To investigate whether the pigmentation related genes (SLC45A2 and TYR) polymorphisms are associated with the geographic environmental variables (altitude, longitude, latitude, and air pressure, sunshine hours, and annual average temperature), we selected randomly selected 795 healthy individuals from eight ethnic groups in nine provinces in China. The results of this study found that the genotype frequency distribution of rs28777 and rs183671 in SLC45A2 and rs1042602 in TYR were significantly different between the Xinjiang-Uighur and other ethnic groups (P < 0.05). Simultaneously, the rs28777, rs183671, rs1042602, rs1126809 polymorphisms were found to be correlated with the geographic environmental variables (longitude, latitude, sunshine hours or annual average temperature).
SLC45A2 (as also AIM1 or MATP) encodes a transporter protein that mediates melanin synthesis, which is expressed in a high percentage of melanoma cell lines. It has been reported that some SLC45A2 mutations cause OCA4 and polymorphisms of this gene were found to be significantly associated with human skin, hair, and eye pigmentation, and its mutation frequency varies significantly among the global population. Yuko Abe et al. found that rs11568737 in SLC45A2 (T500P) was significantly associated with melanin index [16]. A multi-stage GWAS of natural hair color in European ancestry found that the SNP rs28777 in the SLC45A2 gene was associated with skin color and tanning ability [17]. A large Australian population-based case control study reveal that rs28777 exhibited the strongest crude association with risk of cutaneous malignant melanoma [18]. The rs183671 in the SLC45A2 gene is in strong linkage disequilibrium (LD) with rs16891982 (F374L) in CEU. A previous GWAS declared that the frequency of the rs183671 derived allele increased from Southern to Northern Europe, and this SNP was associated with skin pigmentation, and that each copy of the derived allele lightens the skin by 1.2 M index units [19]. Moreover, a previous GWAS demonstrated that the SNP rs183671 can explain skin color variation in three European studies RS, BTNS, and TwinsUK [20].
TYR is located at human chromosome 11q14.3, and encodes tyrosinase, which regulates the biosynthesis of melanin. Previous studies demonstrated that mutations in TYR can cause OCA1 [15]. The non-synonymous polymorphism rs1042602 (Ser192Tyr) in TYR derived allele has specifically high frequency in Europe, and this SNP was significantly associated with eye color, freckles and lighter skin pigmentation [21–24]. The TYR SNP rs1393350 was found to be associated with human hair, eye and skin color and tanning ability [23, 25–27]. A GWAS of melanoma conducted by the GenoMEL consortium identifies the locus rs1393350 associated with melanoma risk [28]. The rs1126809 variant is located in exon 4 of TYR gene and encodes a tyrosinase enzyme with an arginine-to-glutamine substitution at codon 402 (R402Q), and is in LD with rs1393350 [29, 30]. The mutation of rs1126809 (A-G) causes the TYR enzyme to be thermosensitive, thus less active [31]. The rs1126809 has previously been used as a marker for skin pigmentation and also influence brown eye colour formation [23, 30]. Previous GWAS indicated that the allele A of rs1042602 (TYR) was highly associated with lighter skin color in a South Asian descent population [32]. In has reported that the allele A of rs1042602 was over-represented in the IndoEuropeans population [33]. The two polymorphisms (rs1042602 and rs1126809) in TYR appear at high frequency in Europeans and are largely absent in African populations [34].
This study indicated that the genotype frequency distribution of rs28777 and rs18367 in Xinjiang-Uighur were significantly different from other ethnic groups. Moreover, the allele frequencies of rs28777, rs183671, rs1042602, rs1126809 were negatively correlated with the longitude; rs183671, rs1042602 and rs1126809 allele frequencies were positively associated with the latitude and the sunshine hours, while were negatively correlated with the annual average temperature in Chinese population. At present, there are few research reports on the association between genetic polymorphism and environmental factors. In 2010, Ji et al. [35] found that the disease-predisposition polymorphisms of the melatonin receptors were associated with sunshine duration in the global human populations. These results indicated that environmental factors had selective pressure on these loci, and their changes were related to environmental variables, that is, differences in selection caused by differences in environmental factors play an important role in genetic differentiation.
However, this study has some limitations that cannot be ignored. First, the sample size is small and the statistical power is relatively low. Second, this study is the first to explore the correlation between the allele frequencies of these six SNPs and geographical environmental factors. Third, we only selected 6 SNP loci on two genes to explore their correlation with geographical environmental factors. Finally, this study did not design gene functional experiments to explore how allelic variations at SNPs loci lead to the diversity of skin color phenotypes in the human population. Therefore, we will further collect a larger sample and choose more SNPs and design functional experiments to explore the impact of environmental factors on genetic mutations.
In summary, the results of this study indicate that SLC45A2 and TYR polymorphisms (rs28777, rs183671 and 1042602) were different among different populations. More importantly, our results confirm the idea that environmental factors have been an important selective pressure upon pigmentation related gene polymorphisms (rs28777, rs183671, rs1042602 and rs1126809). Further association and functional studies need to confirm our results in a large sample and explore the influence of geographical environment factors on the skin pigmentation-related genes polymorphisms and the mechanism of action.