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Wednesday, August 18, 2010

Signs of positive selection favoring disease risk genes

It is very much counterintuitive but that is what Stanford University researchers conclude after looking at the evidence.

Erik Corona et al., Extreme Evolutionary Disparities Seen in Positive Selection across Seven Complex Diseases. PLoS ONE 2010. Open access.


Positive selection is known to occur when the environment that an organism inhabits is suddenly altered, as is the case across recent human history. Genome-wide association studies (GWASs) have successfully illuminated disease-associated variation. However, whether human evolution is heading towards or away from disease susceptibility in general remains an open question. The genetic-basis of common complex disease may partially be caused by positive selection events, which simultaneously increased fitness and susceptibility to disease. We analyze seven diseases studied by the Wellcome Trust Case Control Consortium to compare evidence for selection at every locus associated with disease. We take a large set of the most strongly associated SNPs in each GWA study in order to capture more hidden associations at the cost of introducing false positives into our analysis. We then search for signs of positive selection in this inclusive set of SNPs. There are striking differences between the seven studied diseases. We find alleles increasing susceptibility to Type 1 Diabetes (T1D), Rheumatoid Arthritis (RA), and Crohn's Disease CD) underwent recent positive selection. There is more selection in alleles increasing, rather than decreasing, susceptibility to T1D. In the 80 SNPs most associated with T1D (p-value less than 7.01×10−5) showing strong signs of positive selection, 58 alleles associated with disease susceptibility show signs of positive selection, while only 22 associated with disease protection show signs of positive selection. Alleles increasing susceptibility to RA are under selection as well. In contrast, selection in SNPs associated with CD favors protective alleles. These results inform the current understanding of disease etiology, shed light on potential benefits associated with the genetic-basis of disease, and aid in the efforts to identify causal genetic factors underlying complex disease.

Maybe the best understood case is that of rheumatoid arthritis, which, following the archaeological record, seems to have only manifested in west central Kentucky (USA) some 6500 years ago, slowly extending to other parts of North America (West Ohio some 1000 years ago) and then scattering worldwide after colonization. In contrast the alleles that favor the disease are much older everywhere and seem to work well against tuberculosis (TB). So it would be a clearly favorable allele (protecting against TB) until whatever (not yet known) pathogen or allergenic that triggers RA spread from the Ohio basin.

So now RA susceptibility alleles have become deleterious in those areas where TB is not anymore a problem but, until a few centuries ago, they were only being selected for, because there was no exogenous trigger for RA outside of the Ohio basin and instead they protected from tuberculosis.

A good example of how fitness value is therefore not absolute but contextual.

There are also some indications that T1D susceptibility alleles may be implied in defense against enteroviruses, which cause some pretty bad diseases such as poliomyelitis and meningitis.

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