Blond as a window to ancient pigmentation variation

Blond hair is relatively common in island Melanesia, even though the skin pigmentation of Melanesian peoples is relatively dark. Eimear Kenny and colleagues report in this week's Science that one SNP variant in the gene TYRP1 explains a high proportion of the variance in hair color in this population Kenny:blond:2012.

Resequencing of TYRP1 exons detected a single previously unknown polymorphism, a C-to-T transition at chr9:12,694,273 (GrCH37/hg19), that corresponds to a predicted arginine-to-cysteine mutation (R93C) in exon 2 of TYRP1 at amino acid position 93 (TT in blond- and CT or CC in dark-haired individuals)...[more on assessing effect in a GWA panel].
We genotyped R93C in 918 Solomon Islanders for whom we had measured hair pigmentation with spectrometry. A recessive model provided the best fit for the data, and R93C genotypes accounted for 46.4% of the variance in hair color (linear regression; P = 2.19 10?90; Fig. 1D and table S2). The frequency of the 93C allele in the Solomon Islands is 0.26, and genotyping of R93C in an additional 941 individuals from 52 worldwide populations revealed that the 93C allele is rare or absent outside of Oceania (table S3). Furthermore, we found no evidence for recent gene flow from Europe (i.e., admixture) (figs. S5 and S6) nor a strong signature of recent positive selection for the 93C allele (figs. S9 to S11).

This paper is very short, only a few paragraphs. When I read through it, I got one impression of the results, and that impression changed greatly when I looked into the supplement.

Some underreported facts:

  1. The blondness allele is present in all the samples from the Solomon Islands, at a frequency as high as 49% in a large sample from Malaita. In this study, the authors found it at its lowest frequency in "Polynesian outlier" islands near the Solomons.

  2. The allele was not found in any of the HGDP samples, even when they were genotyped specifically for this study. That includes the "Melanesian" and "Papuan" samples. These two are relatively small in HGDP (n=14 and n=16 in this study) but even so would probably present this allele were it present at anything like the frequency in the Solomon Islands.

  3. The text of the paper reports that a recessive effect model is the best explanation for the relation of hair pigmentation and TYRP1 genotypes. The supplement shows that the recessive model is only very slightly better than a "codominant" model, as it only explains an additional 3 percent of the variance. In the best case considering this allele along with age and geographic origin of the individuals, only 48% of the variation of hair pigmentation can be explained. That leaves 52% to be explained by other genetic and nongenetic causes. There may be a lot of genetic background, which may include more alleles of large effect.

  4. Skin pigmentation varies greatly among these Solomon Islands samples, with more than a third of the overall variance in skin pigmentation explained by geography. The tables don't make it clear how pigmentation is patterned by geography. The TYRP1 allele that is the subject of this paper does not explain much variation in skin pigmentation.

  5. Sex and age have strong effects on hair pigmentation in this sample, but not on skin pigmentation. Again, these point to background genetic factors. Many populations have sex and age effects on hair pigmentation, so some of the additional causal factors may be widely shared.

I began looking more deeply into TYRP1 R93C for a couple of reasons. The prehistory of human populations in the Solomon Islands goes back more than 30,000 years. Because this allele is not present in mainland Asian populations, as far as we know, but it is present thoughout the Solomons, suggests that it may have become common at or near the initial founding of this population. The LD pattern around the mutation likewise suggests that it has been segregating in this population for a long time. The data are consistent with the idea that blond phenotypes were present in the Solomon Islands as early as the initial colonists who founded the population.

It will be interesting to look further into nearby populations to see if it characterized early colonists more broadly. Blond phenotypes occur very commonly in Aboriginal Australians, also age-dependent in expression, as many children have blond hair that darkens with age. Other Melanesian islands, such as Vanuatu and Fiji, also have a high incidence of blondness. For the islands, I expect that the same allele will be responsible for a similar fraction of the variance. For Australia, I would guess that this allele is also present, but with 40,000 years of evolution, there could well be a more diverse genetic explanation.

Pigmentation variation in Eurasia is clearly a phenotype that has been affected both by recent positive selection and selection on old, standing genetic variants. Europe and East Asia today each have a dozen or more alleles that individually have strong effects on skin, hair, or eye pigmentation. Many of the alleles common in one region are rare in the other. These are well explained by recent selection on pigmentation; if there had been no selection on pigmentation, the populations would not show as extensive a pattern of differences, and new alleles would not have reached high frequencies. But if we had only a single mutation at 30 percent distinguishing one of these populations, which had arisen as early as 30,000 years ago, we would not have a strong case for selection.

In Melanesia, we have just the opening sketch of pigmentation variation. We know that there is substantial variation in skin and hair pigmentation, and that one mutation unique to this part of the world explains a large fraction (but still a minority) of the variance in hair pigment. The other genes that contribute to variation in hair and skin pigmentation are not known. Possibly, skin pigmentation variation among the geographic regions in this study may reflect late prehistoric migration of people through this region, as agriculture moved into the area and Polynesia was settled. But the genetic part of this story remains to be demonstrated.

Both Asia and Europe have a similar pattern of selection which has favored new alleles along with some old, standing alleles. Across the temperate regions of Europe, East Asia, and the Americas, it is plausible that the disadvantages of dark pigment for vitamin D production manifested themselves. It is also plausible across these regions that the advantages of dark pigment as protection from UV radiation would have been relaxed, allowing sexual selection on pigmentation to play an important role.

The evidence here suggests that this allele in Melanesia has not been recently selected from a new mutation. Additionally weighing against recent selection is the observation that the mutation acts recessively on hair pigmentation -- recent selection is much more likely for mutations with dominant or additive effects.

Together, these observations suggest that variation in human pigmentation emerged in stages. Some genes, such as ASIP, have old alleles that explain some of the variation in pigmentation today and are geographically ubiquitous, in Africa, Eurasia, and the Americas. This genetic variation was older than the Late Pleistocene. Such genes (ASIP is probably an example) today have alleles associated with darker pigment that are common in sub-Saharan Africa. Probably many other genes have variation within Africa that are part of the ancestral pigment variation of humanity. As people dispersed throughout the world, mixing with archaic humans, they carried some of these pigmentation variants along with them.

What's interesting is that even though some of these ancient alleles lighten skin pigmentation, they remain segregating in today's light-pigmented populations. They were not selected to fixation, even though there was plenty of time for them to increase toward fixation, and even though strong selection on pigmentation appears to have been present in many high-latitude populations. Later mutations that lighten pigmentation were strongly selected in these same populations, some reaching very high frequencies, while the old mutations still were not selected to fixation.

The story is of course more complex than a simple count of standing and new mutations. Some genetic changes that lighten pigmentation may have countervailing negative effects. Solving the problem of becoming light pigmented in just the right way may really be a different problem in different populations. Founder effects may have shifted the genetic background of early Eurasian populations just enough to create strong path-dependence for later mutations, allowing some to proceed rapidly and blocking the rise of others.

The story of TYRP1 gives a new perspective on the early evolution of pigmentation outside Africa. Here is a novel allele that originated within the earliest colonists to Oceania, which affects hair pigmentation strongly, in a population that was always low-latitude. It did not come from earlier archaic humans as far as we know so far (not in the Denisova genome). It may have become common by a founder effect. We cannot rule out selection, such as social or sexual selection, as a cause of its initial spread or current geographic distribution, but we have no genetic evidence in favor of such selection. We know from the data that there must be many other loci that affect pigmentation in this population.

This may have been much like the original pigmentation genetics of early modern human populations. It may also be much like the pattern that accounts for pigmentation variation within Africa today. It is not a simple story in which a few loci of large effect explain the evolutionary pattern. It is a story in which a substantial store of segregating variation persists within populations for tens of thousands of years.

Why does that matter? Here's one reason: We're looking at possible pigmentation variants in archaic humans, and we have counted many of them. Anyone might begin this project with the presumption that Neandertals and Denisovans had pigmentation variants that were fixed relative to living people. In that context, it would be surprising to find that they had not introgressed.

But if all these ancient populations had a large store of small-effect variants affecting pigmentation, a mutation that we find in one individual might have been rare in the population. The TYRP1 R93C allele varies from 5 to 50 percent in the Solomon Islands samples. We already know that the MC1R coding variant in some Neandertals is not found in the Vindija genomes. Variation in pigmentation loci may have been ubiquitous in human populations, with few fixed alleles separating populations. The ancient landscape was more like ASIP than SLC24A5.