role for distal regulators or epigenetic factors in hotspot activity and provide the first direct evidence for the rapid evolution of recombination hotspots in humans