August 15, 2012

Positive selection for arthritis and short-size alleles in Eurasia?

That is what a new paper suggests for two SNPs whose derived allele is very common outside Africa and non-existent in Africa.

Dong-Dong Wu et al., Positive Selection on the Osteoarthritis-Risk and Decreased-Height Associated Variants at the GDF5 Gene in East Asians. PLoS ONE, 2012. Open access ··> LINK [doi:10.1371/journal.pone.0042553]


GDF5 is a member of the bone morphogenetic protein (BMP) gene family, and plays an important role in the development of the skeletal system. Variants of the gene are associated with osteoarthritis and height in some human populations. Here, we resequenced the gene in individuals from four geographically separated human populations, and found that the evolution of the promoter region deviated from neutral expectations, with the sequence evolution driven by positive selection in the East Asian population, especially the haplotypes carrying the derived alleles of 5′ UTR SNPs rs143384 and rs143383. The derived alleles of rs143384 and rs143383, which are associated with a risk of osteoarthritis and decreased height, have high frequencies in non-Africans and show strong extended haplotype homozygosity and high population differentiation in East Asian. It is concluded that positive selection has driven the rapid evolution of the two osteoarthritis osteoarthritis-risk and decreased height associated variants of the human GDF5 gene, and supports the suggestion that the reduction in body size during the terminal Pleistocene and Holocene period might have been an adaptive process influenced by genetic factors.

Figure 3. World-wide allele frequency distribution of the two SNPs rs143384 and rs143383.

Besides any possible selective pressure, a quick look at both maps shows that there is nearly total linkage disequilibrium among these two loci of chromosome 20. Finding a difference between both maps is practically impossible.

The second allele, rs143383(T), is particularly notorious for its correlation with osteoarthritis (+30% risk with the homozygous variant, +10% risk with the heterozygous one). Interactively with other SNPs, it may also affect height. The other one, rs143384(T) also shows some (epigenetically modified) association with osteoarthritis and congenital hip dislocation. 

Notice please that the use of G/A or C/T nomenclature is arbitrary because each G has a C pair at the other side of the double helix and each A a T one. This can be confusing for the occasional reader however.

The authors think that these two alleles should never have reached such high frequencies in such a short time (c. 100,000 years since the OoA) unless they were subject to marked positive selection. 

However I can only imagine that the opposite is equally possible: that the derived alleles once existed but have been eradicated in Africa because of negative selection but have remained common in Eurasia because of a bad founder effect which only gradually is being eroded. If nothing else, food for thought.

The authors also suggest that this positive selection factor might have been reduction in body size for which the cite a couple of papers (Ruff 2002 and Hawks 2011) which actually fail to determine such claim. The first one actually deals with bone robustness, not length and therefore not height, the latter is about endocranial size, which may be related to intelligence but not too directly to height. 

It seems clear that, on average, we are plausibly dumber, weaker and more androgynous than our Paleolithic ancestors but not that we are shorter in fact. 

So, allow me please to remain healthily skeptic, even if the data presented in this paper is interesting in its own right; even though the interpretative proposal of the authors is plausible we must keep open other possibilities, specially as we do not know yet what such a conjectured selective pressure may have been (arthritis offers no obvious advantages, mind you). 

Notably a bad founder effect phenomenon should be considered or, also the similar possibility of this allele offering its positive side only in combination with another deleterious variant, in one of those exceptional cases in which two wrongs make one right. This could be more easily be determined if we knew more of the genetics of Homo sapiens in the Paleoithic.


  1. I'd always assumed without thinking that evolution would prefer height (because women seemed to prefer taller men) but evolution preferring shortness does make sense from a calorie point of view.

  2. My first thought is that the gene may be a generalized connective tissue gene and that it provides benefit perhaps in brain function or some other adaptive domain.

    Also the harm associated with the condition tends to be late in life after one has reproduced. It could be that the benefit of the gene is that it cleared out "dead weight" old people from the tribe allowing the community as a whole to devote more resources to those who remained.


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