Selection for rs3827760 at EDAR (“shovel-shaped” incisor SNP) during Holocene around the “Ring of Fire”

EDAR and East Asian hair

If you have been reading my blog will you be familiar with the SNP rs3827760
within the EDAR gene. This mutation has high derived frequencies in East Asians and is associated with a suite of physical characteristics. Most famously, the thickness of hair shaft and “shovel-shaped” incisors (a phenotype also found in Neanderthals). So the reason people of East Asian ancestry seem to have very thick straight hair is that their hair strands are actually thicker due to the new variant.

Almost all Africans, West Eurasians, and South Eurasians lack the derived variant. Those populations outside of East Asia which have it in appreciable frequencies, whether it be Munda tribal people in India or Finns in Northern Europe, always have relatively recent East Asian ancestry. The fraction of the derived allele is usually easily inferred from genome-wide East Asian ancestry and source population fraction (southern East Asians have a lower fraction than northern ones).

But there’s another modern group* of people with high frequencies of the derived variant: people of Amerindian heritage. This is reasonable because East Asians and Amerindians share common ancestry, at least in part, going back ~25,000 years ago. The ALFRED database actually has the largest coverage of the New World for this marker that I know of. One inference you can make is that many Amerindian groups were fixed or nearly fixed for the derived variant before some European admixture. For example, the Maya carry ~5% of the ancestral variant, but those samples are known to have a small but significant amount of European admixture (curiously, the derived variant hasn’t swept to fixation in many populations; that implies to me that the phenotypic target of selection has a dominant genetic expression).

So this section of a new ancient DNA paper, Reconstructing the Deep Population History of Central and South America, jumped out at me:

Our data show that a variant in EDAR that affects tooth shape, hair follicles and thickness, sweat, and mammary gland ductal branching and that occurs at nearly 100% frequency in present day Native Americans and East Asians…was not fixed in USR1Anzick-1, a Brazil_LapaDoSanto_9600BP individual and a Brazil_Laranjal_6700BP individual, all of whom carry the ancestral allele. Thus, the derived allele rose in frequency in parallel in both East Asians and in Native Americans.

These are on the older side as far as samples in the paper go. The numbers are small, but looking at modern Amerindian groups to have this much ancestral variant is surprising. The authors’ conclusion seems highly likely. The EDAR locus, and probably this particular SNP, was segregating in the ancient proto-East Asian/Amerindian metapopulation, and during the Holocene, there was selection on both sides of the Pacific.

Why? Unlike some people, I don’t think it was sexual selection for silky hair with full body. EDAR does a lot of things. From GeneCard:

The EDAR gene provides instructions for making a protein called the ectodysplasin A receptor. This protein is part of a signaling pathway that plays an important role in development before birth. Specifically, it is critical for interactions between two embryonic cell layers called the ectoderm and the mesoderm. In the early embryo, these cell layers form the basis for many of the body’s organs and tissues. Ectoderm-mesoderm interactions are essential for the formation of several structures that arise from the ectoderm, including the skin, hair, nails, teeth, and sweat glands.

This locus doesn’t seem to have been targeted elsewhere during the Holocene. Why not? Perhaps there’s another locus (or set of loci) that do similar things and were the targets of selection in other cases.

The bigger story, emphasized more in the other ancient DNA paper about South and North America that came out today in Science, Early human dispersals within the Americas, is that populations in the New World clearly seem to have been changing morphologically over the past ~10,000 years. Well, yeah….

* Ancient Mesolithic Scandinavian hunter-gatherers seem to have carried the derived variant at rs3827760. These people did not contribute much to the ancestry of later Scandinavians.

Natural selection in humans (OK, 375,000 British people)

 


The above figure is from Evidence of directional and stabilizing selection in contemporary humans. I’ll be entirely honest with you: I don’t read every UK Biobank paper, but I do read those where Peter Visscher is a co-author. It’s in PNAS, and a draft which is not open access. But it’s a pretty interesting read. Nothing too revolutionary, but confirms some intuitions one might have.

The abstract:

Modern molecular genetic datasets, primarily collected to study the biology of human health and disease, can be used to directly measure the action of natural selection and reveal important features of contemporary human evolution. Here we leverage the UK Biobank data to test for the presence of linear and nonlinear natural selection in a contemporary population of the United Kingdom. We obtain phenotypic and genetic evidence consistent with the action of linear/directional selection. Phenotypic evidence suggests that stabilizing selection, which acts to reduce variance in the population without necessarily modifying the population mean, is widespread and relatively weak in comparison with estimates from other species.

The stabilizing selection part is probably the most interesting part for me. But let’s hold up for a moment, and review some of the major findings. The authors focused on ~375,000 samples which matched their criteria (white British individuals old enough that they are well past their reproductive peak), and the genotyping platforms had 500,000 markers. The dependent variable they’re looking at is reproductive fitness. In this case specifically, “rRLS”, or relative reproductive lifetime success.

With these huge data sets and the large number of measured phenotypes they first used the classical Lande and Arnold method to detect selection gradients, which leveraged regression to measure directional and stabilizing dynamics. Basically, how does change in the phenotype impact reproductive fitness? So, it is notable that shorter women have higher reproductive fitness than taller women (shorter than the median). This seems like a robust result. We’ve seen it before on much smaller sample sizes.

The results using phenotypic correlations for direction (β) and stabilizing (γ) selection are shown below separated by sex. The abbreviations are the same as above.

 

There are many cases where directional selection seems to operate in females, but not in males. But they note that that is often due to near zero non-significant results in males, not because there were opposing directions in selection. Height was the exception, with regression coefficients in opposite directions. For stabilizing selection there was no antagonistic trait.

A major finding was that compared to other organisms stabilizing selection was very weak in humans. There’s just not that that much pressure against extreme phenotypes. This isn’t entirely surprising. First, you have the issue of the weirdness of a lot of studies in animal models, with inbred lines, or wild populations selected for their salience. Second, prior theory suggests that a trait with lots of heritable quantitative variation, like height, shouldn’t be subject to that much selection. If it had, the genetic variation which was the raw material of the trait’s distribution wouldn’t be there.

Using more complex regression methods that take into account confounds, they pruned the list of significant hits. But, it is important to note that even at ~375,000, this sample size might be underpowered to detect really subtle dynamics. Additionally, the beauty of this study is that it added modern genomic analysis to the mix. Detecting selection through phenotypic analysis goes back decades, but interrogating the genetic basis of complex traits and their evolutionary dynamics is new.

To a first approximation, the results were broadly consonant across the two methods. But, there are interesting details where they differ. There is selection on height in females, but not in males. This implies that though empirically you see taller males with higher rLSR, the genetic variance that is affecting height isn’t correlated with rLSR, so selection isn’t occurring in this sex.

~375,000 may seem like a lot, but from talking to people who work in polygenic selection there is still statistical power to be gained by going into the millions (perhaps tens of millions?). These sorts of results are very preliminary but show the power of synthesizing classical quantitative genetic models and ways of thinking with modern genomics. And, it does have me wondering about how these methods will align with the sort of stuff I wrote about last year which detects recent selection on time depths of a few thousand years. The SDS method, for example, seems to be detecting selection for increasing height the world over…which I wonder is some artifact, because there’s a robust pattern of shorter women having higher fertility in studies going back decades.

Selection for pigmentation in Khoisan?

In the recent paper, Reconstructing Prehistoric African Population Structure, there was a section natural selection. Since my post on the paper was already very long I didn’t address this dynamic.

But now I want to highlight this section:

The functional category that displays the most extreme allele frequency differentiation between present day San and ancient southern Africans is ‘‘response to radiation’’ (Z = 3.3 compared to the genome-wide average). To control for the possibility that genes in this category show an inflated allele frequency differentiation in general, we computed the same statistic for the Mbuti central African rainforest hunter-gatherer group but found no evidence for selection affecting the response to radiation category.

We speculate that the signal for selection in the response to radiation category in the San could be due to exposure to sunlight associated with the life of the Khomani and Juj’hoan North people in the Kalahari Basin, which has become a refuge for hunter-gatherer populations in the last millenia due to encroachment by pastoralist and agriculturalist groups.

I’m a bit puzzled here, because the implication seems to be that the San populations are darker than they were in the past. And yet earlier this summer I saw a talk which strongly suggested that there was a selection in modern Bushman populations for the derived variant of SLC24A5, presumably introduced through admixture from East African populations with Eurasian admixture.

In comparison to their neighbors the San are quite light-skinned, so it’s a reasonable supposition that they have been subject to natural selection recently. The Hadza, in contrast, seem to have the same complexion as their Bantu neighbors.