Genetics of Pigmentation Diversity Dec 31, 2020 19:43:15 GMT
Post by Admin on Dec 31, 2020 19:43:15 GMT
Fig. S6. Light allele frequencies in ancient and present-day European populations for select SNPs (A) rs2675345, (B) rs4778123, (C) rs2153271, (D) rs3758833, (E) rs12203592, and (F) rs1325132. Nearest genes are labelled at the top of each bar plot.
In the supplementary section of this paper (Ju and Mathieson 2021), OCA2 and TYRP1 are identified as light skin alleles for WHGs. Their frequencies are 50% and 100%, respectively. There are several other pigmentation genes attributed to WHGs such as CTSC (55%) and IRF4 (40%). The IRF4 gene is strongly associated with pigmentation and sensitivity of skin to sun exposure. Previous papers on human pigmentation (Günther et al. 2018) had not found these pigmentation genes in WHGs. Figure 4 shows that 100% of WHGs had the OCA2/HERC2 gene, which is associated with blue eye color and light skin (Günther et al. 2018). However, most studies only link this OCA2/HERC2 gene to blue eyes, concluding that WHGs had blue eyes and dark skin. The OCA2 gene is independently involved in the evolution of light skin pigmentation in East Asia and Europe. Two OCA2 polymorphisms (rs1800414 and rs74653330) have been associated with lighter skin pigmentation in East Asian populations. Aside from three genes associated with light skin in Europe (SLC24A5, SLC45A2 and TYRP1) which began to increase in frequency between 19,000 and 11,000 years ago, OCA2 also showed a potential signal of selection in Europeans and played part in light skin pigmentation in Europe. WHGs had fewer depigmentation genes compared to modern Europeans but they were probably as light-skinned as East Asians.
Fig 4. Adaptation to high-latitude environments.
Large whole-genome ancient DNA datasets have, in the past few years, allowed us to track the evolution of variation associated with both simple and complex traits (68, 69). The majority of samples are from Western Eurasia, and we focus on that region, noting that a parallel process of selection for light skin pigmentation has acted in East Asian populations (9, 70). In West Eurasia, selection for skin pigmentation appears to have been dominated by a small number of selective sweeps at large-effect variants. There are a number of possible explanations for this. Many of the variants detected by the UK Biobank GWAS may have such small effects that they were effectively neutral or experienced such weak selection that we cannot detect it. Other variants may not have responded to selection because of pleiotropic constraint. The five SNPs with the largest effect sizes in UK Biobank do have some have small but significant associations with anthropometric phenotypes (for example, rs1805007 at MC1R with standing height), but by far their most significant associations are with hair color, facial aging, tanning, melanoma risk, and other phenotypes that are likely related to pigmentation (64). Finally, GWAS effect size estimates in European populations today may not reflect the impact these variants had in the past due to epistatic or gene–environment interactions. This would not affect the individual SNP time series and PBS analyses since they do not rely on effect sizes as weights but would reduce power for the weighted polygenic score and Qx analyses.
Our analyses centered on 170 skin pigmentation-associated SNPs that are present on the 1240K capture array. To check for possible bias introduced by the capture array, we checked how many of the 242 SNPs used in the shotgun analysis were well tagged by the capture array. Of the 242 SNPs, 33 are shared, a further 67 are tagged at r2 ≥ 0.8, and a further 19 SNPs are tagged at r2 ≥ 0.5. However, while the 142 SNPs that are not tagged at r2 ≥ 0.8 by the capture array do contain some moderate effect size SNPs, they do not contribute to the selection signal (P = 0.31) (SI Appendix, Fig. S15D). Therefore, although the capture array does not capture all of the variation contributing to present-day skin pigmentation variation, it does capture the vast majority of the variation that contributed to the evolution of the phenotype, justifying the use of the capture-shotgun dataset for detailed investigation of the evolutionary trends.
We find little evidence of parallel selection on independent haplotypes at skin pigmentation loci, suggesting that that differences in allele frequency across ancestry groups were mostly due to genetic drift. One exception is that the light allele at SLC24A5 was nearly fixed in both Early Farmer and Steppe ancestry populations due to selection. However, even for this variant we observe a signal of ongoing selection in our data even after admixture with hunter-gatherers, indicating continued selection after admixture. This is analogous to the rapid selection at the same locus for the light allele introduced via admixture into the KhoeSan, who now occupy southern Africa (12, 71).
We are also able to test previous claims about selection on particular pigmentation genes. We find no evidence of positive selection in Europeans at the MC1R locus in contrast to previous reports (72, 73). Among UK Biobank SNPs, rs1805007 near MC1R explains a relatively large amount of variation within the UK but is predicted to explain relatively little of the variation between Europe and West Africa (Fig. 4C). The TYRP1 locus has been previously identified as a target of selection in Europeans (5, 8, 9, 74, 75), although some studies (76, 77) have questioned this finding. Our analysis shows some support for selection at this locus, with a 20-SNP window centered around rs1325132 being in the top 1.1% of genome-wide PBS windows on the hunter-gatherer lineage. Some studies (76, 78) detect a signal of recent selection in Europeans at the KITLG SNP rs12821256 that is functionally associated with blond hair color (79). We find no evidence of selection on the West Eurasian lineage at this SNP in our time series analysis, but this may reflect a lack of power to detect a relatively small change in frequency. Finally, at the OCA2 locus, we recapitulate an observation of independent selection in Europeans and East Asians (70, 80) (SI Appendix, Fig. S9). In the ancient populations, we found an elevated PBS signal around rs9920172 that was most prominent in hunter-gatherers but also elevated in Early Farmer and Steppe ancestry populations (Fig. 3), suggesting a relatively early episode of selection in West Eurasians.
Relatively dark skin pigmentation in Early Upper Paleolithic Europe would be consistent with those populations being relatively poorly adapted to high-latitude conditions as a result of having recently migrated from lower latitudes. On the other hand, although we have shown that these populations carried few of the light pigmentation alleles that are segregating in present-day Europe, they may have carried different alleles that we cannot now detect. As an extreme example, Neanderthals and the Altai Denisovan individual show genetic scores that are in a similar range to Early Upper Paleolithic individuals (SI Appendix, Table S1), but it is highly plausible that these populations, who lived at high latitudes for hundreds of thousands of years, would have adapted independently to low UV levels. For this reason, we cannot confidently make statements about the skin pigmentation of ancient populations.
Our study focused, for reasons of data availability, on the history of skin pigmentation evolution in West Eurasia. However, there is strong evidence that a parallel trend of adaptation to low UVB conditions occurred in East Asia (15, 70, 81, 82). Less is known about the loci that have been under selection in East Asia, aside from some variants at OCA2 (80⇓–82). Similarly, multiple studies have documented selection for both lighter and darker skin pigmentation in parts of Africa (12, 13, 83). Future work should test whether the process of adaptation in other parts of the world was similar to that in Europe. The lack of known skin pigmentation loci in scans of positive selection in East Asian populations (84, 85) raises the possibility that selection may have been more polygenic in East Asians than in Europeans. Finally, the evidence for polygenic directional selection on other complex traits in humans is inconclusive (86, 87). We suggest that detailed studies of other phenotypes using ancient DNA can be helpful at more generally identifying the types of processes that are important in human evolution.