Skin pigmentation gene alleles

Reviewing H. Norton, R. Kittles et al, 2006:

Besides the variations in the “SLC24A5” gene, as mentioned in the intro article, the “TYR” gene, the “OCA2“, the “ASIP“, and to some extent those seen in the MC1R gene, Kittles et al. have noted other genes "MATP C374G", “ADAM17“, “ATRN“, and “DCT” the mutations of which are deemed to have to had influence in promoting paleness…

Taken together (with the results of previous admixture mapping studies), these results point to the importance of several genes in shaping the pigmentation phenotype and a complex evolutionary history involving strong selection. Polymorphisms in 2 genes, ASIP and OCA2, may play a shared role in shaping light and dark pigmentation across the globe, whereas SLC24A5, MATP, and TYR have a predominant role in the evolution of light skin in Europeans but not in East Asians. These findings support a case for the recent convergent evolution of a lighter pigmentation in Europeans and East Asians…

Pairwise Fst estimates for the ASIP A8818G and OCA2 A355G SNPs tentatively suggest a pattern of divergence between 4 populations (Europeans, East Asians, Native Americans, and South Asians) and the relatively more darkly pigmented populations of West Africa and Island Melanesia, or possibly only between West Africans and all other populations. At both loci, West Africans and Island Melanesians have higher frequencies of the ancestral alleles than the other 4 populations. Pairwise locus-specific Fst values falling in the top 5% of the empirical distributions are observed between West Africans and 3 other populations (South Asians, Native Americans, and Europeans) at ASIP A8818G. Fst values between West Africans and East Asians at this locus are elevated but do not reach our cutoff value of 5% (Fst = .489, P = .065). At OCA2 A355G, only West Africans and Europeans show Fst values falling into the top fifth percentile of relevant comparisons (Fst = .516, P<.05). The low pair wise Fst values and higher frequency of ancestral alleles at both SNPs studied in these loci between West Africans and Island Melanesians hint that dark pigmentation associated with both loci in these populations may have a common evolutionary origin (Mean Fst (WA-IM) = .182; ASIP A8818G Fst (WA-IM) = .260, P = .282; OCA2 A355G Fst (WA-IM) = .101, P=.525).

Continuing with regards to OCA2 gene, we are told…

In contrast, the ancestral allele associated with dark pigmentation has a shared high frequency in sub-Sharan African and Island Melanesians. A notable exception is the relatively lightly pigmented San population of Southern Africa where the derived allele predominates (93%), although this may be simply due to small sample size (n=14).

The distributions of the derived and ancestral alleles at TYR A192C, MAPT C374G, and SLC24A5 A111G are consistent with Fst results suggesting strong European specific divergence at these loci. The derived allele at TYR, 192*A (previously linked with lighter pigmentation [Shriver et al. 2003]), has a frequency of 38% among European populations but a frequency only 14% among non-Europeans. The differences between Europeans and non-Europeans for the MAPT 374*G and SLC24A5 111*A alleles (both derived alleles associated with lighter pigmentation) were even more striking (MAT [European] = 87%; MATP [non-European] = 17%; SLC24A5 [European] = 100%; SLC24A5 [non-European] = 46%). The frequency of the SLC24A5 111*A allele outside of Europe is largely accounted for by high frequencies in geographically proximate populations in northern Africa, the Middle East, and Pakistan (ranging from 62% to 100%).

By way of negative Tajima D values, which when strongly negative, indicate selective pressure, or more specifically—“directional selection”, especially when taken into account with both high locus-specific branch length and strongly negative heterozygosity values, the authors continue...

These data confirm the unusual European-specific patterns at MATP and SLC24A5. Both genes display long range (consecutive windows) and significant indications of positive selection for all 3 statistics. In contrast, there is little evidence of a European-specific pattern in the TYR locus although the non-synonymous TYR A192C SNP does individually show a strongly significant CEU-LSBL (P<.003) in the HapMap data as in our original findings. The contrast may be explained by the limitations of our HapMap sliding windows analyses, whereby adjacent SNPs are averaged using a method that does not consider Haplotype structure.

East Asians showed relatively stronger selection for a different set of genes…

…In particular, 2 genes (ADAM17 and ATRN) showed East Asian-specific signatures comparable in strength with those observed for MATP and SLC24A5 in Europeans.

While…

The ADTB3A gene also shows a strong and focused signature of positive selection in Africans...

Many hypotheses predict that natural selection will eliminate genetic variants associated with lighter skin in the regions of high UVR as a protection against photo damage (e.g., sunburn, melanoma, and basal and squamous cell carcinomas) (Blum 1961; Kollias et al. 1991) and folic acid photo degradation (Branda and Eaton 1978; Jablonski and Chaplin 2000). The photo protective properties of a highly melanized skin and the recent African origin of modern humans suggest that the ancestral phenotype is one of the relatively dark skin (Jablonski and Chaplin 2000; Rogers et al. 2004). If dark skin is the ancestral phenotype, then we may assume that the first migrants out of Africa were relatively darkly pigmented…

There are 2 primary explanations for the evolution of lighter skin in regions of low UVR:

—1)The first suggests that light skin is merely due to the relaxation of functional constraint and that derived alleles associated with lighter pigmentation may have simply drifted to high frequency in the absence of strong purifying selection (Brace 1963).

—2)The second explanation suggests that in lower UVR regions, positive selection would have favored mutations leading to lighter skin as a way to maximize cutaneous vitamin D synthesis (Rana et al. 1999; Jablonski and Chaplin 200). Given the relatively recent arrival and divergence of humans in and across Europe and Asia, the most parsimonious evolution of light skin would involve such mutations arising in a proto-Eurasian population soon after humans left Africa.

Consequently, these mutations should be shared between modern Asian and European populations. Alternatively, if separate existing functional variants were driven to high frequency in East Asian and Europeans or independent de novo mutations arose and were selected in each population after divergence of Europeans and Asians, then these would be obvious as high allele frequency differences between modern European and East Asian populations. Reduced levels of heterozygosity surrounding the SLC24A5 A111G polymorphism in the European, but not East Asian, HapMap populations support the latter hypothesis (Lamason et al. 2005), as do reduced polymorphism levels based on full resequencing data from MATP in populations of European descent (Soejima et al. 2005).

So basically, while “SLC24A5, MATP, and TYR have a predominant role in the evolution of light skin in Europeans,” the ADAM17, ATRN, and DCT appear to play a dominant role in the evolution of light skin in East Asians.

Current archeological evidence suggests human presence in Island Melanesia by at least 40ky ago and in other parts of Sahul by at least 45ky ago (O’Connell and Allen 2004). If the original migrants to Oceania arrived there via a corridor of relatively high UVR, then we might expect their descendants to share ancestral pigmentation variants with African populations. However, if the ancestors of modern day Island Melanesians spent a significant amount of time in low-UVR, then it is possible that mutations associated with lighter pigmentation could have accumulated and a readaptation to high-UVR conditions would have been necessary, leading to potential divergence between Island Melanesians and Africans at functional pigmentation loci. In actuality, both of these scenarios may apply, as we know that modern Island Melanesian populations are descended broth early migrants (arriving 40ky ago) as well as later proto-Austronesian-speaking peoples from a southeast Asian homeland ~ 3,200 years ago (Spriggs 1997).

The discordance between our Fst -based divergence values and allele frequencies in the Melanesian CEPH populations at ASIP largely stem from the relatively low frequency of the ancestral allele in the 2 CEPH Island Melanesian populations relative to our original Island Melanesian sample. These discrepancies make it difficult to determine if ASIP truly underlies broad pigmentation differences between darkly and lightly pigmented populations or instead inter-population variation at this locus can largely be explained by differences between Africans and non-Africans. The discordance between the frequencies of the ASIP ancestral allele in our original Island Melanesian sample and the Melanesian samples from the CEPH panel may be indicative of both the complex demographic history of Island Melanesia (involving several migratory events (Spriggs 1997) and probable extensive genetic drift (Friendlaender 1975, 1987) as well as the importance of multiple loci in determining pigmentation phenotype…

Thus possible further extensions of variations detected amongst Melanesians can be explained by successive demographic events After their African ancestors migrated over 40ky ago. The “original Melanesian sample” appears to have more ancestral pigmentation genes in common with tropical Africans, which is to be expected given that they are direct descendants of the earliest Eurasians, as demonstrated as follows with the OCA2 gene…

In general, the derived allele (associated with lighter pigmentation) is most common in Europeans and East Asians, and the ancestral allele predominates in sub-Saharan Africa and Island Melanesia.

The mutations in the OCA2 gene may well have implications on imparting paleness, as demonstrated in the south African San people…

The lightly pigmented hunter-gatherer San populations of Southern Africa is exceptional in having a high frequency of the derived allele relative to geographically proximate and more darkly pigmented African populations (Jablonski and Chaplin 2000), further supporting the importance of OCA2 in regulating normal variation in pigmentation. The widespread distribution of the derived allele in the CEPH-Diversity Panel suggests that it is not necessarily a new mutation, nor has it been restricted to a specific geographic area.

While it seems plausible that the “derived” OCA2 gene came to being before the out-of-Africa migration that give rise to modern Eurasians, it doesn’t appear that this derived allele was necessarily widespread, and may well have been later on selected for in European and East Asians…

Interestingly, derived allele frequencies at this locus are quite different between Native American (15%) and East Asian populations (45%), suggesting that perhaps the derived allele at this locus did not reach very high frequencies in East Asians until after the colonization of the Americas

Contrast the situation with OCA2 gene with that of the MATP 374*G allele…

The virtual absence of MATP 374*G-derived allele in the sub-Saharan African populations that we examined in the CEPH-Diversity Panel is consistent with the origin of this mutation outside of Africa AFTER the divergence of modern Asians and Europeans.

Contrasting that of the “derived” SLC24 A5 [as in the case with the “derived” OCA2 allele], where two possible scenarios arise…

In contrast, the SLC24 A5 11*A-derived allele is found at low frequencies in several sub-Saharan populations including the West African Mandinka and Yoruba, the Southern African San, and South West Bantu. *The presence of the derived allele (albeit at low frequencies) in some sub-Saharan populations may be due to recent gene flow from European and Central Asian populations...

—1)The relatively high frequencies of the derived allele in Central Asian, Middle Eastern, and North Africa seem likely to be due to recent gene flow with European populations.

—2)Alternatively, the derived allele may have lost in the ancestors of modern East Asians but retained in the ancestral European populations. The allele then rose to high frequency in Europeans following the divergence of Europeans and East Asian ancestral groups.

The different mechanism of the evolution of light skin in Europeans and East Asians apparent from genetic examination, supports the understanding that evolution of pale skin came very late, because if had occurred prior to the divergence of the Europeans and East Asians, then it seems highly plausible that they would share more in common with one another the dominating alleles in playing a role in skin lightening…but as demonstrated, different set of alleles play dominating role in the lightening effect of the skin in Europeans and East Asians…

These results simultaneously and strongly suggest that Europeans and East Asians have evolved lighter skin independently and via distinct genetic mechanism, as there is an absence of any unusual pattern of diversity at SLC24A5, MATP, and TYR in East Asians.

The interesting part of the study, is this about the MC1R gene about its…

The MCIR gene was the only locus examined in detail that did not show any signal of potential positive selection. Previous sequence-based studies have reached conflicting conclusions about whether or not MC1R has been subject to positive selection outside of Africa (Rana et al. 1999; Harding et al. 2000; Makova et al. 2001).

Although MC1R’s association with red hair, fair skin, freckles, and melanorma risk in European and European-derived populations primarily from the British Isles (Box et al. 1997; Smith et al. 1998a; Schioth et al. 1999; Flanagan et al. 2000; Bastiaens et al. 2001) clearly demonstrates the important regional role that it plays in pigmentation, MC1R may have (with some exceptions [John et al. 2003; Nakayama et al. 2006]) little effect on variation outside of Europe (Myles et al. 2006). Consequently, no signal will be detected using our approaches.

Although the 2 SNPs that we typed in MC1R are not strongly associated with the red hair and fair skinned phenotype for which MC1R is so well known (Sturm et al. 2003), both are polymorphic in global surveys of populations (Rana et al. 1999; Harding et al. 2000). In addition, the MC1r G92A SNP may have a ”mild” effect on pigmentation phenotype (Motokawa et al. 2006). The 92*A allele at this site is known to have a lower affinity for alpha-MSH than wild-type MC1R alleles (Xu et al. 1996), which suggests that it may contribute to **normal** variation in pigmentation. However, if positive directional selection has acted on MC1R, we would expect variation at linked sites to be affected. As such, even if have not assayed the relevant SNP, we should still have observed some signal selection, especially given the small size (~3 kb) of this gene.

So polymorphisms in the MC1R gene seem to have had relatively more impact in Europeans than other populations. Perhaps this might have something to do with the effects of MCIR mutations in Europeans having an "exacerbating effect", i.e. in addition to those of other “pigmentation”-influencing alleles therein…or maybe to some degree, tenuously linked to the effects of one or the other, or a few of those lightening alleles in Europeans.

Finally, the seem to be a strong case for the ASIP and OCA2 genes in playing a role as a tale-teller [by way of ‘ancestral‘ genes and their ‘derived’ counterparts ] of the derivation of non-Africans from Africans, the populations wherein polymorphisms at these loci could well have played a role in skin tone variation to some degree or another…

The pattern of diversity at ASIP 8818*G allele (the ancestral allele associated with darker pigmentation) indicates a role primarily in African/non divergence (sub-Saharan African frequency; 66%, all other populations; 14%) rather than between darkly and lightly pigmented populations. At OCA2 355, the derived allele (linked with lighter pigmentation) occurs at its highest frequencies across Europe and Asia, but is also relatively common among Native American populations (18-34%) and is present at much lower frequencies (0-10%) among Bantu-speaking African groups. In contrast, the ancestral allele associated with **dark** pigmentation has a shared **high frequency** in sub-Saharan African and Island Melanesians...

Observed patterns of global skin pigmentation diversity and their correlation with environmental UV exposure suggest an adaptive response. Although we cannot rule out a role for sexual selection, our results support multiple genetic mechanisms for evolution of skin color. We provide evidence that at least 2 genes, ASIP and OCA2, probably played a shared role in shaping light and dark pigmentation across the globe.

Aside from non-sequitur about the need for “uniformity” in dark hue in ancestral humans, considering that not even a single immediate family or household will necessarily pass for such a ridiculous test, all in all, Kittles et al.’s analysis lend strong support to the claims made by the likes of Jablonski, about dark skin being the original or default state of Homo Sapien Sapiens!

As a matter of fact, this paper discredits Frank Sweet's claim on his "Onedroprule" site, about the "default" human skin tone being light brown of the likes of Khoisan, and the "supposed dark tone of Bantus being more recent", as others and the present author himself have demonstrated in "Egyptsearch.com" discussions. There is no evidence that Africans in their ancestral skin tone state were uniformly dark skin, but preponderance of evidence does show that dark skin was the ancestral state of human skin pigmentation. As noted already, the ancestral alleles appear to be shared between dark skin populations like Melanesisans and tropical Africans.

This posting above, is itself a slightly modified repro of earlier posting in the following link: White race very young [clickable Egyptsearch link]

Referenced source: Genetic Evidence for the Convergent Evolution of Light Skin in Europeans and East Asians, by Rick Kittles et al. , 2006.

Link to part 2: Skin pigmentation gene alleles — Part 2 [clickable]