Post by Admin on May 31, 2021 21:10:06 GMT
Discussion
The analyses presented here highlight the complex genetic architecture of pigmentation variation in Latin Americans, with multiple gene regions as well as multiple independent variants at the OCA2/HERC2 and GRM5/TYR regions, and several epistatic interactions, affecting pigmentation variation. Since the history of the New World involved the extensive admixture of Native Americans, Europeans and Africans, it is to be expected that variants impacting on pigmentation in those continental populations are segregating in Latin America. Further, since Native Americans trace their ancestry to East Asia, it is likely that certain pigmentation variants present in Latin Americans should be shared with East Asians. Consistent with this scenario, we replicate 7 allelic variants that have been previously associated with pigmentation phenotypes in Europeans and one variant previously reported in East Asians (rs885479 in MC1R). It seems likely that we did not detect some of the other variants previously associated with pigmentation variation in Old World populations due to a combination of factors affecting power across studies. For instance, some of the reported variants could have high frequency in Old World populations that did not contribute to admixture in Latin America. Dissimilarities in phenotype assessment approaches and in trait definitions are also likely to explain some of the differences in association results across studies. For example, GWAS carried out in Europeans have mostly focused on variation in the brown to blue color spectrum. By contrast, the C (saturation) color component examined here, with which two new loci have been associated, captures variation within brown eyes (Fig. 2b) and the index SNPs at these loci have highest derived allele frequencies in East Asians (Fig. 4).
The convergent evolution of lighter skin pigmentation in Western and Eastern Eurasia stems partly from allelic heterogeneity at two well-established pigmentation genes initially identified in Europeans: OCA2 and MC1R. In addition to allelic heterogeneity at these two genes, here we identify rs224071 at MFSD12 as another pigmentation variant specific to populations of East Asian/Native American ancestry. This gene region has been recently implicated in a study of skin pigmentation variation in Sub-Saharan Africans5. Strongest association in that study was seen for synonymous and intronic SNPs in MFSD12, variable only in Africans, and in an upstream regulatory region, variable in Africans and South and South East Asians, but not in Europeans or East Asians. By contrast, we found that in our sample the strongest association with skin pigmentation is seen for the Y182H amino-acid substitution in MFSD12, a variant seen at high frequency only in East Asians and Native Americans. It is thus likely that this variant rose in frequency in East Asia and was carried into the Americas during Native American migrations. This establishes MFSD12 as an additional gene involved in the convergent evolution of lighter skin pigmentation in Eurasians. Furthermore, consistent with what is observed at several other pigmentation gene regions, we observe a strong signal of selection in this gene region in East Asians (dated after their split from Europeans), and a correlation of the frequency of the MFSD12 Y182H variant with solar radiation levels in East Asia (Fig. 8). The pattern of variation at MFSD12 is thus reminiscent of what is observed for certain pigmentation genes in Europeans (e.g., OCA2 or SCL45A2). Associated SNPs at those genes are polymorphic mainly in Europeans, show strong signals of selection and a correlation of derived allele frequencies with latitude44,45.
Our estimate of the selection coefficient for MFSD12 is best viewed in the context of estimates for other pigmentation loci. Beleza et al.32 used forward Monte Carlo simulations coupled with a rejection algorithm to estimate the selection coefficient at four pigmentation genes. Under an additive model, the selection coefficient for KITLG (rs642742 G allele) in Europe and East Asia was estimated to be 0.02, whereas the coefficients for TYRP1 (rs2733831 G allele), SLC45A2 (rs16891982 G allele) and SLC24A5 (rs1426654 A allele) were estimated to be 0.03, 0.04 and 0.08, respectively. López et al.46 estimated the selection coefficient of SLC45A2 (rs16891982 G allele) to be 0.01 to 0.02 in a South European population. Similarly, using an ancient DNA forward simulation approach restricted to European populations, Wilde et al.47 estimated the selection coefficient of SLC45A2 (rs16891982 G allele), TYR (rs1042602 A allele) and HERC2 (rs12913832 G allele) to be 0.03, 0.03 and 0.04, respectively. The selection coefficient that we estimated (0.01) for MFSD12 thus lies at the lower end of those estimated for other pigmentation genes that appear to have been under selection. This result is in line with the relatively weaker phenotypic effect of MFSD12, relative to genes such as SLC45A2 and SLC24A5. Our estimate for the age since the start of selection (10,833 ya (95% CI of 5266–33,801 ya)) suggests that it would have started long after the split of proto-East Asians from proto-Europeans.
Considering the evidence for solar radiation having contributed to shape the diversity of certain genomic regions in Old World populations, it is interesting that we do not detect pigmentation variants private to the Americas in the CANDELA sample (with the caveat that we might be unable to detect the effects of rare local variants). The American continent shows extensive variation in solar radiation levels as its territory extends along a North–South axis encompassing circumpolar and Equatorial latitudes (Fig. 8c). However, Native Americans do not exhibit a variation in skin pigmentation like that seen in Old World populations living at similar latitudes48. It has been suggested that this difference between continents might relate to cultural adaptations, environmental factors, or to another mechanism of biological adaptation, such as a better tanning ability8,48. It is possible that the lack of novel genetic adaptations to solar radiation levels in the Americas could relate to the relatively recent settlement of the New World, which started about 15,000 years ago. This recent settlement limits the time-span over which new genetic variants could have arisen and changed in frequency in response to selection pressures, particularly considering the magnitude of the selection coefficients that have been estimated for pigmentation associated loci.
The analyses presented here highlight the complex genetic architecture of pigmentation variation in Latin Americans, with multiple gene regions as well as multiple independent variants at the OCA2/HERC2 and GRM5/TYR regions, and several epistatic interactions, affecting pigmentation variation. Since the history of the New World involved the extensive admixture of Native Americans, Europeans and Africans, it is to be expected that variants impacting on pigmentation in those continental populations are segregating in Latin America. Further, since Native Americans trace their ancestry to East Asia, it is likely that certain pigmentation variants present in Latin Americans should be shared with East Asians. Consistent with this scenario, we replicate 7 allelic variants that have been previously associated with pigmentation phenotypes in Europeans and one variant previously reported in East Asians (rs885479 in MC1R). It seems likely that we did not detect some of the other variants previously associated with pigmentation variation in Old World populations due to a combination of factors affecting power across studies. For instance, some of the reported variants could have high frequency in Old World populations that did not contribute to admixture in Latin America. Dissimilarities in phenotype assessment approaches and in trait definitions are also likely to explain some of the differences in association results across studies. For example, GWAS carried out in Europeans have mostly focused on variation in the brown to blue color spectrum. By contrast, the C (saturation) color component examined here, with which two new loci have been associated, captures variation within brown eyes (Fig. 2b) and the index SNPs at these loci have highest derived allele frequencies in East Asians (Fig. 4).
The convergent evolution of lighter skin pigmentation in Western and Eastern Eurasia stems partly from allelic heterogeneity at two well-established pigmentation genes initially identified in Europeans: OCA2 and MC1R. In addition to allelic heterogeneity at these two genes, here we identify rs224071 at MFSD12 as another pigmentation variant specific to populations of East Asian/Native American ancestry. This gene region has been recently implicated in a study of skin pigmentation variation in Sub-Saharan Africans5. Strongest association in that study was seen for synonymous and intronic SNPs in MFSD12, variable only in Africans, and in an upstream regulatory region, variable in Africans and South and South East Asians, but not in Europeans or East Asians. By contrast, we found that in our sample the strongest association with skin pigmentation is seen for the Y182H amino-acid substitution in MFSD12, a variant seen at high frequency only in East Asians and Native Americans. It is thus likely that this variant rose in frequency in East Asia and was carried into the Americas during Native American migrations. This establishes MFSD12 as an additional gene involved in the convergent evolution of lighter skin pigmentation in Eurasians. Furthermore, consistent with what is observed at several other pigmentation gene regions, we observe a strong signal of selection in this gene region in East Asians (dated after their split from Europeans), and a correlation of the frequency of the MFSD12 Y182H variant with solar radiation levels in East Asia (Fig. 8). The pattern of variation at MFSD12 is thus reminiscent of what is observed for certain pigmentation genes in Europeans (e.g., OCA2 or SCL45A2). Associated SNPs at those genes are polymorphic mainly in Europeans, show strong signals of selection and a correlation of derived allele frequencies with latitude44,45.
Our estimate of the selection coefficient for MFSD12 is best viewed in the context of estimates for other pigmentation loci. Beleza et al.32 used forward Monte Carlo simulations coupled with a rejection algorithm to estimate the selection coefficient at four pigmentation genes. Under an additive model, the selection coefficient for KITLG (rs642742 G allele) in Europe and East Asia was estimated to be 0.02, whereas the coefficients for TYRP1 (rs2733831 G allele), SLC45A2 (rs16891982 G allele) and SLC24A5 (rs1426654 A allele) were estimated to be 0.03, 0.04 and 0.08, respectively. López et al.46 estimated the selection coefficient of SLC45A2 (rs16891982 G allele) to be 0.01 to 0.02 in a South European population. Similarly, using an ancient DNA forward simulation approach restricted to European populations, Wilde et al.47 estimated the selection coefficient of SLC45A2 (rs16891982 G allele), TYR (rs1042602 A allele) and HERC2 (rs12913832 G allele) to be 0.03, 0.03 and 0.04, respectively. The selection coefficient that we estimated (0.01) for MFSD12 thus lies at the lower end of those estimated for other pigmentation genes that appear to have been under selection. This result is in line with the relatively weaker phenotypic effect of MFSD12, relative to genes such as SLC45A2 and SLC24A5. Our estimate for the age since the start of selection (10,833 ya (95% CI of 5266–33,801 ya)) suggests that it would have started long after the split of proto-East Asians from proto-Europeans.
Considering the evidence for solar radiation having contributed to shape the diversity of certain genomic regions in Old World populations, it is interesting that we do not detect pigmentation variants private to the Americas in the CANDELA sample (with the caveat that we might be unable to detect the effects of rare local variants). The American continent shows extensive variation in solar radiation levels as its territory extends along a North–South axis encompassing circumpolar and Equatorial latitudes (Fig. 8c). However, Native Americans do not exhibit a variation in skin pigmentation like that seen in Old World populations living at similar latitudes48. It has been suggested that this difference between continents might relate to cultural adaptations, environmental factors, or to another mechanism of biological adaptation, such as a better tanning ability8,48. It is possible that the lack of novel genetic adaptations to solar radiation levels in the Americas could relate to the relatively recent settlement of the New World, which started about 15,000 years ago. This recent settlement limits the time-span over which new genetic variants could have arisen and changed in frequency in response to selection pressures, particularly considering the magnitude of the selection coefficients that have been estimated for pigmentation associated loci.
