About a year and a half ago at ASHG, I had a discussion with Dan Ju and Iain Mathieson about their work on ancient pigmentation. Or, more precisely, ancient pigmentation related genes. Now it’s out in a preprint, The evolution of skin pigmentation associated variation in West Eurasia:

…It is unclear whether selection has operated on all the genetic variation associated with skin pigmentation as opposed to just a small number of large-effect variants. Here, we address this question using ancient DNA from 1158 individuals from West Eurasia covering a period of 40,000 years combined with genome-wide association summary statistics from the UK Biobank. We find a robust signal of directional selection in ancient West Eurasians on skin pigmentation variants ascertained in the UK Biobank, but find this signal is driven mostly by a limited number of large-effect variants. Consistent with this observation, we find that a polygenic selection test in present-day populations fails to detect selection with the full set of variants; rather, only the top five show strong evidence of selection. Our data allow us to disentangle the effects of admixture and selection. Most notably, a large-effect variant at SLC24A5 was introduced to Europe by migrations of Neolithic farming populations but continued to be under selection post-admixture. This study shows that the response to selection for light skin pigmentation in West Eurasia was driven by a relatively small proportion of the variants that are associated with present-day phenotypic variation.

There are a lot of moving parts in this preprint. Look closely, and you will notice that the authors are careful to stipulate that they can’t really infer the pigmentation of ancient peoples, only the alleles ascertained in modern populations. This matters, because naive deployments of polygenic risk score models trained on modern populations projected on ancient ones seem highly suspect. I’m thinking here mostly of the “Cheddar Man is black” meme. It is true that using modern SNP batteries Mesolithic Europeans are predicted to be rather dark-skinned, but higher latitude humans tend to be paler, on average, than lower latitude humans (albeit, not as pale as the typical Northern European!). But, we can be sure about the alleles we do know about, and, their likely effect (the functional understanding of these pathways is pretty good).

The best modern genetic analyses of pigmentation suggest that variation is dominated by some large-effect loci, but that there is a large residual of smaller-effect loci segregating within the population (I’ve seen 50% accounted for with SNPs, and 50% as “ancestry”, which really masks small-effect QTLs). This is in contrast with the architecture in height, where there are few large-effect loci, and almost all of the variance is small-effect loci. What Ju et al. confirm is that selection “for pigmentation” is due to the large-effect loci; there’s no polygenic selection detectable on the smaller-effect loci for the ancient populations. Importantly, the change in allele frequency isn’t just due to admixture. It’s also due to selection after admixture.

I use quotes above because honestly, I think these sorts of results make it unclear what the selection was for. The general prior is conditioned on the fact that even after a few decades we still think of EDAR as a hair-thickness gene, but it’s one of the strongest signals of selection in the human genome. The “light” allele in SLC24A5 is at an incredibly high frequency in Europe today, and has increased in the last 4,000 years. Though this SNP is impactful for the complexion, it’s hard to imagine how strong selection must be to drive it from 95% to 99.5% (as per 2005 paper on this SNP, the “light” allele exhibits some phenotypic dominance).

As noted in the preprint, there’s not enough data on other regions of the world. It’s hard to assess what’s going on Europe without assessing other regions. The authors do present an intriguing suggestion: that lighter pigmentation in East Asia is driven by smaller-effect genes shifted through polygenic selection.

I’ll present a strange hypothesis: selection for lighter skin at high latitudes through polygenic selection on standing variation naturally takes populations to the coloring of Northeast Asians. But very light complexion, as you see in Northern Europe, could be due to strong selection on the large-effect pigmentation genes, and pigmentation itself may simply be a side effect due to a genetic correlation with the true target of selection.