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Genetics. Jul 2001; 158(3): 1253–1268.
PMCID: PMC1461732

Human DNA sequence variation in a 6.6-kb region containing the melanocortin 1 receptor promoter.

Abstract

An approximately 6.6-kb region located upstream from the melanocortin 1 receptor (MC1R) gene and containing its promoter was sequenced in 54 humans (18 Africans, 18 Asians, and 18 Europeans) and in one chimpanzee, gorilla, and orangutan. Seventy-six polymorphic sites were found among the human sequences and the average nucleotide diversity (pi) was 0.141%, one of the highest among all studies of nuclear sequence variation in humans. Opposite to the pattern observed in the MC1R coding region, in the present region pi is highest in Africans (0.136%) compared to Asians (0.116%) and Europeans (0.122%). The distributions of pi, theta, and Fu and Li's F-statistic are nonuniform along the sequence and among continents. The pattern of genetic variation is consistent with a population expansion in Africans. We also suggest a possible phase of population size reduction in non-Africans and purifying selection acting in the middle subregion and parts of the 5' subregion in Africans. We hypothesize diversifying selection acting on some sites in the 5' and 3' subregions or in the MC1R coding region in Asians and Europeans, though we cannot reject the possibility of relaxation of functional constraints in the MC1R gene in Asians and Europeans. The mutation rate in the sequenced region is 1.65 x 10(-9) per site per year. The age of the most recent common ancestor for this region is similar to that for the other long noncoding regions studied to date, providing evidence for ancient gene genealogies. Our population screening and phylogenetic footprinting suggest potentially important sites for the MC1R promoter function.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Gao C, Jin R, Yu G. ISMh2, a novel insertion sequence-like element associated with nifA from Mesorhizobium huakuii. Plasmid. 2001 Jul;46(1):10–15. [PubMed]
  • Chen FC, Li WH. Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. Am J Hum Genet. 2001 Feb;68(2):444–456. [PMC free article] [PubMed]
  • Don RH, Cox PT, Wainwright BJ, Baker K, Mattick JS. 'Touchdown' PCR to circumvent spurious priming during gene amplification. Nucleic Acids Res. 1991 Jul 25;19(14):4008–4008. [PMC free article] [PubMed]
  • Fu YX. Estimating the age of the common ancestor of a DNA sample using the number of segregating sites. Genetics. 1996 Oct;144(2):829–838. [PMC free article] [PubMed]
  • Fu YX. Statistical tests of neutrality of mutations against population growth, hitchhiking and background selection. Genetics. 1997 Oct;147(2):915–925. [PMC free article] [PubMed]
  • Fu YX, Li WH. Statistical tests of neutrality of mutations. Genetics. 1993 Mar;133(3):693–709. [PMC free article] [PubMed]
  • Fu YX, Li WH. Estimating the age of the common ancestor of men from the ZFY intron. Science. 1996 May 31;272(5266):1356–1362. [PubMed]
  • Fu YX, Li WH. Estimating the age of the common ancestor of a sample of DNA sequences. Mol Biol Evol. 1997 Feb;14(2):195–199. [PubMed]
  • Fullerton SM, Clark AG, Weiss KM, Nickerson DA, Taylor SL, Stengârd JH, Salomaa V, Vartiainen E, Perola M, Boerwinkle E, et al. Apolipoprotein E variation at the sequence haplotype level: implications for the origin and maintenance of a major human polymorphism. Am J Hum Genet. 2000 Oct;67(4):881–900. [PMC free article] [PubMed]
  • Goodman M, Porter CA, Czelusniak J, Page SL, Schneider H, Shoshani J, Gunnell G, Groves CP. Toward a phylogenetic classification of Primates based on DNA evidence complemented by fossil evidence. Mol Phylogenet Evol. 1998 Jun;9(3):585–598. [PubMed]
  • Hamblin MT, Di Rienzo A. Detection of the signature of natural selection in humans: evidence from the Duffy blood group locus. Am J Hum Genet. 2000 May;66(5):1669–1679. [PMC free article] [PubMed]
  • Harding RM, Healy E, Ray AJ, Ellis NS, Flanagan N, Todd C, Dixon C, Sajantila A, Jackson IJ, Birch-Machin MA, et al. Evidence for variable selective pressures at MC1R. Am J Hum Genet. 2000 Apr;66(4):1351–1361. [PMC free article] [PubMed]
  • Hudson RR, Kreitman M, Aguadé M. A test of neutral molecular evolution based on nucleotide data. Genetics. 1987 May;116(1):153–159. [PMC free article] [PubMed]
  • Kaessmann H, Heissig F, von Haeseler A, Päbo S. DNA sequence variation in a non-coding region of low recombination on the human X chromosome. Nat Genet. 1999 May;22(1):78–81. [PubMed]
  • Kikuno R, Nagase T, Ishikawa K, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O. Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 1999 Jun 30;6(3):197–205. [PubMed]
  • Moro O, Ideta R, Ifuku O. Characterization of the promoter region of the human melanocortin-1 receptor (MC1R) gene. Biochem Biophys Res Commun. 1999 Aug 27;262(2):452–460. [PubMed]
  • Nachman MW, Crowell SL. Estimate of the mutation rate per nucleotide in humans. Genetics. 2000 Sep;156(1):297–304. [PMC free article] [PubMed]
  • Nachman MW, Bauer VL, Crowell SL, Aquadro CF. DNA variability and recombination rates at X-linked loci in humans. Genetics. 1998 Nov;150(3):1133–1141. [PMC free article] [PubMed]
  • Abdel-Malek Z, Suzuki I, Tada A, Im S, Akcali C. The melanocortin-1 receptor and human pigmentation. Ann N Y Acad Sci. 1999 Oct 20;885:117–133. [PubMed]
  • Nickerson DA, Taylor SL, Weiss KM, Clark AG, Hutchinson RG, Stengård J, Salomaa V, Vartiainen E, Boerwinkle E, Sing CF. DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nat Genet. 1998 Jul;19(3):233–240. [PubMed]
  • Adachi S, Morii E, Kim D k, Ogihara H, Jippo T, Ito A, Lee YM, Kitamura Y. Involvement of mi-transcription factor in expression of alpha-melanocyte-stimulating hormone receptor in cultured mast cells of mice. J Immunol. 2000 Jan 15;164(2):855–860. [PubMed]
  • Nickerson DA, Taylor SL, Fullerton SM, Weiss KM, Clark AG, Stengård JH, Salomaa V, Boerwinkle E, Sing CF. Sequence diversity and large-scale typing of SNPs in the human apolipoprotein E gene. Genome Res. 2000 Oct;10(10):1532–1545. [PMC free article] [PubMed]
  • Begun DJ, Aquadro CF. Levels of naturally occurring DNA polymorphism correlate with recombination rates in D. melanogaster. Nature. 1992 Apr 9;356(6369):519–520. [PubMed]
  • Payseur BA, Nachman MW. Microsatellite variation and recombination rate in the human genome. Genetics. 2000 Nov;156(3):1285–1298. [PMC free article] [PubMed]
  • Bentley NJ, Eisen T, Goding CR. Melanocyte-specific expression of the human tyrosinase promoter: activation by the microphthalmia gene product and role of the initiator. Mol Cell Biol. 1994 Dec;14(12):7996–8006. [PMC free article] [PubMed]
  • Przeworski M, Hudson RR, Di Rienzo A. Adjusting the focus on human variation. Trends Genet. 2000 Jul;16(7):296–302. [PubMed]
  • Rana BK, Hewett-Emmett D, Jin L, Chang BH, Sambuughin N, Lin M, Watkins S, Bamshad M, Jorde LB, Ramsay M, et al. High polymorphism at the human melanocortin 1 receptor locus. Genetics. 1999 Apr;151(4):1547–1557. [PMC free article] [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]
  • Rieder MJ, Taylor SL, Clark AG, Nickerson DA. Sequence variation in the human angiotensin converting enzyme. Nat Genet. 1999 May;22(1):59–62. [PubMed]
  • Watterson GA. On the number of segregating sites in genetical models without recombination. Theor Popul Biol. 1975 Apr;7(2):256–276. [PubMed]
  • Rozas J, Rozas R. DnaSP version 3: an integrated program for molecular population genetics and molecular evolution analysis. Bioinformatics. 1999 Feb;15(2):174–175. [PubMed]
  • Wingender E, Chen X, Hehl R, Karas H, Liebich I, Matys V, Meinhardt T, Prüss M, Reuter I, Schacherer F. TRANSFAC: an integrated system for gene expression regulation. Nucleic Acids Res. 2000 Jan 1;28(1):316–319. [PMC free article] [PubMed]
  • Schmid CW. Does SINE evolution preclude Alu function? Nucleic Acids Res. 1998 Oct 15;26(20):4541–4550. [PMC free article] [PubMed]
  • Schwartz S, Zhang Z, Frazer KA, Smit A, Riemer C, Bouck J, Gibbs R, Hardison R, Miller W. PipMaker--a web server for aligning two genomic DNA sequences. Genome Res. 2000 Apr;10(4):577–586. [PMC free article] [PubMed]
  • Yu N, Zhao Z, Fu YX, Sambuughin N, Ramsay M, Jenkins T, Leskinen E, Patthy L, Jorde LB, Kuromori T, et al. Global patterns of human DNA sequence variation in a 10-kb region on chromosome 1. Mol Biol Evol. 2001 Feb;18(2):214–222. [PubMed]
  • Tajima F. Evolutionary relationship of DNA sequences in finite populations. Genetics. 1983 Oct;105(2):437–460. [PMC free article] [PubMed]
  • Zhao Z, Jin L, Fu YX, Ramsay M, Jenkins T, Leskinen E, Pamilo P, Trexler M, Patthy L, Jorde LB, et al. Worldwide DNA sequence variation in a 10-kilobase noncoding region on human chromosome 22. Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11354–11358. [PMC free article] [PubMed]
  • Tajima F. Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics. 1989 Nov;123(3):585–595. [PMC free article] [PubMed]
  • Takahata N. Allelic genealogy and human evolution. Mol Biol Evol. 1993 Jan;10(1):2–22. [PubMed]

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