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Evidence for Variable Selective Pressures at MC1R
Both African and non-African data suggest that the time to the most recent common ancestor is ª1 million years and that the age of the global 314 variant is 650,000 years. On this time scale, ages for the Eurasian distributed Val60Leu, Val92Met, and Arg163Gln variants are 250,000–100,000 years; the ages for African silent variants—Leu106Leu, Cys273Cys, and Phe300Phe—are 110,000–40,000 years. For the European red hair–associated Arg151Cys and Arg160Trp variants, we estimate an age of ª80,000 years; for Asp294His, and Ser316Ser, we estimate an age of <30,000 years. SDs are approximately half these expectations.
These ages are entirely compatible with age distributions estimated for African and non-African mutations in other nuclear genes (Harding et al. 1997; Zietkiewicz et al. 1998). The ages estimated for the Arg151Cys and Arg160Trp red hair–associated variants are consistent with a widespread European distribution, as we also observed.
Red hair associated MC1R variants are Arg151Cys, Asp294His and Arg160Trp (two are 80,000 years old, one 30,000). Val60Leu is associated with fair or light brown hair and is estimated at 250,000 ot 100,000 years.
More MC1R studies..
Melanocortin 1 receptor (MC1R) gene variants are associated with an increased risk for cutaneous melanoma which is largely independent of skin type and hair color
Individuals carrying melanocortin 1 receptor gene variants have an increased risk for the development of cutaneous melanoma. Melanocortin 1 receptor gene variants are also associated with other risk factors for melanoma such as fair skin and red hair. We evaluated the relationship of melanocortin 1 receptor gene variants, fair skin, red hair and the development of melanoma in 123 patients with cutaneous melanoma and 385 control subjects. To analyze the association between melanocortin 1 receptor gene variants and skin type or hair color we also made use of 453 patients with nonmelanoma skin cancer. We analyzed the coding sequence of the melanocortin 1 receptor gene region by single-stranded conformation polymorphism analysis, followed by DNA sequence analysis. Risk of melanoma dependent on the various melanocortin 1 receptor variant alleles was estimated by exposure odds ratios. The analyses of all different melanocortin 1 receptor gene variants combined, showed that the presence of melanocortin 1 receptor gene variants amounted to a higher melanoma risk, which, in stratified analyses, was independent of skin type and hair color. The odds ratios after adjusting for skin type were 3.6 (95% CI 1.7-7.2) for two variants and 2.7 (95% CI 1.5-5.1) for one variant, respectively. Compound heterozygotes and homozygotes for the Val60Leu, Val92Met, Arg142His, Arg151Cys, Arg160Trp, Arg163Gln, and His260Pro variants had odds ratios of about 4 to develop melanoma, whereas heterozygotes for these variants had half the risk. The presence of the melanocortin 1 receptor gene variant Asp84Glu appeared to impose the highest risk for cutaneous melanoma with odds ratios of 16.1 (95% CI 2.3-139.0) and 8.1 (95% CI 1.2-55.9) in compound heterozygotes and heterozygotes, respectively. The broad confidence intervals, when the different variants were analyzed separately, however, do not allow drawing definite conclusions about the magnitude of these risks. Of the more frequently occurring melanocortin 1 receptor variant alleles the Asp84Glu, Arg142His, Arg151Cys, Arg160Trp, His260Pro, and Asp294His variants were strongly associated with both fair skin and red hair. The Val60Leu, Val92Met, and Arg163Gln variant alleles, however, were only weakly or not associated with fair skin type and/or red hair, which further illustrates the finding that skin type, hair color, and melanoma are independent outcomes of the presence of melanocortin 1 receptor gene variants. We conclude that numerous melanocortin 1 receptor variants predispose to cutaneous melanoma and that possibly the Asp84Glu variant confers the highest risk. This predisposition is largely independent of skin type and hair color.
Melanocortin-1 receptor gene variants in four Chinese ethnic populations
There is strong relationship between melanocortin-1 receptor (MC1R) gene variants and human hair color and skin type. Based on a sequencing study of MC1R gene in 50 individuals from the Uygur, Tibetan, Wa and Dai ethnic populations, we discuss the occurrence of 7 mc1r variants consisting of 5 nonsynonymous sites (Val60Leu, Arg67Gln, Val92Met, Arg163Gln and Ala299Val) and 2 synonymous sites (C414T and A942G), among which C414T and Ala299Val were reported for the first time. Confirmation and analysis were also made of 122 individuals at three common point mutations (Val92Met, Arg163Gln, A942G) using PCR-SSCP. The frequency of Arg163Gln variant varies in the four ethnic populations, with percentage of 40%, 85.0%, 66.2% and 72.7%, respectively, while those of Val92Met and A942G are roughly similar in these four populations. The different environments, migration and admixture of various ethnic groups in China might have impact on the observed frequency of Arg163Gln.
The variation in human hair and skin color in different geographic regions of the world is the result of differences in two principal forms of melanin, the red-yellow phaeomelanins and the black-brown eumelanins, which are present in the epidermal layer of human skin and hair1,2. The type of melanin produced is under the control of two genes, identified initially by the mouse mutation, extension and agouti. The extension gene is expressed in melanocytes, producing the melanocyte stimulating hormone receptor (MSHR) or melanocortin-1 receptor ( MC1R)3,4. The human MC1R gene, homologous to the mouse extension locus, was cloned3,5,6, located to chromosome 16q247 and shown to encode the MC1R protein. Expressed on cutaneous melanocytes3, MC1R is a seven transmembrane domain G protein-coupled receptor of 317 amino acids belonging to the melanocotin receptor subfamily and has high binding affinity for MSH and ACTH8, 9. In addition, some other studies show that MC1R variants are associated with the coat colors in cattle10,11, fox12, and horse13.
Studies of MC1R polymorphism have been made in European, African and Asian populations. Valverde et al14, Box et al15 and Smith et al16 reported 18 variants of MC1R in red hair/fair skin individuals. In a recent study by Rana et al4, Africans were reported to be lack of variation while six variants were found in Asian populations. However, little is known about the variants of MC1R gene in Chinese populations, let alone data in Chinese ethnic populations. In this paper we examined the polymorphism of the human MC1R gene in four Chinese ethnic populations.
MC1R variants
The entire coding sequence of the MC1R gene was sequenced in 50 individuals from the Urgur, Tibeten, Dai, and Wa nationalities. Compared to the published sequences3, 4, 5, 6, 18, sequences of our samples differed from the human consensus sequence at five nonsynonymous sites (at codon 60, 67, 92, 163 and 299) and at two synonymous sites (at nucleotide 414 and 942) (Tab 1). In the previous study of MC1R variants, Val92Met and Val60Leu were reported to be frequent in the red hair/fair skin samples14. In this study, heterozygous Val60Leu was found only in one Uygur individual; whereas the Val92Met variant was found in Uygur, Dai, Wa ethnic populations, but no homozygote in Tibetan. Furthermore, the Val92Met variant always went with the A942G variant in our samples.
Rana et al4 reported the Arg163Gln variant to be associated with the East and Southeast Asian populations. In this study, a very common Arg163Gln variant was also found in the four ethnic groups concerned, including 21 of 35 Uygurs, 19 of 20 Tibetans, 29 of 34 Was and 27 of 33 Dais. The Arg67Gln/Arg163 variant in one Dai individual was also observed in other East and Southeast Asian populations (Rana et al, 1999), which is a combination of the Arg163Gln variant. Besides, one synonymous mutation and one nonsynonymous mutation were first found in Uygur (C414T and Ala299Val).
Gene frequency
The PCR-SSCP analysis was used to genotype the three variants, Val92Met, Arg163Gln and A942G in 122 individuals. The gene frequency of the Arg163Gln variant was found to be significantly different in the four ethnic groups, with the highest (85.0%) in Tibetan, the lowest (40%) in Uygur, and the intermediate in Dai (72.7%) and Wa (66.2%). The gene frequency of the Val92Met differed in the Dai (31. 8%), the Tibetans (10%), the Wa (11.8%) and the Uygur (11.4%). The A942G and Val92Met variant gene frequency for each of the four ethnic groups remained roughly similar, as listed in Tab 2. Hardy-Weinberg equilibrium was not rejected in all these ethnic groups (Data not shown).
Three alleles (Arg151Cys, Arg160Trp and Asp294His) that are associated with red hair/fair skin phenotype have been reported in European individuals 5,16. Recently, Franderberg et al19 found new evidence that the Arg151Cys mutation of MC1R can cause the synthesis of the red pigment. This evidence explains why the red hair person carries the Arg151Cys mutation. The Arg163Gln variant is present with relatively high frequency in the East and Southeast Asian populations 4,20. In consistent with those reports, our result shows a very common Arg163Gln variant in the four ethnic groups. It might suggest that the Arg163Gln polymorphism is associated with phaemomelanin-rich skin. But further functional study is required to confirm our expectation.
The Arg163Gln variant is found in American Indians as well as in East and Southeast Asian populations, while the allele appears at a very low frequency or even disappears in both Europeans and Africans. Rana et al4 considered that the allele has increased rapidly in frequency in East Asians by positive Darwinian selection. We suggest that the random genetic drift, migration and the admixture of various ethnic groups might have impact on the frequency of the Arg163Gln variant in different populations. Firstly, the highest frequency and the most homozygous state in Tibetans might arise from genetic drift and little possibility of gene flows among different ethnic groups. The positive Darwinian selection is also a possible explanation. Secondly, the lowest frequency in Uygurs might be the result of their genetic admixture with Caucasians. This assumption can be further supported by results from other reports17,22. On the other hand, considering the genetic admixture, it is explicable that an European specific allele, Val60Leu, is present in one Uygur individual. Lastly, the similar frequencies in the Dai and the Wa might be explained by their similar geographic locations and living environments.
High polymorphism at the human melanocortin 1 receptor locus.
Rana BK, Hewett-Emmett D, Jin L, Chang BH, Sambuughin N, Lin M, Watkins S, Bamshad M, Jorde LB, Ramsay M, Jenkins T, Li WH.
Human Genetics Center, School of Public Health and Graduate School of Biomedical Sciences, University of Texas, Houston, Texas 77030, USA.
Variation in human skin/hair pigmentation is due to varied amounts of eumelanin (brown/black melanins) and phaeomelanin (red/yellow melanins) produced by the melanocytes. The melanocortin 1 receptor (MC1R) is a regulator of eu- and phaeomelanin production in the melanocytes, and MC1R mutations causing coat color changes are known in many mammals. We have sequenced the MC1R gene in 121 individuals sampled from world populations with an emphasis on Asian populations. We found variation at five nonsynonymous sites (resulting in the variants Arg67Gln, Asp84Glu, Val92Met, Arg151Cys, and Arg163Gln), but at only one synonymous site (A942G). Interestingly, the human consensus protein sequence is observed in all 25 African individuals studied, but at lower frequencies in the other populations examined, especially in East and Southeast Asians. The Arg163Gln variant is absent in the Africans studied, almost absent in Europeans, and at a low frequency (7%) in Indians, but is at an exceptionally high frequency (70%) in East and Southeast Asians. The MC1R gene in common and pygmy chimpanzees, gorilla, orangutan, and baboon was sequenced to study the evolution of MC1R. The ancestral human MC1R sequence is identical to the human consensus protein sequence, while MC1R varies considerably among higher primates. A comparison of the rates of substitution in genes in the melanocortin receptor family indicates that MC1R has evolved the fastest. In addition, the nucleotide diversity at the MC1R locus is shown to be several times higher than the average nucleotide diversity in human populations, possibly due to diversifying selection
Interactive effects of MC1R and OCA2 on melanoma risk phenotypes.
Duffy DL, Box NF, Chen W, Palmer JS, Montgomery GW, James MR, Hayward NK, Martin NG, Sturm RA.
Queensland Insititute of Medical Research, Brisbane, Australia.
The relationships between MC1R gene variants and red hair, skin reflectance, degree of freckling and nevus count were investigated in 2331 adolescent twins, their sibs and parents in 645 twin families. Penetrance of each MC1R variant allele was consistent with an allelic model where effects were multiplicative for red hair but additive for skin reflectance. Of nine MC1R variant alleles assayed, four common alleles were strongly associated with red hair and fair skin (Asp84Glu, Arg151Cys, Arg160Trp and Asp294His), with a further three alleles having low penetrance (Val60Leu, Val92Met and Arg163Gln). These variants were separately combined for the purposes of this analysis and designated as strong ‘R’ (OR=63.3; 95% CI 31.9-139.6) and weak ‘r ‘ (OR=5.1; 95% CI 2.5-11.3) red hair alleles. Red-haired individuals are predominantly seen in the R/R and R/r groups with 67.1 and 10.8%, respectively. To assess the interaction of the brown eye color gene OCA2 on the phenotypic effects of variant MC1R alleles we included eye color as a covariate, and also genotyped two OCA2 SNPs (Arg305Trp and Arg419Gln), which were confirmed as modifying eye color. MC1R genotype effects on constitutive skin color, freckling and mole count were modified by eye color, but not genotype for these two OCA2 SNPs. This is probably due to the association of these OCA2 SNPs with brown/green not blue eye color. Amongst individuals with a R/R genotype (but not R/r), those who also had brown eyes had a mole count twice that of those with blue eyes. This suggests that other OCA2 polymorphisms influence mole count and remain to be described.
Skin pigmentation, biogeographical ancestry and admixture mapping.
Shriver MD, Parra EJ, Dios S, Bonilla C, Norton H, Jovel C, Pfaff C, Jones C, Massac A, Cameron N, Baron A, Jackson T, Argyropoulos G, Jin L, Hoggart CJ, McKeigue PM, Kittles RA.
Department of Anthropology, Penn State University, 409 Carpenter Bld., University Park, PA 16802, USA.
Ancestry informative markers (AIMs) are genetic loci showing alleles with large frequency differences between populations. AIMs can be used to estimate biogeographical ancestry at the level of the population, subgroup (e.g. cases and controls) and individual. Ancestry estimates at both the subgroup and individual level can be directly instructive regarding the genetics of the phenotypes that differ qualitatively or in frequency between populations. These estimates can provide a compelling foundation for the use of admixture mapping (AM) methods to identify the genes underlying these traits. We present details of a panel of 34 AIMs and demonstrate how such studies can proceed, by using skin pigmentation as a model phenotype. We have genotyped these markers in two population samples with primarily African ancestry, viz. African Americans from Washington D.C. and an African Caribbean sample from Britain, and in a sample of European Americans from Pennsylvania. In the two African population samples, we observed significant correlations between estimates of individual ancestry and skin pigmentation as measured by reflectometry (R(2)=0.21, P<0.0001 for the African-American sample and R(2)=0.16, P<0.0001 for the British African-Caribbean sample). These correlations confirm the validity of the ancestry estimates and also indicate the high level of population structure related to admixture, a level that characterizes these populations and that is detectable by using other tests to identify genetic structure. We have also applied two methods of admixture mapping to test for the effects of three candidate genes (TYR, OCA2, MC1R) on pigmentation. We show that TYR and OCA2 have measurable effects on skin pigmentation differences between the west African and west European parental populations. This work indicates that it is possible to estimate the individual ancestry of a person based on DNA analysis with a reasonable number of well-defined genetic markers. The implications and applications of ancestry estimates in biomedical research are discussed.
Association of the SLC45A2 gene with physiological human hair colour variation
Wojciech Branicki, Urszula Brudnik, Jolanta Draus-Barini, Tomasz Kupiec and Anna Wojas-Pelc
Journal of Human Genetics Early online
Abstract: Pigmentation is a complex physical trait with multiple genes involved. Several genes have already been associated with natural differences in human pigmentation. The SLC45A2 gene encoding a transporter protein involved in melanin synthesis is considered to be one of the most important genes affecting human pigmentation. Here we present results of an association study conducted on a population of European origin, where the relationship between two non-synonymous polymorphisms in the SLC45A2 gene — rs26722 (E272K) and rs16891982 (L374F) — and different pigmentation traits was examined. The study revealed a significant association between both variable sites and normal variation in hair colour. Only L374F remained significantly associated with hair colour when both SNPs were included in a logistic regression model. No association with other pigmentation traits was detected in this population sample. Our results indicate that the rare allele L374 significantly increases the possibility of having black hair colour (OR = 7.05) and thus may be considered as a future marker for black hair colour prediction.
A list of MC1R articles on pubmed (reference)
The main impression I get from this is that human colouring is a very complex process. I’m intrigued by the extremely old dates for some of the MC1R variants. If the dates are accurate, it’s an archaic human era they occurred in.
Mathilda's Anthropology Blog. 