• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of geneticsGeneticsCurrent IssueInformation for AuthorsEditorial BoardSubscribeSubmit a Manuscript
Genetics. Apr 1999; 151(4): 1547–1557.
PMCID: PMC1460552

High polymorphism at the human melanocortin 1 receptor locus.

Abstract

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.

Full Text

The Full Text of this article is available as a PDF (204K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Chhajlani V, Wikberg JE. Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA. FEBS Lett. 1992 Sep 14;309(3):417–420. [PubMed]
  • Cone RD, Lu D, Koppula S, Vage DI, Klungland H, Boston B, Chen W, Orth DN, Pouton C, Kesterson RA. The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Prog Horm Res. 1996;51:287–318. [PubMed]
  • Frändberg PA, Muceniece R, Prusis P, Wikberg J, Chhajlani V. Evidence for alternate points of attachment for alpha-MSH and its stereoisomer [Nle4, D-Phe7]-alpha-MSH at the melanocortin-1 receptor. Biochem Biophys Res Commun. 1994 Aug 15;202(3):1266–1271. [PubMed]
  • Gantz I, Konda Y, Tashiro T, Shimoto Y, Miwa H, Munzert G, Watson SJ, DelValle J, Yamada T. Molecular cloning of a novel melanocortin receptor. J Biol Chem. 1993 Apr 15;268(11):8246–8250. [PubMed]
  • HARRISON GA, OWEN JJ. STUDIES ON THE INHERITANCE OF HUMAN SKIN COLOUR. Ann Hum Genet. 1964 Sep;28:27–37. [PubMed]
  • Hearing VJ, Jiménez M. Mammalian tyrosinase--the critical regulatory control point in melanocyte pigmentation. Int J Biochem. 1987;19(12):1141–1147. [PubMed]
  • Joerg H, Fries HR, Meijerink E, Stranzinger GF. Red coat color in Holstein cattle is associated with a deletion in the MSHR gene. Mamm Genome. 1996 Apr;7(4):317–318. [PubMed]
  • Klungland H, Våge DI, Gomez-Raya L, Adalsteinsson S, Lien S. The role of melanocyte-stimulating hormone (MSH) receptor in bovine coat color determination. Mamm Genome. 1995 Sep;6(9):636–639. [PubMed]
  • Kobayashi T, Vieira WD, Potterf B, Sakai C, Imokawa G, Hearing VJ. Modulation of melanogenic protein expression during the switch from eu- to pheomelanogenesis. J Cell Sci. 1995 Jun;108(Pt 6):2301–2309. [PubMed]
  • Koppula SV, Robbins LS, Lu D, Baack E, White CR, Jr, Swanson NA, Cone RD. Identification of common polymorphisms in the coding sequence of the human MSH receptor (MCIR) with possible biological effects. Hum Mutat. 1997;9(1):30–36. [PubMed]
  • Kwon HY, Bultman SJ, Löffler C, Chen WJ, Furdon PJ, Powell JG, Usala AL, Wilkison W, Hansmann I, Woychik RP. Molecular structure and chromosomal mapping of the human homolog of the agouti gene. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9760–9764. [PMC free article] [PubMed]
  • Abdel-Malek Z, Swope VB, Suzuki I, Akcali C, Harriger MD, Boyce ST, Urabe K, Hearing VJ. Mitogenic and melanogenic stimulation of normal human melanocytes by melanotropic peptides. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1789–1793. [PMC free article] [PubMed]
  • Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, Wilkison WO, et al. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature. 1994 Oct 27;371(6500):799–802. [PubMed]
  • Magenis RE, Smith L, Nadeau JH, Johnson KR, Mountjoy KG, Cone RD. Mapping of the ACTH, MSH, and neural (MC3 and MC4) melanocortin receptors in the mouse and human. Mamm Genome. 1994 Aug;5(8):503–508. [PubMed]
  • Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. [PMC free article] [PubMed]
  • Box NF, Wyeth JR, O'Gorman LE, Martin NG, Sturm RA. Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair. Hum Mol Genet. 1997 Oct;6(11):1891–1897. [PubMed]
  • Szabó G, Gerald AB, Pathak MA, Fitzpatrick TB. Racial differences in the fate of melanosomes in human epidermis. Nature. 1969 Jun 14;222(5198):1081–1082. [PubMed]
  • Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. The cloning of a family of genes that encode the melanocortin receptors. Science. 1992 Aug 28;257(5074):1248–1251. [PubMed]
  • Thody AJ, Higgins EM, Wakamatsu K, Ito S, Burchill SA, Marks JM. Pheomelanin as well as eumelanin is present in human epidermis. J Invest Dermatol. 1991 Aug;97(2):340–344. [PubMed]
  • Ohta T. Synonymous and nonsynonymous substitutions in mammalian genes and the nearly neutral theory. J Mol Evol. 1995 Jan;40(1):56–63. [PubMed]
  • Våge DI, Lu D, Klungland H, Lien S, Adalsteinsson S, Cone RD. A non-epistatic interaction of agouti and extension in the fox, Vulpes vulpes. Nat Genet. 1997 Mar;15(3):311–315. [PubMed]
  • Prota G. Recent advances in the chemistry of melanogenesis in mammals. J Invest Dermatol. 1980 Jul;75(1):122–127. [PubMed]
  • Valverde P, Healy E, Jackson I, Rees JL, Thody AJ. Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nat Genet. 1995 Nov;11(3):328–330. [PubMed]
  • Valverde P, Healy E, Sikkink S, Haldane F, Thody AJ, Carothers A, Jackson IJ, Rees JL. The Asp84Glu variant of the melanocortin 1 receptor (MC1R) is associated with melanoma. Hum Mol Genet. 1996 Oct;5(10):1663–1666. [PubMed]
  • Robbins LS, Nadeau JH, Johnson KR, Kelly MA, Roselli-Rehfuss L, Baack E, Mountjoy KG, Cone RD. Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell. 1993 Mar 26;72(6):827–834. [PubMed]
  • Shriver MD, Jin L, Ferrell RE, Deka R. Microsatellite data support an early population expansion in Africa. Genome Res. 1997 Jun;7(6):586–591. [PubMed]
  • Wilson BD, Ollmann MM, Kang L, Stoffel M, Bell GI, Barsh GS. Structure and function of ASP, the human homolog of the mouse agouti gene. Hum Mol Genet. 1995 Feb;4(2):223–230. [PubMed]
  • Stern C. Model estimates of the number of gene pairs involved in pigmentation variability of the Negro-American. Hum Hered. 1970;20(2):165–168. [PubMed]
  • Xu X, Thörnwall M, Lundin LG, Chhajlani V. Val92Met variant of the melanocyte stimulating hormone receptor gene. Nat Genet. 1996 Dec;14(4):384–384. [PubMed]
  • Suzuki I, Cone RD, Im S, Nordlund J, Abdel-Malek ZA. Binding of melanotropic hormones to the melanocortin receptor MC1R on human melanocytes stimulates proliferation and melanogenesis. Endocrinology. 1996 May;137(5):1627–1633. [PubMed]
  • Yang Y k, Dickinson C, Haskell-Luevano C, Gantz I. Molecular basis for the interaction of [Nle4,D-Phe7]melanocyte stimulating hormone with the human melanocortin-1 receptor. J Biol Chem. 1997 Sep 12;272(37):23000–23010. [PubMed]

Articles from Genetics are provided here courtesy of Genetics Society of America

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • Gene
    Gene
    Gene links
  • Gene (nucleotide)
    Gene (nucleotide)
    Records in Gene identified from shared sequence links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene
    HomoloGene links
  • MedGen
    MedGen
    Related information in MedGen
  • Nucleotide
    Nucleotide
    Published Nucleotide sequences
  • PopSet
    PopSet
    Published population set
  • Protein
    Protein
    Published protein sequences
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...