Complex evolution of pigmentation in modern humans

Last fall Crawford  et al., Loci associated with skin pigmentation identified in African populations, was published in Science and made a huge splash. As I’ve been saying recently, and most people agree, much of the remaining “low hanging fruit” in human evolutionary genomics, and to some extent, human medical genetics, is going to be in Africa on Africans. From an evolutionary perspective, that’s probably because from a gene-centric viewpoint most of our recent evolutionary history was within Africa. As a friend once told me, “most of the last 200,000 years is about the collapse of ancient population structure.” This goes too far, but at least it gets at something we’ve not been too conscious of.

Crawford  et al. was important because it was a deep dive into a topic which has been understudied, the variation of pigmentation genetics within Africa (also see Martin et al.). The fact that there is variation in pigmentation within Africa should not be surprising, though some people are surprised that there is variation in pigmentation within Sub-Saharan Africa. But anyone who has seen photos of San Bushmen, knows they are very distinct from South Sudanese, who are very distinct from West Africans. As documented by both Crawford  et al. and Martin et al. some of this variation is likely novel.

By this, I mean there has been backflow of the derived Eurasian variant of a mutation on SLC24A5. Arguably the first major human pigmentation locus of the “post-genomic era”, its discovery was enabled by its huge effect in explaining variation among Eurasian populations and their differences from African groups. In Crawford  et al. the author observes within Africans nearly ~30% of the trait variance was due to four loci, with ~13% due to SLC24A5. In earlier work comparing just people of European and African descent, SLC24A5 variance explains closer to 30% of the pigmentation difference. It seems that pigmentation effects genetically exhibit an exponential distribution. A small number of loci have a large effect, and a numerous number of loci have small effects.

The results from Crawford  et al. and Martin et al., a naive inspection of the modern distribution of the derived rs1426654 allele, and ancient DNA, seem to indicate a mutation associated with lighter skin emerged after 40,000 years ago. After the expansion of non-African humans, and, the divergence between eastern and non-eastern branches of non-Africans. A common haplotype around this mutation suggests that it wasn’t part of the ancestral “standing variation” of the human lineage. Ancient samples from Scandinavia, the Caucasus, and modern samples from Eurasia and from Africa, all exhibit the same pattern, suggesting recent common descent.

And though a mutation on rs1426654 is associated with lighter skin, it does not produce white skin. I have the homozygote derived genotype on rs1426654, as does my whole nearby pedigree. All of us have brown skin, to varying degrees. And interestingly, the locus around rs1426654 seems to be under strong selection in both South Asia and Africa, including East Africa. This makes me somewhat skeptical that there is a simple story to tell on this locus in relation to skin pigmentation being the driver here.

Let me quote from  Crawford  et al.:

Most alleles associated with light and dark pigmentation in our dataset are estimated to have originated prior to the origin of modern humans ~300 ky ago (26). In contrast to the lack of variation at MC1R, which is under purifying selection in Africa (61), our results indicate that both light and dark alleles at MFSD12, DDB1, OCA2, and HERC2 have been segregating in the hominin lineage for hundreds of thousands of years (Fig. 4). Further, the ancestral allele is associated with light pigmentation in approximately half of the predicted causal SNPs…These observations are consistent with the hypothesis that darker pigmentation is a derived trait that originated in the genus Homo within the past ~2 million years after human ancestors lost most of their protective body hair, though these ancestral hominins may have been moderately, rather than darkly, pigmented (63, 64). Moreover, it appears that both light and dark pigmentation has continued to evolve over hominid history….

For over ten years it has been clear that very light skin in eastern and western Eurasia are due to different mutational events. Crawford  et al. give us results that indicate this pattern of evolutionary complexity is primal and ancient.

But there is often a tacit understanding that the selection process is the same over time and space. Something to do with protection from UV light and also synthesization of vitamin D at higher latitudes. So this paper that just came out definitely piqued my interest, Darwinian Positive Selection on the Pleiotropic Effects of KITLG Explain Skin Pigmentation and Winter Temperature Adaptation in Eurasians. The authors looked at a lot of variants in KITLG with a focus on East Asians. They confirmed that there were at least two selection events, one just around the “Out of Africa” period, and possibly another one later, during a period when West and East Eurasians were genetically distinct.

This section is very intriguing: “Besides pigmentation, KITLG is also involved in mitochondrial function and energy expenditure in brown adipose tissue under cold condition (Nishio et al. 2012; Huang et al. 2014). We demonstrated that winter temperature showed a much stronger correlation than UV for rs4073022.” Earlier the authors review work which suggests that large melanocytes are much more susceptible to damage due to cold than than smaller ones. Dark-skinned individuals tend to have large melanocytes (and more of them!). The KITLG locus does a lot of things; some of you may know its relationship to testicular cancer.

What  Crawford  et al. tells us that there seems to have been recurrent and sometimes balancing selection around loci implicated in pigmentation for hundreds of thousands of years. What ancient DNA is telling us is that the genetic architectures we take for granted as typical across much of Eurasia are relatively novel. But, I think people are perhaps taking the implications of modern genetic architecture too far in predicting the variation of characteristics in the past. Even the best genomic predictors seem to account for only around half the variance in pigmentation. “Ancestry” accounts for the rest, which basically means there are many other loci which are not accounted for. It is not unreasonable to suppose that ancient northern Eurasian populations may have been light-skinned due to genetic variants which we are not aware of.

Of course, there are people at high latitudes who retain darker complexions. From what we know the Aboriginal people of Tasmania were isolated for about 10,000 years at the same latitude as Beijing and Barcelona, and yet their skin color remained dark brown. In contrast, Martin et al. report that Khoisan people who lived 10 degrees further north, in a much sunnier climate, were selected at loci that strongly correlate with lighter skin.

I think it is safe to say that in the near future we will close in on much of the reamining genetic factor accounting for variation in pigmentation in modern populations. It is polygenic, but almost certainly far less polygenic and more tractable than height or intelligence. But the story of why humans have varied so much over time, and why loci implicated in pigmentation are so often targets of selection in some many contexts, remains to be told.