OCA2 makes East Asians white and Europeans blue

Over the history of this weblog I have blogged about pigmentation a fair amount. The major reason is that that's where the money is; unlike height, let alone intelligence, the genetic architecture and evolutionary history of pigmentation has been elucidated with relative clarity. That is, we know roughly the number and nature of the genes which control much of the between population variation in pigmentation. And, we also have some sense of whether the variation is due to natural selection, as well the historical trajectory of the between population differences.

For example, consider the HERC2-OCA2 region of the genome in West Eurasians. It is responsibe for ~75% of the variation in blue vs. non-blue eye color. It also seems to be responsible for some variation in skin complexion. This makes sense, as one would presume that different pigmentation related phenotypes would be controlled by the same set of genes. Finally, the genomic region is characterized by a very long haplotype, which might be an indication of rather recent natural selection driving one variant to high frequency. More plainly, it seems probable that the genetic variants around HERC2-OCA2 which are correlated with light eye colors rose to high frequency with the last 10,000 years or so.

A major reason we have such clarity on these issues is that only a handful of genes seem to be responsible for most of the between-population variation in pigmentation. This was expected from older studies using classical genetic techniques, see The Genetics of Human Populations. But theory is one thing, science has a way of upsetting expectations. This is one case where new techniques have solidified and fleshed out the inferences of the old. But there is a twist in the simple story, though there seems to be only one way that humans are dark in regards to genetic architecture, there are at least two ways to be pale. More precisely West Eurasians and East Eurasians seem to have developed lighter complexions by different genetic pathways in relatively recent evolutionary time. As an example, the derived variant of SLC24A5 is present at very high frequencies across West Eurasia, and is responsible for 20-40% of the difference in complexion between Europeans and Africans, and around 35% of the variation in complexion among South Asians. But, Africans and East Asians have the ancestral variant. Obviously Africans and East Asians have very different complexions, so there must be other variants which East Asians carry which have not been detected.

Though genome-wide analyses have pinpointed many genes implicated in pigmentation pathways as having been targets of selection in East Asians there have been relatively few association studies which see if those genes actually correlate with pigmentation with East Asian populations. Today PLoS Genetics published a paper which does just that, Association of the OCA2 Polymorphism His615Arg with Melanin Content in East Asian Populations: Further Evidence of Convergent Evolution of Skin Pigmentation:

The last decade has witnessed important advances in our understanding of the genetics of pigmentation in European populations, but very little is known about the genes involved in skin pigmentation variation in East Asian populations. Here, we present the results of a study evaluating the association of 10 Single Nucleotide Polymorphisms (SNPs) located within 5 pigmentation candidate genes (OCA2, DCT, ADAM17, ADAMTS20, and TYRP1) with skin pigmentation measured quantitatively in a sample of individuals of East Asian ancestry living in Canada. We show that the non-synonymous polymorphism rs1800414 (His615Arg) located within the OCA2 gene is significantly associated with skin pigmentation in this sample. We replicated this result in an independent sample of Chinese individuals of Han ancestry. This polymorphism is characterized by a derived allele that is present at a high frequency in East Asian populations, but is absent in other population groups. In both samples, individuals with the derived G allele, which codes for the amino acid arginine, show lower melanin levels than those with the ancestral A allele, which codes for the amino acid histidine. An analysis of this non-synonymous polymorphism using several programs to predict potential functional effects provides additional support for the role of this SNP in skin pigmentation variation in East Asian populations. Our results are consistent with previous research indicating that evolution to lightly-pigmented skin occurred, at least in part, independently in Europe and East Asia.

Their method here was simple, they focused on pigmentation genes which have given positive signals in tests of natural selection, and ran an association analysis. The sample size was small, on the order of the low hundreds, and they had individuals from the core East Asian nations as well as some Indochinese.

Here is the effect of OCA2 SNP in question (substitutions of the derived from left to right):

The effect is roughly "co-dominant," each substitution of the G allele, which is ancestral, with the A allele, which is derived, has a significant lightening effect on the phenotype. The heterozygote is 1.6 melanin units lighter than GG, and the AA is 2.6 melanin units lighter than GG. For comparison, in African Americans (who are admixed between West Africans and Europeans) for SLC24A5 GG versus AG and GG versus AA genotypes were separated by about 7 and 9.5 melanin units, respectively. While SLC24A5 can explain 20-40% of the variance between Europeans and Africans, this SNP on OCA2 can explain only 10% of the variance within East Asians.

Here is the conclusion of their discussion:

Our study provides new evidence regarding the genetic and evolutionary processes driving the lightening of skin following the migration of anatomically modern humans from Africa to high latitude regions in Europe and East Asia. Evidence is growing that the reduction in melanin content took place, at least in part, independently in these two regions. We now know that the evolution of skin pigmentation has been quite complex: some genes were the target of positive selection only in one population group (eg. SLC24A5 and SLC45A2 in Europe), whereas other genes were under selection independently in more than one group (eg. OCA2 in Europe and East Asia). However, there are still many aspects of the evolution of skin pigmentation that remain unclear. Our picture of the genetics of normal pigmentation variation in non-European populations is still incomplete, and the evolutionary time frame remains to be elucidated. When did the evolution to light skin take place in Europe and East Asia? It has been suggested, based on evidence collected for the SLC24A5 gene, that the evolution to light skin occurred in Europe long after the arrival of anatomically modern humans to this continent...but it will be necessary to collect information on additional genes and from different geographic regions to gain a better understanding of the evolution of skin pigmentation in human populations.

It is not surprising that there is an SNP within OCA2 associated with pigment variation. A lot of the genes implicated in population X are often implicated in population Y (e.g., SLC24A5 is a cross-West Eurasian gene in terms of its effect on skin color). In fact, many genes implicated in species X and often implicated in species Y (SLC24A5 started out in a fish model). OCA2 and its flanking genes have a lot to do with pigmentation in Europeans, so that should increase the probability that might do the same in East Asians. Additionally, doing simple comparisons of between population differences in allele frequencies on OCA2 shows large differences between light and dark skinned groups generally. Finally, I suspected that much of the action was going to be on different alleles/SNPs on the same small set of genes. Though most of the genes implicated in skin lightened are roughly additive/co-dominant in effect, that is, heterozygotes have a phenotype between the two homozygotes, there tends to be a "light" allele partial dominance on some of these genes. I'm thinking here especially of KITLG and SLC24A5. If East Asians and Europeans had genetic differences on all their skin lightening genes, and there was some dominance in effect of these alleles, then Eurasians should be quite ghostly indeed! To my knowledge this isn't what's occurring. If the alleles are on the same genes, even if they're of different allele variants their effect is the same and they can't both be partially dominant. Of course I wouldn't put great stock in the architecture I'm assuming here, especially since I'm a bit perplexed how loss of function mutations would have a dominant effect on melanin index (molecular geneticists step forward!). But for what it's worth, you see the same effect with this SNP in OCA2, diminishing returns in the AA homozygote.

Citation: Edwards M, Bigham A, Tan J, Li S, Gozdzik A, et al. 2010 Association of the OCA2 Polymorphism His615Arg with Melanin Content in East Asian Populations: Further Evidence of Convergent Evolution of Skin Pigmentation. PLoS Genet 6(3): e1000867. doi:10.1371/journal.pgen.1000867