High polymorphism at the human melanocortin 1 receptor locus

Variation in human skin/hair pigmentation is due to varied amounts of eumel anin (brown/black melanins) and phaeomelanin (red/yellow melanins) produced by the melanocytes. The melanocortin 1 receptor (MC1R) is a regulator of e u- and phaeomelanin production in the melanocytes, and MC1R mutations causi ng 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 (resulti ng in the variants Arg67Gln, Asp84Glu, Val92Met, Arg151Cys, and Arg163Gln), but at only one synonymous site (A942G). interestingly, the human consensu s protein sequence is observed in all 25 African individuals studied, but a t lower frequencies in the other populations examined, especially in East a nd Southeast Asians. The Arg163Gln variant is absent in the Africans studie d, 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. T he MC1R gene in common and pygmy chimpanzees, gorilla, orangutan, and baboo n was sequenced to study the evolution of MC1R. The ancestral human MC1R se quence is identical to the human consensus protein sequence, while MC1R var ies considerably among higher primates. A comparison of the rates of substi tution in genes in the melanocortin receptor family indicates that MC1R has evolved the fastest, In addition, the nucleotide diversity at the MC1R loc us is shown to be several rimes higher than the average nucleotide diversit y in human populations, possibly due to diversifying selection.