Genetics, Vol. 151, 1547-1557, April 1999, Copyright © 1999

High Polymorphism at the Human Melanocortin 1 Receptor Locus

Brinda K. Ranaa, David Hewett-Emmetta, Li Jina, Benny H.-J. Changa, Naymkhishing Sambuughinb, Marie Linc, Scott Watkinsd, Michael Bamshadd, Lynn B. Jorded, Michele Ramsaye, Trefor Jenkinse, and Wen-Hsiung Lia
a Human Genetics Center, School of Public Health and Graduate School of Biomedical Sciences, University of Texas, Houston, Texas 77030,
b Neurology Research, Phoenix, Arizona 85013,
c Mackay Memorial Hospital, Taipei, Taiwan,
d Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112
e Department of Human Genetics, South African Institute for Medical Research, Johannesburg, South Africa 2050

Corresponding author: Wen-Hsiung Li, Department of Ecology and Evolution, University of Chicago, 1101 E. 57th St., Chicago, IL 60637., whli{at}uchicago.edu (E-mail)

Communicating editor: N. TAKAHATA

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.




This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
Y. Suzuki, A. Pasch, O. Bonny, M. G. Mohaupt, M. A. Hediger, and F. J. Frey
Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation
Hum. Mol. Genet., June 1, 2008; 17(11): 1613 - 1618.
[Abstract] [Full Text] [PDF]

Home page
 ScienceHome page
C. Lalueza-Fox, H. Rompler, D. Caramelli, C. Staubert, G. Catalano, D. Hughes, N. Rohland, E. Pilli, L. Longo, S. Condemi, et al.
A Melanocortin 1 Receptor Allele Suggests Varying Pigmentation Among Neanderthals
Science, November 30, 2007; 318(5855): 1453 - 1455.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
L. Fernandez, R. Milne, J Bravo, J. Lopez, J. Aviles, M. Longo, J Benitez, P Lazaro, and G Ribas
MC1R: three novel variants identified in a malignant melanoma association study in the Spanish population
Carcinogenesis, August 1, 2007; 28(8): 1659 - 1664.
[Abstract] [Full Text] [PDF]

Home page
 Mol Biol EvolHome page
A. R. Rogers, S. Wooding, C. D. Huff, M. A. Batzer, and L. B. Jorde
Ancestral Alleles and Population Origins: Inferences Depend on Mutation Rate
Mol. Biol. Evol., April 1, 2007; 24(4): 990 - 997.
[Abstract] [Full Text] [PDF]

Home page
 Mol Biol EvolHome page
H. L. Norton, R. A. Kittles, E. Parra, P. McKeigue, X. Mao, K. Cheng, V. A. Canfield, D. G. Bradley, B. McEvoy, and M. D. Shriver
Genetic Evidence for the Convergent Evolution of Light Skin in Europeans and East Asians
Mol. Biol. Evol., March 1, 2007; 24(3): 710 - 722.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
F. Rouzaud, G.-E. Costin, Y. Yamaguchi, J. C. Valencia, W. F. Berens, K. G. Chen, T. Hoashi, M. Bohm, Z. A. Abdel-Malek, and V. J. Hearing
Regulation of constitutive and UVR-induced skin pigmentation by melanocortin 1 receptor isoforms
FASEB J, September 1, 2006; 20(11): 1927 - 1929.
[Abstract] [Full Text] [PDF]

Home page
 Mol Biol EvolHome page
N. Izagirre, I. Garcia, C. Junquera, C. de la Rua, and S. Alonso
A Scan for Signatures of Positive Selection in Candidate Loci for Skin Pigmentation in Humans
Mol. Biol. Evol., September 1, 2006; 23(9): 1697 - 1706.
[Abstract] [Full Text] [PDF]

Home page
 Genome ResHome page
J. L. Kelley, J. Madeoy, J. C. Calhoun, W. Swanson, and J. M. Akey
Genomic signatures of positive selection in humans and the limits of outlier approaches
Genome Res., August 1, 2006; 16(8): 980 - 989.
[Abstract] [Full Text] [PDF]

Home page
 Mol Biol EvolHome page
M. Soejima, H. Tachida, T. Ishida, A. Sano, and Y. Koda
Evidence for Recent Positive Selection at the Human AIM1 Locus in a European Population
Mol. Biol. Evol., January 1, 2006; 23(1): 179 - 188.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
V. Chaudru, K. Laud, M.-F. Avril, A. Miniere, A. Chompret, B. Bressac-de Paillerets, F. Demenais, and The French Familial Melanoma Study Group
Melanocortin-1 Receptor (MC1R) Gene Variants and Dysplastic Nevi Modify Penetrance of CDKN2A Mutations in French Melanoma-Prone Pedigrees
Cancer Epidemiol. Biomarkers Prev., October 1, 2005; 14(10): 2384 - 2390.
[Abstract] [Full Text] [PDF]

Home page
 J HeredHome page
T. Hosoda, J. J. Sato, T. Shimada, K. L. Campbell, and H. Suzuki
Independent Nonframeshift Deletions in the MC1R Gene Are Not Associated with Melanistic Coat Coloration in Three Mustelid Lineages
J. Hered., September 1, 2005; 96(5): 607 - 613.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Corre, A. Primot, E. Sviderskaya, D. C. Bennett, S. Vaulont, C. R. Goding, and M.-D. Galibert
UV-induced Expression of Key Component of the Tanning Process, the POMC and MC1R Genes, Is Dependent on the p-38-activated Upstream Stimulating Factor-1 (USF-1)
J. Biol. Chem., December 3, 2004; 279(49): 51226 - 51233.
[Abstract] [Full Text] [PDF]

Home page
 Mol Biol EvolHome page
J. Klovins, T. Haitina, D. Fridmanis, Z. Kilianova, I. Kapa, R. Fredriksson, N. Gallo-Payet, and H. B. Schioth
The Melanocortin System in Fugu: Determination of POMC/AGRP/MCR Gene Repertoire and Synteny, As Well As Pharmacology and Anatomical Distribution of the MCRs
Mol. Biol. Evol., March 1, 2004; 21(3): 563 - 579.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
D. L. Duffy, N. F. Box, W. Chen, J. S. Palmer, G. W. Montgomery, M. R. James, N. K. Hayward, N. G. Martin, and R. A. Sturm
Interactive effects of MC1R and OCA2 on melanoma risk phenotypes
Hum. Mol. Genet., February 15, 2004; 13(4): 447 - 461.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
E Matichard, P Verpillat, R Meziani, B Gerard, V Descamps, E Legroux, M Burnouf, G Bertrand, F Bouscarat, A Archimbaud, et al.
Melanocortin 1 receptor (MC1R) gene variants may increase the risk of melanoma in France independently of clinical risk factors and UV exposure
J. Med. Genet., February 1, 2004; 41(2): e13 - 13.
[Full Text] [PDF]

Home page
 Mol Biol EvolHome page
G. Zhou, Y. Zhai, X. Dong, X. Zhang, F. He, K. Zhou, Y. Zhu, H. Wei, Z. Yao, S. Zhong, et al.
Haplotype Structure and Evidence for Positive Selection at the Human IL13 Locus
Mol. Biol. Evol., January 1, 2004; 21(1): 29 - 36.
[Abstract] [Full Text] [PDF]

Home page
 Genome ResHome page
J. M. Akey, G. Zhang, K. Zhang, L. Jin, and M. D. Shriver
Interrogating a High-Density SNP Map for Signatures of Natural Selection
Genome Res., December 1, 2002; 12(12): 1805 - 1814.
[Abstract] [Full Text] [PDF]

Home page
 GeneticsHome page
M. A. Saunders, M. F. Hammer, and M. W. Nachman
Nucleotide Variability at G6pd and the Signature of Malarial Selection in Humans
Genetics, December 1, 2002; 162(4): 1849 - 1861.
[Abstract] [Full Text] [PDF]

Home page
 J. Exp. Biol.Home page
J. L. Rupert and P. W. Hochachka
Genetic approaches to understanding human adaptation to altitude in the Andes
J. Exp. Biol., March 11, 2002; 204(18): 3151 - 3160.
[Abstract] [Full Text] [PDF]

Home page
 Mol Biol EvolHome page
B. A. Payseur and M. W. Nachman
Gene Density and Human Nucleotide Polymorphism
Mol. Biol. Evol., March 1, 2002; 19(3): 336 - 340.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
Y. Gilad, S. Rosenberg, M. Przeworski, D. Lancet, and K. Skorecki
Evidence for positive selection and population structure at the human MAO-A gene
PNAS, January 22, 2002; 99(2): 862 - 867.
[Abstract] [Full Text] [PDF]

Home page
 Arch DermatolHome page
J. V. Schaffer and J. L. Bolognia
The Melanocortin-1 Receptor: Red Hair and Beyond
Arch Dermatol, November 1, 2001; 137(11): 1477 - 1485.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
L.B. Jorde, W.S. Watkins, and M.J. Bamshad
Population genomics: a bridge from evolutionary history to genetic medicine
Hum. Mol. Genet., October 1, 2001; 10(20): 2199 - 2207.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
J. A. W. Metzelaar-Blok, J. A. C. ter Huurne, H. M. H. Hurks, J. E. E. Keunen, M. J. Jager, and N. A. Gruis
Characterization of Melanocortin-1 Receptor Gene Variants in Uveal Melanoma Patients
Invest. Ophthalmol. Vis. Sci., August 1, 2001; 42(9): 1951 - 1954.
[Abstract] [Full Text] [PDF]

Home page
 Genome ResHome page
D. J. Mathews, C. Kashuk, G. Brightwell, E. E. Eichler, and A. Chakravarti
Sequence Variation Within the Fragile X Locus
Genome Res., August 1, 2001; 11(8): 1382 - 1391.
[Abstract] [Full Text] [PDF]

Home page
 GeneticsHome page
K. D. Makova, M. Ramsay, T. Jenkins, and W.-H. Li
Human DNA Sequence Variation in a 6.6-kb Region Containing the Melanocortin 1 Receptor Promoter
Genetics, July 1, 2001; 158(3): 1253 - 1268.
[Abstract] [Full Text] [PDF]

Home page
 GeneticsHome page
Y. Koda, H. Tachida, H. Pang, Y. Liu, M. Soejima, A. A. Ghaderi, O. Takenaka, and H. Kimura
Contrasting Patterns of Polymorphisms at the ABO-Secretor Gene (FUT2) and Plasma {{alpha}}(1,3)Fucosyltransferase Gene (FUT6) in Human Populations
Genetics, June 1, 2001; 158(2): 747 - 756.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
S. Alonso and J. A. L. Armour
A highly variable segment of human subterminal 16p reveals a history of population growth for modern humans outside Africa
PNAS, December 14, 2000; (2000) 11244998.
[Abstract] [Full Text]

Home page
 Hum Mol GenetHome page
N. Flanagan, E. Healy, A. Ray, S. Philips, C. Todd, I. J. Jackson, M. A. Birch-Machin, and J. L. Rees
Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation
Hum. Mol. Genet., October 1, 2000; 9(17): 2531 - 2537.
[Abstract] [Full Text] [PDF]

Home page
 Genome ResHome page
D. A. Nickerson, S. L. Taylor, S. M. Fullerton, K. M. Weiss, A. G. Clark, J. H. Stengård, V. Salomaa, E. Boerwinkle, and C. F. Sing
Sequence Diversity and Large-Scale Typing of SNPs in the Human Apolipoprotein E Gene
Genome Res., October 1, 2000; 10(10): 1532 - 1545.
[Abstract] [Full Text]

Home page
 GeneticsHome page
M. W. Nachman and S. L. Crowell
Contrasting Evolutionary Histories of Two Introns of the Duchenne Muscular Dystrophy Gene, Dmd, in Humans
Genetics, August 1, 2000; 155(4): 1855 - 1864.
[Abstract] [Full Text]

Home page
 GeneticsHome page
J. D. Wall and M. Przeworski
When Did the Human Population Size Start Increasing?
Genetics, August 1, 2000; 155(4): 1865 - 1874.
[Abstract] [Full Text]

Home page
 ScienceHome page
K. Owens and M. King
Genomic Views of Human History
Science, October 15, 1999; 286(5439): 451 - 453.
[Abstract] [Full Text]

Home page
 Proc. Natl. Acad. Sci. USAHome page
S. Alonso and J. A. L. Armour
A highly variable segment of human subterminal 16p reveals a history of population growth for modern humans outside Africa
PNAS, January 30, 2001; 98(3): 864 - 869.
[Abstract] [Full Text] [PDF]

Home page
 Genome ResHome page
R. Martinez-Arias, F. Calafell, E. Mateu, D. Comas, A. Andres, and J. Bertranpetit
Sequence Variability of a Human Pseudogene
Genome Res., June 1, 2001; 11(6): 1071 - 1085.
[Abstract] [Full Text] [PDF]