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.
@Razib: Do you have any speculative idea? Something concrete about the true target?
Also, I think its remarkable that the lactase persistence variant rose to higher frequency somewhat parallel to very light pigmentation.
Could it be that e.g. Northern Chinese had a different strategy to deal with vitamin D deficiency than Northern Europeans? Something about their skin, their digestion, their nutrition?
How is vitamin D deficiency in Northern China?
I found this study on that matter:
“Furthermore, differences in population genetics can play a part in vitamin D synthesis and metabolism47. Studies have found that group-specific component gene (GC) polymorphisms were associated with 25(OH)D levels, and allele frequencies were different among geographic regions worldwide48. For example, the GC1S haplotype which is related to a higher level of 25(OH)D is found to have the maximum frequency in white population, while the GC1F haplotype which is associated with lower vitamin D-binding protein levels, is more likely to be carried by Asians49.”
https://www.nature.com/articles/s41598-019-56297-y
So Northern Europeans seem to have been, on every level, selected for a low vitamin D producing environment and lifestyle in my opinion. Even the lactase persistence points in the same direction.
I like simple arguments and you allude to a simple argument that is underappreciated. The breeder’s equation says that a dominant allele will not rise to fixation and that a new mutation of a recessive mutation will not grow. If they do, they must not really be dominant/recessive, but must have some other effect that is (also) a target of selection, but has different dominance.
It’s good to get confirmation from papers like these, but we should have already known this from the simple argument. I first heard this from Greg Cochran in the recessive case: What do blue eyes do?
domestication syndrome?
Nice to see the results of this after seeing a few abstracts here and there.
Razib: I’ve seen 50% accounted for with SNPs, and 50% as “ancestry”, which really masks small-effect QTLs. Yeah, I’ve seen the same – I wonder how this is compatible with an absence of trend of selection on small QTL lighter pigmentation alleles in the West Eurasian populations here. Drift? Seems like that shouldn’t have a directional tendency?
Re; greater polygenic basis in East Asian than West Eurasians (authors raise as a possibility; unsure if your thinking is Europeans = same polygenic as East Asians+extra large effect alleles?). Seems like that would predict differences in intra population variation patterns in Europeans, East Asians and European-East Asian mixed populations.
Europeans should have highest SD (as some individuals will have all “light” major variants, some none). Unless they won’t if they’ve reached homozygosity for most variants. East Asians lower SD. Hybrid individuals should then have variable pigmentation (more variable than Europeans if Europeans are homozygous). Central limit theorem?
From what I know, Martin and Henn’s paper that did a meta-analysis of within population SD of pigmentation didn’t find anything like this – https://www.sciencedirect.com/science/article/pii/S0092867417313247#fig1. More like lower latitude populations having higher SD.
Or am I thinking about this the wrong way, and there’s no obvious connection between how polygenic selection has been, and within population pigmentation SD? 5 major variants is indistinguishable in SD from 500, somehow?
On the topic of the score over time, for all the caveats about not being able predict ancient samples phenotype (though IMO this applies much more strongly to HG at 16kya for’ex, than steppe people at 5kya who contributed to people), the result from Fig 1 suggests that the Steppe ancestry group and EEF group were more similar to each other than they were to EUR today. Normalizing the 170 Biobank SNPs, where AFR = 1, EUR = 0, then EEF5000YBP= 0.4 and Steppe5000YBP = 0.32 (SAS, South Asian 1000 Genomes = 0.67). With same with the manually curated 10 SNPs (unweighted), EEF5000YBP = 0.24, Steppe5000YBP = 0.17 (SAS, South Asian 1000 Genomes = 0.52).
Like long bones suggest in height, despite some difference, they may have been more similar to each other than we would think from extrapolations of populations with different still existing maximums of each ancestry today. (When I looked at Rosenstock’s paper from last year – https://link.springer.com/article/10.1007/s12520-019-00850-3, it showed that bones suggests about 2-3cm> I think in height, comparing PC steppe, region K, to Central European EEF, region E.)
Hasn’t lactase persistence also been selected for in the Indus Valley? I saw some maps indicating Southern European like frequencies of LCT 13910? I also remember seeing on some old forums that LCT 22018 is more common in Central/South Asia which might indicate why almost every South Asian I’ve encountered has no problems drinking milk.
Also does anybody know the frequencies of the derived alleles for light skin, light eyes and light hair in Central and South Asia?
I have been a nuance in the past. Because I miss read your motives. I enjoy your detailed, intelligent, objective to topics. Anyways…..
When talking about origins of skin color in West Eurasia, one has to mention the anomaly of Caucasus pops. They are basically white skinned even though they don’t have recent common ancestry with Europeans.
In my opinon What they tell us is “white skin” in West Eurasia is not just a European thing. And that white skin may have been the norm in the prehistoric Caucasus and European Steppe. Maybe Mesolithic pops in Russia, Ukraine, Caucasus had mainly white skin.
Georgian people.
https://www.tapatalk.com/groups/anthroscape/georgian-people-t61983.html
Northeast Caucasus people (Dagestan).
https://www.tapatalk.com/groups/anthroscape/faces-of-the-north-caucasus-t61829.html
I have studied a lot on the origins of Middle East using Eurogenes G25 PCA.
As far as I can see, Caucasus variation can be split into Northeast and Northwest Caucasus. Here’s the basics of their ancestry.
West Caucasus: 60-70% Maykop, 0-20% Central Asian, 0-15% Russian (Slavic), 0-20% excess Anatolian farmer.
East Caucasus: 37% Maykop, 25% Kura-Araxes, 38% Yamnaya.
*Kura Araxes is 50% Maykop+35% Iran Chl+15% AnatoliaNeo.
West Caucasians are basically 100% Middle Eastern, excluding the ones who have Central Asian or Russian admix. And yet, they basically have white skin.
More pale skin in Caucasus than in roughly similar pops from the Middle East, can be maybe explained by the fact Caucasians have been insulated from Middle East geneflow since at least 3000 BC and probably since 5000 BC.
East Caucasians have lots of Yamnaya ancestry. They’re roughly 38% Yamnaya. They lack European farmer anecsrty, which means they must have received their Yamnaya ancestry before 1500 BC which is when Srubnaya took over East European Steppe (spreading European farmer ancestry with them).
I think the skin color of modern Caucasus pops, suggest pops living in and around the Caucasua have had pretty white skin for a long time. Mesolithic CHG and EHG in Mesolithic may have been pretty white skinned. And I think Yamnaya almost certainly was “white.”
You’ve said Yamnaya probably had skin color similar to modern Sardinians. This makes sense when purely looking at SNP allele frequencies. But, we have to consider Sadinians aren’t related to Yamnaya in any meaningful way. Caucasus pops are related to Yamnaya in a meaningful way. As are mainstream Europeans. Both group shave more or less white skin.
The natural selection in pigmentation in Europe which we see from 2500-1000 BC, is mainly about hair color not skin color. It explains the origins of lots of blonde hair in Europe. But it doesn’t explain the origins of white skin.
I mean if you think, it does seem like a stretch to say most of European’s ancestors as recently as 3000 BC had intermediate skin color (mixture of brown and white).
In my opinon, Steppe pops were already “white” in 4000-3000 BC (like I said maybe since the Mesolithic). European farmer pops probably had intermediate skin color like modern Sardinians do. But Sardinians are more white than brown.
The natural selection in pigmentation in Europe which we see from 2500-1000 BC, is mainly about hair color not skin color.
why hair? i.e., what evidence from the loci?
please note that the SDS method detects pigmentation selection down to the medieval period in England! (where the data is best)
In an old study the loci for hair and skin variation were correlated. Anything about that? In Europeans people with blond hair and blue eyes, but with darker skin, are really, really, exceptional and mainly appear in people with other ancestry, if at all.
Considering the variation in skin color in some places, if its unrelated, that kind of mixed (hair/eye vs skin) phenotype should appear more often, but it does not. I think that too tells you something about the linked traits.
There are some hints in studies:
“HERC2 together with OCA2 are found to be the most involved in human pigmentation, especially in the iris and hair color (Walsh et al. 2012; Donnelly et al. 2012). In particular, an intronic variant rs12913832 in HERC2 acts as a functional enhancer for OCA2 promoter, therefore, facilitating melanin production (Visser et al. 2012). This variant not only explains the most blue and brown iris color variation but also is considered to be associated with skin color showing a strong geographical pattern in genotype distribution across Europe”
We know this from rutilism too:
“According to other authors, rs4911414-T indeed seemed to be associated with sunburns, freckling and red hair”
https://link.springer.com/article/10.1007/s00439-019-02012-w
I first heard this from Greg Cochran in the recessive case: What do blue eyes do?
it’s not selecting on blue eyes at least it wasn’t initially. the length of the haplotype doesn’t look like recessive selection. the trajectory doesn’t match either
I’m incredibly interested (yet also incredibly layman) in ancient DNA and paleo-anthropology. So please forgive a stupid question asked in good faith re: “may simply be a side effect due to a genetic correlation with the true target of selection.” What is the true target of selection? Or is that the point – we don’t know yet? Thanks for all your great work. Love your blog and podcast.