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Post by Admin on Jan 25, 2021 23:26:29 GMT
Skin color adaptation in modern Eurasians In Europeans, SLC24A5 and SLC45A2 [16,17,18,19] are two golden genes related to the evolution of the light skin color. SLC24A5 encodes the NCKX5 protein, which is a member of the transmembrane protein family and regulates the calcium concentration in the melanosome [16]. This gene has been confirmed to affect pigmentation in zebrafish and mice [16, 20]. Especially, the derived allele of rs1426654 in SLC24A5 was found to be nearly fixed in Europeans, but almost missing in populations without any European ancestry (Fig. 2) [21]. A 78-kb haplotype around SLC24A5, which is in linkage disequilibrium with rs1426654, was also identified to accumulate in Europeans [22]. A similar pattern can be observed at rs16891982 in SLC45A2 [23], which has been reported to be associated with pigmentation in several species, e.g., mice, fish, birds, and horses [24,25,26]. Other variants in this gene, including rs26722, rs2287949, and rs40132, were also shown to be coloration-associated in Europeans [23, 27, 28]. Another important pigmentation-related gene identified in European is MC1R [29,30,31]. This gene is expressed in melanocytes and plays a key role in controlling the switch from pheomelanin to eumelanin [31]. The pigmentary phenotypes associated with MC1R has been studied in a wide range of animals [32,33,34]. Many variants have been identified in MC1R, such as rs1805007, rs1805008, and rs3212357 [35, 36], despite its small size (951 bp). Other important European-specific loci include rs1393350 in TYR, rs2733831 in TYRP1, and rs1900758 in OCA2 [17, 28, 37,38,39]. The derived allele frequencies at these loci are high in Europeans but low in Africans and East Asians, which could be a clear signal of positive selection in Europeans, as indicated by statistical analysis [40]. Fig. 2 Evolutionary model of human pigmentation in three continental populations. The rooted tree shows the genetic phylogeny of human populations from Africa, North Europe and East Asia, with the colors of the branches roughly indicating the generalized skin pigmetation level of these populations (adapted from McEvoy et al. (2006) [39]). Genetic loci reported to be under positive selection in the common ancestor of modern Eurasians are represented by rs1881227 in KITLG, and those independently evolved in Europeans and East Asians, indicating possible convergent evolution, are represented by rs12913832 in OCA2 and rs885479 in MC1R, respectively. The maps of allele frequency were drawn using R (version 3.2.1, , based on these loci in 53 global populations provided by the Human Genome Diversity Panel CEPH (HGDP, www.hagsc.org/hgdp/index.html). Blue and red colors denote the ancestral and derived alleles, respectively Genes involved in the skin color adaptation in East Asians are not that well studied compared to the long list of adaptive genes identified in Europeans. Notable examples include OCA2 and MC1R. Each harbors several non-synonymous mutations, e.g. rs1800414 and rs74653330 in OCA2, and rs885479 in MC1R [40,41,42,43], which exhibit high derived allele frequencies in East Asians, but low derived allele frequencies in Europeans and Africans (Fig. 2). The OCA2 protein is thought to be a mature melanosomal membrane protein [44], with a potential role in protein transportation into melanosomes [45]. The East Asian-specific variant of rs1800414 was first reported in an exome sequencing study aiming to figure out albinism-related variants [46]. The derived allele at rs1800414 was thought to contribute to the skin lightening in an association study of Han Chinese, which measured the skin color of individuals using the melanin index [47]. Another non-synonymous variant in OCA2, rs74653330, has also been confirmed to be pigmentation-related in an association study of Japanese [48]. Additional examples of East Asian-specific pigmentation-associated alleles include rs10809814 in TYRP1 and rs1407995 in DCT [40, 49], both of which show differentiation between Asians and non-Asians [47], and strong signals of positive selections in Asians [43, 49]. Despite distinct genes and variants under respective local adaptations in Europeans and East Asians, some genes have derived alleles reaching high frequencies in both continental groups. For instance, KITLG exhibits a selective sweep in non-Africans [50,51,52]. This gene is widely expressed in multiple tissues, including the skin, and functions in organ morphogenesis and cell proliferation. The Kit-ligand encoded by KITLG is known as the steel factor and plays a crucial role in the normal development and maintenance of the melanocyte lineage in adult skin [53]; this has been proved in human, fish, and mice [54,55,56]. The effects of this gene on pigmentation have also been confirmed in a series of association studies [57,58,59,60]. One of the key variants is rs642742, which is located at 326 kb upstream to the transcription start site of KITLG. At this variant, the ancestral allele frequency is over 90% in Africans, comparable to the derived allele frequency in Europeans and East Asians (Fig. 2). Similar patterns were observed in other genes, e.g., ASIP and BNC2 [39]. Two models of the evolutionary architecture of human pigmentation were proposed on the basis of the above results and other related studies (Fig. 2). One is a convergent evolution model [17, 40, 43, 49], suggesting that depigmentation has, to some degree, evolved independently in Europeans and East Asians, as different genes and variants have been suggested to explain the light skin and positive selection in these two continental groups. A recent study estimated the time of selective sweeps for the European-specific pigmentation variants to be around 11,000–19,000 years ago, after the divergence of Europeans and Asians [61]. An alternative model fits for the shared selective sweeps of Europeans and East Asians, which could possibly occur in proto-Eurasians. The onset of the sweep was estimated to be approximately 30,000 years ago, right after the “Out-of-Africa” migration, but earlier than the European-specific evolution on pigmentation [61]. The coexistence of these two models suggests a complex evolutionary history of skin color in modern humans. Another clue of the complex genetic basis of skin color evolution is the allelic heterogeneity observed in a single gene, like OCA2 and MC1R. In each of these genes, some alleles are specific to Europeans, whereas others are specific to Asians, although they all have been proved to be depigmentation-related. In addition, OCA2 provides evidence of independent sweeps as well as convergent evolution in Europeans and Asians. Since results were obtained from studies using different samples, data, and methods, there could be some confounding factors leading to these different observations. However, more importantly, skin color is a complex trait that could not be simply explained by a single gene or variant; rather, it is likely to involve a huge network of genes and phenotypes. For instance, ASIP, an adaptive pigmentation gene in populations with European ancestry [62, 63], encodes the agouti signaling protein, which blocks MC1R in the eumelanin synthesis in response to the UV-induced DNA damage [40]. In the melanin production, TYR acts as the catalyzer of the key initial step, and its stability is maintained by TYRP1 and DCT. In addition, scans for selection on skin pigmentation indicate two different selection behaviors acting on de novo mutations and standing variations, respectively. Some variants, represented by rs1805007 and rs1805008 in MC1R (in Europeans) and rs1800414 in OCA2 (in Asians), only show derived alleles in populations under positive selection at these loci, from which we could conjecture that they are new mutations that appeared after modern humans settled in Europe or Asia. In contrast, some variants, such as rs3212357 in MC1R (under positive selection in Europeans), present low frequencies in Africans. Regardless of possible mutation events and genetic drift in African populations, it is more likely that the derived allele at this locus has presented for some time before they became favored. Similar cases have been found in the high-altitude adaptation of Tibetans and the immunity adaptation in some modern human populations, and even in the evolution of pigmentation phenotypes in non-human species [56, 64].
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Post by Admin on Jan 26, 2021 19:38:54 GMT
Skin color adaptation in the admixed populations Admixed populations, the hybrid offspring of two previously isolated populations, may provide important insights in understanding the genetics of geographical variation for two reasons. First, the loci underlying phenotypic differences in ancestral populations are also overlapping the highly informative markers of ancestry, which makes the admixed populations particularly useful for tracing population history. Second, the admixed populations usually have a wide range of variations regarding some specific phenotypes, which may increase the power of locating genes associated with complex traits/diseases after controlling potential population stratification. Despite these advantages, admixed populations have rarely been considered in studies of human pigmentation variation. Current studies investigating pigmentation genes in admixed populations mainly involved those with African and European ancestry, such as African Americans, European Africans, and Latin Americans, since their ancestral populations are substantially differentiated in skin color. The ancestral genetic makeups differ among these three populations. African-Americans obtained the largest genetic contribution (~80%) from the African ancestry [65], Latin American mestizos have the least proportion of African ancestry (~10%) [66, 67], while in European Africans, the genetic components inherited from Europeans (~42%) and Africans (~58%) are comparable [68]. Uniquely in the Latin Americans, a considerable proportion of Native American ancestry (~45%) exists [66, 67]. Moreover, on the individual level, the proportion of each ancestry exhibits a large variance in each admixed population. For instance, the fraction of European ancestry varies from 2% to 98% among African American individuals [65]. The large variance of skin color in admixed individuals could result from their highly diverse genetic makeup, as a substantial correlation has been observed between ancestry proportion and skin color [68,69,70]. Multiple well-known candidate genes for pigmentation in Europeans have also been identified by admixture mapping (Fig. 3) or association studies in admixed populations. For instance, TYR, carrying a non-synonymous substitution rs1042602 (S192Y), was identified in African Americans [69] and European Africans from Cape Verde [68]. Variants in ASIP, such as rs6058017, which has been found to occur at different frequencies in global populations [63], were also reported to be associated with dark hair and brown eyes in European Americans [71], African Americans [62] and Brazilians [72]. Furthermore, KITLG showed strong signals of selective sweep in African Americans [51], with a significant preference to homozygotes of the African-specific allele (ancestral allele) at rs642742 in individuals with high melanin index (dark skin) [69]. Similar cases include rs1426654 in SLC24A5 in European Africans [68] and Latin Americans [72], and rs35395 in SLC45A2 in European Africans [68]. Fig. 3 However, some studies reported discrepant results. The correlation between Native American ancestry and skin pigmentation reported in a Hispanic population [73] was not observed in a group of Puerto Rican women [70]. One of the key single nucleotide polymorphism loci (SNPs) in OCA2, rs1800404, showed a significant effect on skin pigmentation when analyzing African Americans and a combined population of African American and African-Caribbean, but was absent in an independent analysis of the African-Caribbean samples [69]. It is possible that different genetic mechanisms of skin color variation exist in various populations, but cautions should be taken regarding detailed information in the data, such as sample size and the ancestral populations selected for analyzing the admixed populations, which could lead to biased results [67, 69]. The identification of genetic determinants of natural variation of skin pigmentation was also conducted in other admixed populations. One successful example is a genome-wide association study of a population of South Asian descent [74], in which polymorphisms in SLC24A5, TYR and SLC45A2 showed significant associations with the melanin content in skin. The light skin alleles in South Asian could possibly be inherited from their European ancestors [75], who initially arrived at this region around 3500–4000 years ago along with Indo-European language expansion [76], followed by recent colonization in the last few centuries. In addition, Central Asia and Southeast Asia are home to various admixed populations, which are likewise of great potential in the study of skin color adaptation. Admixed population analyses may greatly enrich our understanding of skin color variation in modern human populations.
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Post by Admin on Jan 26, 2021 22:53:18 GMT
Skin color adaptation in the aboriginal populations The aboriginal populations in different areas around the world have many implications for human evolutionary history. They have been regarded as the early settlers in respective areas. Despite having been assimilated by their surrounding agriculturalists to some extent, some aboriginal people have preserved their traditional livelihoods as hunter-gatherers, as well as their original physical traits – dark skin, short stature, and curly hair. The hunter-gatherer populations with dark skin, short stature and curly hair have attracted much attention (Fig. 4a). The genetic mechanism underlying the shared phenotypes among these geographically distant populations (collectively called Negritos or Pygmies), from Central Africa, the Andaman Islands, Southeast Asia and Oceania, are still controversial; for example, whether they were the common descent from a pre-Neolithic substrate of humanity or a consequence of convergent evolution [77, 78]. To date, most genetic studies on this issue have focused on height [78,79,80,81]. One study provided clues for convergent evolution from the view of skin pigmentation adaptation by analyzing MC1R diversity in the Melanesians [82]. This study showed that the ancestral haplotypes of MC1R are not highly conserved between Northern Island Melanesians and Africans, although both populations live in the high UV region, which is in contrast to previous findings based on very limited samples [30, 83]. Besides, a non-synonymous polymorphism, rs2228479, shows enriched derived alleles specifically in East Asians, but is not significantly associated with skin or hair pigmentation in Melanesians. Actually, the Melanesian population exhibits striking skin pigmentation variation [84], and consistently, some variants have been identified to be region-specific, which could partly explain this phenotypic variation. A notable example is a non-synonymous variant, rs387907171, in TYRP1 [85]. It is restricted to the Solomons and parts of the Bismarck Archipelago, and might contribute to the ‘blond hair’ in this region [85, 86]. These results emphasize the complex genetic architecture of pigmentation phenotypes, and also highlight the role that population history (e.g., the complex population history of the Southwest Pacific [87,88,89]) can play a role in influencing phenotypic diversity. Skin pigmentation studies on other modern aboriginal populations (besides Melanesians) are scarce, except for one investigating the Senoi population (an indigenous population) from the Malay Peninsula, which is an admixture of the Negrito (dark-skinned) and the southern Mongoloid from Indo-China (yellow-brown-skinned), and has a wide skin color spectrum [90]. The authors of this study found that despite the low derived allele frequency, the A111T mutation (rs1426654) in SLC24A5 is significantly associated with the light skin in Senoi, which was suspected to result from the admixture of the Mongoloid and South Asians. Fig. 4 Another interesting issue concerning human skin color adaptation comes from the arctic people. The Inuit people, in far North Eastern Asia and the American Subarctic, have yellowish-brown skin despite the far northern latitude at which they live, unlike other populations living at the same latitude, such as the Swedes and Finnish (Fig. 4b). This makes the Inuit population an exception of the latitude-correlated distribution of skin color. One possible reason is that the dark skin could protect the Inuits from the severe UV exposure because of the long daylight hours in winter and high levels of UV reflection from the snow. While the dark skin is a disadvantage for vitamin D production, plenty of vitamins including vitamin D could be compensated from their diets [91, 92]. Another cause could be the founder effect of the ancient East Asian ancestry of the Inuits, who have inhabited the arctic region since nearly 5000 years ago, and had higher melanin production than the European ancestry. However, very few genetic studies have been conducted to determine the genetic basis of dark skin in arctic populations. Skin color adaptation in the ancient hominins The dark skin in modern humans was established around 1.2 million years ago, driven by the loss of body hair after divergence from apes, presumably to protect against UV-induced damages [13, 93,94,95,96]. Then, when did modern Eurasians start to depigment? The studies on skin color adaptation summarized above are based on modern population genetic data, which may suffer from limited temporal resolution caused by the population demographic history, and insensitivity to selection acting on standing variations [97]. The advent of ancient DNA analyses makes it possible to directly observe the evolution processes, and thus would facilitate our understanding of this key question. A study on the genomes of Anatolian Neolithic farmers in West Eurasia (6500–300 BC), who are probably the source population of the first European farmers, suggests that the light skin color has been evolved since at least 6500–4000 years ago [98]. Several popular genes identified in modern Eurasians, e.g., SLC45A2, GRM5 and HERC2/OCA2 showed strong signal of selection in these ancient samples. This conclusion is supported by another study based on the Eneolithic (6500–5000 BP) and Bronze Age (5000–4000 BP) samples, representing the early European farmers or late hunter-gatherers in central Europe [99]. One possible motivation of the skin depigmentation in prehistoric Eurasia is agriculturalization, which led to a switch from vitamin D-rich hunter-gatherer diet to a vitamin D-poor agriculturalist diet, together with the increased danger of folic acid deficiency at higher latitudes [14, 100]. Moreover, the selective pressures have kept operating for a long time after they initiated the adaptation of skin color, as some ancestral pigmentations alleles were identified in a Mesolithic European (7000 BP), and some adaptive alleles under selection in the ancient Eurasians are still evolving in modern humans [98, 99, 101]. Recent studies on archaic hominins (e.g., Neanderthals, an extinct hominid group living in Eurasia ~400,000–28,000 years ago [102]) further improved our understanding of skin color evolution in modern humans. Neanderthals met modern humans in the Middle East ~60,000–50,000 years ago, and contributed to about 1–4% of modern human genomes [103,104,105]. Some pigmentation-associated genes are identified in the introgressed haplotypes from Neanderthals in modern Eurasians, such as POU2F3, BNC2 and MC1R [106, 107]. Specifically, the introgressive alleles were reported to result in light skin color, suggesting an ‘adaptive introgression’ strategy of human skin color adaptation. Other introgressive genes related to skin phenotypes include HYAL genes, which are associated with cellular responses to UV and are under strong positive selection in East Asians [108], and those involved in keratin filaments formation [109]. Although these genes are not direct determinants of skin pigmentation, they, like those pigmentation-related genes, possibly helped modern humans adapt to non-African environments. When drawing conclusions of adaptive introgression, we are actually claiming that Neanderthals could be light-complexioned. This inference is just based on some pigmentation-associated genes or alleles identified in existing modern human populations, since visible phenotypes of Neanderthals and other extinct species are not available. However, when using some other priory genes as potential clues, different results can be obtained. For instance, the derived state of MC1R, which is responsible for pale skin, presents in Neanderthal individuals from Italy and Spain but is missing in Croatian Neanderthals and Denisova [110], suggesting skin color variation in the archaic hominins. In addition, the light skin in Neanderthals and modern Eurasians could also result from convergent evolution, rather than adaptive introgression [111]. The hypothesis of adaptive introgression seems to predate when modern human became pale – long before the late Mesolithic age, as Neanderthals went extinct around 28,000 years ago. However, we should reconsider whether the genes affecting skin color in archaic hominins indeed determined skin color in modern humans. Even if this is the case, it is also possible that modern human retained these introgressive variants until they showed some phenotypic effects under some specific strong selective pressures. Thus, more data resources and analyses are necessary to address this issue in the future. Selection coefficient and effect size As one of the most obvious changes in the environment after modern human migrated out of Africa to higher latitudes, UV has exerted considerable selective pressures on human skin pigmentation, which can be reflected by selection coefficients of the pigmentation-related genes. The estimation of selection coefficients largely depends on the genes considered and the methodologies. Beleza et al. estimated the coefficient of selection at several loci representing SLC24A5, SLC45A2, TYRP1, and KITLG [61]. For example, the estimates are 0.05/0.04 for SLC45A2 and 0.16/0.08 for SLC24A5 under a dominant/an additive model of inheritance in Europeans. Meanwhile, López et al. reported the selection coefficient of a variant in SLC45A2 to be 0.01–0.02 in a South European populations [112]. These estimations are comparable to the selection coefficients inferred directly from serially sampled data at HERC2, SLC45A2, and TYR, ranging from 0.02–0.1 [99]. The selection coefficients estimated for pigmentation genes are best understood in the context of estimates for other recently selected loci. The selection advantages are inferred to be 0.01–0.08 for LCT, a gene strongly associated with lactase persistence in populations with European ancestry [113, 114], 0.019–0.048 for G6PD, a gene conferring malaria resistance in African populations [115], 0.03–0.19 for EDAR associated with the increased scalp hair thickness and changed tooth morphology in the Han Chinese [116], and 0.0004–0.0023 for EGLN1 and EPAS1 gene regions contributing to the high-altitude adaptation in Tibetans [117]. The selection coefficients for pigmentation genes are among the most strongly selected genes in the human genome, indicating a severe selective pressure caused by UV or some other environmental changes in non-African regions. Although a large number of genes have been identified to contribute to skin color variation, how much could they explain the skin color variation in modern humans? Is there a gene or variant that has a dominant effect on the skin color? Some genes could possibly play a major role in determining skin color in specific populations. For instance, the light skin variant at rs1426654 in SLC24A5 could explain 22–32% of the variance of the melanin index in South Asian [75] and 25–38% in African-American and African-Caribbean populations [118]. Additionally, the derived allele at rs642742 in KITLG may account for lightening of a person’s skin by 6 to 7 melanin units, nearly 1/5 of the overall skin reflectance difference between West Africans and Europeans (30 melanin units) [56]. However, there are relatively more genes and variants with smaller effects. One of the key variants in OCA2, rs1800414, could explain around 4% of the pigmentation variation in East Asian populations [47]. In South Asians, rs16891982 in SLC45A2 and rs1042602 in TYR account for 3.6% and 2.5% skin color variation, respectively, much less than the effect size of rs1426654 in SLC24A5 [74]. The inheritance mode of skin pigmentation follows an additive model, or at least an incomplete additive model [16, 17, 47, 56, 75]. Conclusions Overall, human skin color is a highly variable and complex trait as a consequence of strong selection pressure and is controlled by multiple genetic loci ( summarized in Table 1). Skin color adaptation is a complex process because different populations have shared and independent genetic mechanisms involving a large number of genes with different effect advantages on the phenotype. Skin color adaptation is also a long evolutionary process influenced by various historical, even pre-historical, population genetic events. Current studies provide comprehensive insights into the natural selection process and mechanisms of human skin color variation. A richer resource of high-coverage whole-genome sequences and phenotype data may provide opportunities to further speculate an accurate model of genetic architecture and gene-environment effects, and advance our understanding of skin pigmentation in certain minor ethnic groups, such as hunter-gatherers and highlanders. We believe that these studies may greatly enrich our knowledge of human evolution history and elucidate the genetic basis of complex traits in humans.
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Post by Admin on Jan 27, 2021 21:16:44 GMT
Darwinian Positive Selection on the Pleiotropic Effects of KITLG Explain Skin Pigmentation and Winter Temperature Adaptation in Eurasians
Abstract Human skin color diversity is considered an adaptation to environmental conditions such as UV radiation. Investigations into the genetic bases of such adaptation have identified a group of pigmentation genes contributing to skin color diversity in African and non-African populations. Here, we present a population analysis of the pigmentation gene KITLG with previously reported signal of Darwinian positive selection in both European and East Asian populations. We demonstrated that there had been recurrent selective events in the upstream and the downstream regions of KITLG in Eurasian populations. More importantly, besides the expected selection on the KITLG variants favoring light skin in coping with the weak UV radiation at high latitude, we observed a KITLG variant showing adaptation to winter temperature. In particular, compared with UV radiation, winter temperature showed a much stronger correlation with the prevalence of the presumably adaptive KITLG allele in Asian populations. This observation was further supported by the in vitro functional test at low temperature. Consequently, the pleiotropic effects of KITLG, that is, pigmentation and thermogenesis were both targeted by natural selection that acted on different KITLG sequence variants, contributing to the adaptation of Eurasians to both UV radiation and winter temperature at high latitude areas.
Modern humans originated in Africa ∼200,000–300,000 years ago, and they spread to the other parts of the world <75,000 years ago (Pagani et al. 2016; Hublin et al. 2017). During the “Out of Africa” migration, modern humans moved from a near-equator tropical environment into high-latitude subtropical and frigid regions with entirely different environmental conditions, such as reduced UV radiation and much colder weather in winter.
Skin color is thought to be one of the key human traits responding to the environmental changes (Jablonski and Chaplin 2000, 2010). Recent studies on diverse African populations indicated a complex architecture of skin pigmentation due to different local evolutionary pressures, with derived alleles in several genes associated with both light and dark skin (e.g., SLC24A5, MFSD12, DDB1, TMEM138, SMARCA2/VLDLR, and SNX13) (Crawford et al. 2017; Martin et al. 2017). By contrast, Europeans and East Asians live in high-latitude environments with weak light, and selection on vitamin D synthesis, a key nutrient for bone development would favor a lighter skin in these populations (Loomis 1967). Previous investigations into skin lightening in Eurasians have found a set of pigmentation genes showing molecular signatures of Darwinian positive selection. For example, OCA2 serves as the key gene for skin lightening in East Asians (Yuasa et al. 2007; Edwards et al. 2010; Donnelly et al. 2012; Eaton et al. 2015; Murray et al. 2015; Gittelman et al. 2016; Yang et al. 2016; Rawofi et al. 2017 ). In Europeans, there are other responsible genes including SLC24A5, SLC45A2, KITLG, TYR, OCA2, MC1R, ASIP, and IRF4 (Graf et al. 2005; Lamason et al. 2005; Izagirre et al. 2006; McEvoy et al. 2006; Norton et al. 2006; Yuasa et al. 2006; Lao et al. 2007; Miller et al. 2007; Sabeti et al. 2007; Soejima and Koda 2007; Sulem et al. 2007; Han et al. 2008; Basu Mallick et al. 2013; Beleza, Johnson, et al. 2013). Interestingly, most of the identified pigmentation genes responsible for skin lightening are not shared between East Asians and Europeans, suggesting convergent evolution of skin pigmentation in non-African populations (Norton et al. 2006; Edwards et al. 2010; Yang et al. 2016).
In addition to UV radiation, temperature is also an important environmental factor that could affect human skin color. During the Korean War in 1950s, it was observed that soldiers of African–American descent were more susceptible to cold injury than those of European–American descent (Post et al. 1975). In addition, it was reported that melanocytes are more susceptible to cold injury than the hair follicle. Cooling or freezing the skin of black rats could kill the melanocytes, but not the hair follicles which subsequently produced hair of normal shape and texture, albeit lacking pigment (Taylor 1949; Post et al. 1975). This finding was further supported by another hair neogenesis study (Mikhail 1963). Consequently, it was proposed that cold climate might be a contributing factor during the emergence of “white” skin (Post et al. 1975). However, during the past half a century, this “cold hypothesis” has not been rigorously tested.
Recently, the pigmentation gene KITLG (also named the stem cell factor, SCF) was reported involved in mitochondrial function and energy expenditure in brown adipose tissue under cold condition (Nishio et al. 2012; Huang et al. 2014). Overnight exposure of mice to cold temperature increases the level and ratio of soluble Kitl protein (encoded by KITLG) in brown adipose tissue and increases thermogenesis and reduces weight gain (Huang et al. 2014). KITLG also serves as an essential factor of brown adipocytes derived from human pluripotent stem cells (Nishio et al. 2012). Additionally, it was shown that working in the cold can retain brown adipose tissue in “strategic” places in human adults (Huttunen et al. 1981).
Besides playing a key role in mitochondrial function and energy expenditure, the KITLG gene has been well known as a pigmentation gene. It is associated with synthesis of skin and hair pigment, skin sensitivity to sun and freckles (Miller et al. 2007; Sulem et al. 2007; Han et al. 2008; Mengel-From et al. 2009; Guenther et al. 2014), familial progressive hyperpigmentation and hypopigmentation (FPHH) (Wang et al. 2009; Amyere et al. 2011; Cuell et al. 2015) as well as with tumor pathogenesis and Warrdensburg Syndrome Type 2 (with pigmentary abnormalities) (Rapley et al. 2009; Zazo Seco et al. 2015). KITLG encodes the ligand for the receptor tyrosine kinase KIT that rivet on the melanocyte. KITLG and its protein–tyrosine kinase receptor KIT are implicated in the regulation of diverse biological processes, particularly in melanogenesis, including melanoblast and melanocyte migration, proliferation and differentiation during embryogenesis, and also for maintaining postnatal cutaneous melanogenesis (Bedell et al. 1995; Grichnik et al. 1998; Wehrle-Haller 2003; Kasamatsu et al. 2008). For example, a regulatory sequence change in KITLG contributed to natural variation in vertebrate pigmentation, and that similar mechanism underlies pigmentary change in both fish and humans (Miller et al. 2007). Additionally, a strong signal of positive selection on the regulatory regions surrounding the gene was also reported in Eurasians, and two variants (rs642742 and rs12821256) located 300- to 350-kb upstream of the KITLG transcription start site had a significant effect on skin color of African–Americans and hair color of Europeans (Miller et al. 2007; Williamson et al. 2007; Guenther et al. 2014). Taken together, these data suggest that KITLG is pleiotropic and may contribute to human adaptation to both UV radiation and temperature change.
In the current study, we conducted a population analysis of KITLG, and we showed that besides UV radiation, winter temperature may have an even stronger correlation with the prevalence of the presumably adaptive allele of KITLG in Asian populations. Natural selection had acted on different KITLG sequence variants, leading to the adaptation of Eurasians to both the weak UV radiation and the cold winter temperature at high latitude areas.
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Post by Admin on Jan 28, 2021 1:30:02 GMT
Results Detection of Positive Selection and the Molecular History of KITLG in Eurasians We obtained the selection test results of KITLG (549 kb, including upstream and downstream of KITLG; chr12_88, 803, 520–89, 352, 520, hg19) from the 1000 Genomes Selection Browser (http://hsb.upf.edu). The haplotype-based EHH test detects extended homozygosity surrounding the variant under positive selection, which is sensitive to relatively recent selection (<100,000 years) (Sabeti et al. 2006). In the EHH test, we saw strong selection signals in both Europeans and East Asians, especially in the upstream region (126- to 375-kb upstream of KITLG) (fig. 1A), and this is in agreement with the previous observation (Miller et al. 2007). In the downstream region (57.5 kb downstream of KITLG), we observed a signal of selection in East Asians. In contrast, we did not observe obvious selection signal in Africans in the EHH test. The selection signals of the KITLG upstream and downstream regions in Eurasians were further confirmed by the XP-CLR test (a population-differentiation method, and Africans was used as outgroup), in which the selection on the upstream region is strong in Europeans and relatively weak in East Asians. In addition, the downstream region selection in East Asians was confirmed (fig. 1B). FIG. 1. Test of selection on KITLG in Europeans and East Asians. (A) The EHH score distribution across the 549-kb KITLG region. Each spot in the graph indicates the average value of a 3-kb window. (B) The XP-CLR score distribution across the 549-kb KITLG region. Each spot in the graph indicates the average value of a 2-kb window. The red, blue, and black dotted lines indicate P = 0.05 in East Asians (CHB), Europeans (CEU), and Africans (YRI), respectively. The black arrow indicates the genomic position and transcriptional direction of the KITLG gene. The selection signals in Eurasian populations were also validated by the results of other tests, including Fay and Wu’s H test, Fu and Li’s test, Tajima’s D test, and XP-EHH test (supplementary fig. S1, Supplementary Material online). Interestingly, we detected selection signals in Africans from three allele-frequency-based tests (Fay and Wu’s H test, Fu and Li’s test, and Tajima’s D test). However, Kumar and Liu (2014) have shown that the signal seen in the allele-frequency-based tests was not due to positive selection, and the EHH profile of Africans suggested a trend of neutral evolution. Taken together, these tests suggest selection signals in both Europeans and East Asians in the upstream region of KITLG, and an additional signal of selection in East Asians in the downstream of KITLG. To look into the molecular history of KITLG in human populations, we constructed a maximum-likelihood phylogenetic tree using the 549-kb KITLG sequence data (a total of 540 haplotypes were phased) of three world populations from the 1,000 Genomes Project, including Africans (YRI), Europeans (CEU), and East Asians (CHB). The homologous sequences of chimpanzee and archaic humans (Neanderthal and Denisovan) were used as outgroup. As shown in figure 2A, there are three major clades in the population tree. The allelic status (red for major allele and blue for minor allele) of 727 variants with minor allele frequency >0.05 is illustrated in figure 2B. As expected, Clade-1 is the basal clade and is mostly composed of Africans, and this clade displays a major-allele block in the KITLG gene region (fig. 2B). Clade-2 is similar with Clade-1 in view of major-allele blocks and it includes more Eurasians. Clade-3 is a Eurasian clade and a large major-allele block was observed in the KITLG upstream and downstream region, consistent with the detected strong signal of selection of this region in both Europeans and East Asians (fig. 1).
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