Thursday, February 15, 2007

Thrifty genotype, again and again   posted by p-ter @ 2/15/2007 05:17:00 PM

Speaking of the thrifty genotype hypothesis, a new paper from the cats at deCODE Genetics takes an in depth look at one of the loci consistently implicated in Type II diabetes. According to the authors, the succeptibility allele is ancestral, and the other, non-ancestral allele shows signs of being under recent positive selection in all the populations studied. Even more interestingly, the protective allele is associated with decreases in levels of circulating ghrelin (a hormone that increases appetite) and increases in levels of circulating leptin (a hormone that decreases appetite). This would seem, by my reckoning, to be consistent with the thrifty genotype hypothesis. In addition,
We obtained rough age estimates for HapA [the protective allele] based on its recombination history: 11,933, 8,401 and 4,051 years for the CEU, East Asian and YRI HapMap groups, respectively. Although tentative, these ages coincide broadly with the onset of agriculture in the three geographic regions represented by the HapMap groups.

On the other hand, the succeptibility allele is associated with decreased BMI after controlling for diabetic status, though I'm not sure that has any bearing on the hypothesis.

The authors conclude, bizarrely, "we note our findings contradict a key prediction of the thrifty-genotype hypothesis, insofar as HapBT2D, a major risk factor for type 2 diabetes, is negatively associated with BMI and is not the variant that contributed to adaptive evolution in the recent past."


I can only conclude, based on that statement, that the authors aren't really clear on what the thrifty genotype hypothesis is. The original Neel paper (which is cited in this paper, so the authors have hopefully read it) makes a few simple claims, the most important of which is that the "diabetic genotype" was favorable up until the transition from the hunter-gatherer lifestyle to agriculture. It certainly does not claim that a diabetes-causing allele should be under recent positive selection, nor am I sure how anyone could get that impression. I'm inclined to take the exact opposite conclusion from this paper than the authors--that is, this data seems to support, rather than contradict, a key prediction of the thrifty genotype hypothesis, insofar as the ancestral allele leads to succeptibility, and the derived allele, which arose at about the time of agriculture, mat be associated with reduced appetite.

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