Europeans got less shaded in stages

By Razib Khan | August 27, 2012 11:55 pm

The Pith: the evolution of lighter skin is complex, and seems to have occurred in stages. The current European phenotype may date to the end of the last Ice Age.

A new paper in Molecular Biology and Evolution, The timing of pigmentation lightening in Europeans, is rather interesting. It’s important because skin pigmentation has been one of the major successes of the first age of human genomics. In 2002 we really didn’t know the nature of normal human variation in skin color in terms of specific genes (basically, we knew about MC1R). This is what Armand Leroi observed in Mutants in 2005, wondering about our ignorance of such a salient trait. Within a few years though Leroi’s contention was out of date (in fact, while Mutants was going to press it became out of date) . Today we do know the genetic architecture of pigmentation. This is why GEDmatch can predict that my daughter’s eyes will be light brown from just her SNPs (they are currently hazel). This genomic yield was facilitated by the fact that pigmentation seems to be a trait where most human variation is controlled by half a dozen genes. In contrast, height or I.Q. are controlled by innumerable genes.

But first, a major gripe. In the discussion they write: “Our estimates additionally show that the onset of selective sweeps at SLC24A5, SLC45A2, and TYRP1, the three genes in which the geographic distribution of the polymorphisms is primarily restricted to European populations.” This is just not literally true. SLC24A5 in its derived skin lightening state is found outside of Europe. As the map from the HGDP browser to the left indicates, the derived “European” variant is nearly fixed in Middle Easterners. If you subtract Sub-Saharan admixture it almost is fixed in Middle Easterners. It is also found in high frequencies in South Asians. The HGDP samples are Pakistani, but the derived variant is present at a frequency of 95% in the HapMap Gujaratis! My parents are also homozygotes for the derived “European” variant. I’m rather sure there are more copies of the derived “European” allele among non-Europeans: South Asians, Middle Easterners, and North Americans. The problem here is semantic I think. The authors were really talking about West Eurasians in a generic sense, but because their data utilized Europeans, East Asians, and Africans, they felt like they had to speak about Europeans specifically. Additionally, during the Last Glacial Maximum much of Europe was not inhabited, or very sparsely so. That suggests to me that much of the evolution of “European pigmentation” may have taken outside of geographical Europe proper.

As for the paper, the results are pretty simple and striking. And speaking of striking, I’ll just paste this figure illustrating a neighbor-joining network of haplotypes at four skin pigmentation loci first to orient you. The yellow bubbles are derived lineages (in this case, they are often associated with SNPs correlated with lighter skin), while the black are ancestral ones.

What you see in the first two panels is that derived lineages are tightly clustered. SLC24A5 looks in particular to have almost a “star phylogeny,” so that you are seeing signatures of rapid expansion of this haplotype. SLC45a2 in contrast is dispersed across the networks. The authors posit that there may have been a recombination event which resulted in the jumping of the derived lineage onto the background of the ancestral one. Finally, with KITLG you see a pattern where numerous derived lineages are widely dispersed, albeit differentiated from the ancestral branch.

How did they do this? For the purposes of this blog post what I will say is that they first focused on a SNP, a single nucelotide polymorphism, associated with the lightening of the skin. This need not be the causal mutation, but generally they are strongly associated with the trait, and so can serve as useful markers. Second, around these focal SNPs they assembled a set of microsatellites with which they could perform phylogenetic tests. Microsatellites mutate fast, and accumulate variation. The main issue is that they mutate so fast you lose resolution at deeper time depths.

With the combination of SNP and microsatellite data the authors tested their empirical patterns against explicit models from which they generated simulations. Basically the goal here was to test for neutrality. In other words, you have a set of outcomes you’d expect based on neutral dynamics (i.e., just drift changing the frequencies), and you see how the “real world” results fit in. If the empirical data are not well explained by the neutral model, perhaps it was selection? Looking at patterns of variation around these loci you can also get a sense of the strength of the selection and time since the last common ancestor. Here’s a table with the outcomes:

Just so you know, a selection coefficient of 0.01 is respectable, and 0.10 is massive. In particular in the case of SLC24A5 it looks like there was a lot of selection, and recently. A few years ago a conference presentation implied that the selective sweep around SLC24A5  began ~6,000 years ago. To my knowledge a paper never came out of this, and from what I’ve heard in part that’s because that very low number is probably not right, and you may have to push it back some. These results look around to be in the right range from what I’ve heard. Others have found similar ages for SLC24A5 and SLC45A2 sweeps. But take a look at the confidence intervals. This is a case where I would really like to play around with their data and the model assumptions, and see how robust they are.

More intuitively obvious though are the patterns of KITLG in terms of geography, as well as the haplotype phylogenetic tree. The authors basically conclude that KITLG is a variant which precedes the differentiation between Europeans and East Asians, while the other genes have sweeps which postdated the divergence. The latter makes sense in light of the differentiation in skin pigmentation architecture in western and eastern Eurasians. Repeatedly the authors basically admit that this is a complicated issue, so I wouldn’t take these results home. It does concern me that they assume a demographic model which is a tree without reticulation. My own question in regards to the ~25,000 year values for divergence of west and east Eurasians is the extent to which admixture and gene flow are pulling forward in time the node. Second, the authors focused on a few representative populations in Europe, East Asia, and Africa. But there’s a whole world out there. It isn’t as if evolution occurred in isolation at these antipodes, and everyone else is a linear combination of subsequent admixture. In fact, I have to wonder if the estimates here are for populations which are intrusive to Europe, rather than indigenous. One point is that one might speculate that newcomers assimilated old lightening variants from the European Ice Age hunter-gatherers. But the haplotype structure mitigates against this. You should see more diverse derived variants if they’re drawn from the reservoir of ancient variants extant in Ice Age Europe.

So what’s the explanation from the authors? One proposal they make is that human evolution is accelerating due to more genetic variation because of larger effective population sizes. I assume they make this argument because it doesn’t look like the more recently selected variants emerged from standing variation, the diversity already present at the time of the sweep. Rather, the sweeps are triggered by new mutations which emerged recently (ergo, fewer “steps” away mutationally in the network for all the derived variants).

Ultimately there’s a lot to think about here. But I do wonder how ancient DNA is going to update and revise things. As I’ve said over and over again I’m a lot more skeptical of inferences and simulations after the dozens of phylogenetic model papers I read in the 2000s which “proved” no admixture between archaics and modern humans.

Image credit: Rita Molnar

  • http://forwhattheywereweare.blogspot.com/ Maju

    Very well explained, thanks, Razib.

    I’d say that the actual dates (if molecular-clock-o-logy still makes any sense) must be towards the high end of the confidence interval because, as the authors admit the KITLG derived allele must pre-date West/East Eurasian differentiation and that effectively puts us in 80,000 years ago more or less. Before c. 55,000 years ago in any case, when the first West Eurasian AMHs with Aurignacoid technologies are known in West Asia.

    That’s quite older than their average of 31-32 Ka, at least double (more like 2.5x IMO). That would make the Western-specific alleles to evolve in the range of 28-38 Ka ago, everything else equal.

  • Justin Giancola

    blog’s worn grooves: white, height, and IQ (pronounce Ike)

    “I’m rather sure there are
    more copies of the derived
    “European” allele among non-
    European South Asians,
    Middle Easterners, and North
    Americans, than among
    Europeans and European-
    derived peoples!”

    I hope people don’t interpret this wrong, like I did at first. You might consider a colon after non-European.

  • http://carlzimmer.com Carl Zimmer

    Do these alleles change the phenotype in an additive way? Or is there some interaction? I’m curious what the sequence of stages means for the appearance of Europeans–a gradual lightening, or fits and starts.

  • Sandgroper

    “Do these alleles change the phenotype in an additive way?”

    I have that question too – my daughter is more pale skinned than both my (north-eastern Chinese) wife and myself (mostly northern European).

    She has never been sunburnt, and barely ever tans at all, despite school sports days and such when she was out in the sub-tropical summer sun all day.

  • https://plus.google.com/109962494182694679780/posts Razib Khan

    Do these alleles change the phenotype in an additive way?

    basically. though two of the largest effect alleles in mixed euro-african pops exhibit some dominance toward whiteness

    http://blogs.discovermagazine.com/gnxp/2008/05/fear-of-a-white-planet/

  • Sandgroper

    Good post.

    For interest, when my daughter was a baby, her eyes were black, no one could distinguish any colour in the irises at all, but as she grew older they turned very dark brown – much darker than either mine or my wife’s, or anyone in my family or my wife’s family. I’m also curious to understand how that happens. (To other readers, for the avoidance of doubt, she is definitely my offspring, so no ‘non-paternal event’ jokes, please.)

  • Sandgroper

    I did wonder if that came from my Aboriginal ancestry, but it seems way too remote.

    Beautiful eyes, though.

  • https://plus.google.com/109962494182694679780/posts Razib Khan

    #4, easy to explain. she sampled from both your “light alleles.” re: #7, there is some issue in fully characterizing the mapping between genes and phenotype on this trait. explaining most of the variance doesn’t explain all of it. then again, who knows what happens when you cross parents with very different genetic architectures for light skin? i guess ask hawaiians.

  • Grey

    “That suggests to me that much of the evolution of “European pigmentation” may have taken outside of geographical Europe proper.”

    I was wondering about that. The assumption based on current distribution leads to people looking for answers related to northern latitudes (vitamins etc) but if the people further south were lighter once when populations were more isolated and got darker again later through migration / slavery / use of mercenaries from Africa etc when populations became more connected again then the list of potential explanations becomes a lot wider.

  • Sandgroper

    Thanks.

  • pconroy

    @Sandygroper,

    Yes, eye color, is not fully there yet in terms of SNP’s

    My wife’s parents are a case in point, each parent is 1/2 Sicilian and 1/2 Northern European. Each Sicilian grandmother had brown eyes, each Northern European Grandfather had blue eyes – yet all their kids have blue eyes, so I guess that each brown eyed grandmother must have carried a blue eye recessive.

    Then, in the next generation, both my wife’s parents have blue eyes but my wife has pure green eyes – her other 3 siblings have blue eyes though.

    My father has almost identical results for eye color SNP’s as my wife but has the bluest of blue eyes?!

  • http://forwhattheywereweare.blogspot.com/ Maju

    @Sandgroper: East Asian pigmentation genetics are even worse understood than West Eurasian ones. We know that the East Asian way to paleness is different from that of the West (evolved separately, even if probably for the same reasons) and (from memory) there was some study indicating that East Asians almost never get skin cancer, regardless of skin shade, what was tentatively attributed to the “yellow” pigment, whose genetics are still not well known. I cannot refer you to sources because I’m digging from my memory and these studies are from maybe 6 or more years ago.

  • https://plus.google.com/109962494182694679780/posts Razib Khan
  • Spike Gomes

    8:

    My great great hanai aunt was 1/2 Irish 1/2 Hawaiian. When she was younger she was often mistaken for Italian. There’s not much true half-Hawaiians left (much less pure), but there are lots of pictures from the turn of the century. They do have a very distinctive “look”. Some variation on whether the Euro component was Northern European or Southern.

    I’m much darker than both my parents, so is my sister, FWIW.

  • Solis

    “To my knowledge a paper never came out of this, and from what I’ve heard in part that’s because that very low number is probably not right, and you may have to push it back some.”

    There was something quite akin to a paper, by Ann Gibbons, but it was more of a press release: European skin turned pale only recently, gene suggests. You’re right, no paper ever came out on this. It still became quite popular though, specially among black racist groups that also say that “white people are one mutation away from being albino”. What do you think of that?

    Btw didn’t know you also wrote papers:

    http://www.ncbi.nlm.nih.gov/pubmed/20409647

  • https://plus.google.com/109962494182694679780/posts Razib Khan

    #16, the ann gibbons report is what i’m talking about. i’ve heard that that estimate was way too low in hindsight, so i think that’s why the paper didn’t get written/published.

  • Luke Raines

    I think it is likely that there are other skin pigmentation genes out there that haven’t been discovered yet which will explain why Northern Europeans tend to be lighter skinned than Southern Europeans and other Caucasoids.

  • https://plus.google.com/109962494182694679780/posts Razib Khan

    #17, variation in frequencies of SLC45A2, KITLG, and OCA2-HERC2 don’t explain it for you? out of curiosity why?

  • Sandgroper

    Paul, Maju – thanks.

    Coming from the ‘skin cancer capital of the world’, as I do, where virtually 100% of white adults get some issues at some point (at least solar keratoses, but a high % get actual cancers), and where an annual all-over skin inspection by a specialist is a “must” for older adults, the total lack of skin cancer problems among the Chinese population of Hong Kong is really striking.

    Given that the skin reflectance for East Asians and Europeans is pretty much the same, just some differences in the spectrum (East Asians have somewhat less pink), this is really intriguing.

  • Sandgroper

    Anecdote – last time I saw my old skin specialist in Australia and he went all over the usual suspect parts (shoulders, cheek bones, nose, forearms, etc), he said “Your skin is good.”

    My wife nearly choked. Compared to white Australians my age, my skin is in good shape. Compared to Chinese my age, it’s not good.

  • pconroy

    @20,

    I hear ya!

    My wife – who is an MD – has suggested that I see a skin specialist yearly, as I have little lumps on the back of my hands and lower legs – where I got badly burned years ago. An aunt who used to spend time in the Canaries on summer vacations had a few pre-cancerous lumps removed too.

  • pconroy

    Since I don’t tan, I always wear a large hat in summer – to protect my face and neck – much to the amusement of my eldest daughter who has inherited a more Corsican complexion and tans easily.

  • Luke Raines

    #18, I’m sure that scientists have found most or even all of the major skin pigmentation genes but there could possibly be minor skin pigmentation genes that have not yet been identified.

  • https://plus.google.com/109962494182694679780/posts Razib Khan

    #23, you didn’t address the question prompted by your original comment. the architecture is power law; there are LOTS of minor variants. back to what you said: skin pigmentation genes out there that haven’t been discovered yet which will explain why Northern Europeans tend to be lighter skinned than Southern Europeans and other Caucasoids. you don’t think the genes i listed are sufficient to explain intra-european difference? the reality is that most of this work is done ON EUROPEANS as a reference population (ie, it tends to be euro vs. other group), so it’s biased in particular to fleshing out intra-european differences (e.g., herc2-oca2). but if that’s not sufficient, i’m curious what your thought process is. are you talking a REALLY fine grain? it seems north vs. south euro is taken care of already to a great, if not total, extent.

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Gene Expression

This blog is about evolution, genetics, genomics and their interstices. Please beware that comments are aggressively moderated. Uncivil or churlish comments will likely get you banned immediately, so make any contribution count!

About Razib Khan

I have degrees in biology and biochemistry, a passion for genetics, history, and philosophy, and shrimp is my favorite food. In relation to nationality I'm a American Northwesterner, in politics I'm a reactionary, and as for religion I have none (I'm an atheist). If you want to know more, see the links at http://www.razib.com

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