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Human Genetics

, Volume 131, Issue 7, pp 1073–1080 | Cite as

OPRM1 and EGFR contribute to skin pigmentation differences between Indigenous Americans and Europeans

  • Ellen E. QuillenEmail author
  • Marc Bauchet
  • Abigail W. Bigham
  • Miguel E. Delgado-Burbano
  • Franz X. Faust
  • Yann C. Klimentidis
  • Xianyun Mao
  • Mark Stoneking
  • Mark D. Shriver
Original Investigation

Abstract

Contemporary variation in skin pigmentation is the result of hundreds of thousands years of human evolution in new and changing environments. Previous studies have identified several genes involved in skin pigmentation differences among African, Asian, and European populations. However, none have examined skin pigmentation variation among Indigenous American populations, creating a critical gap in our understanding of skin pigmentation variation. This study investigates signatures of selection at 76 pigmentation candidate genes that may contribute to skin pigmentation differences between Indigenous Americans and Europeans. Analysis was performed on two samples of Indigenous Americans genotyped on genome-wide SNP arrays. Using four tests for natural selection—locus-specific branch length (LSBL), ratio of heterozygosities (lnRH), Tajima’s D difference, and extended haplotype homozygosity (EHH)—we identified 14 selection-nominated candidate genes (SNCGs). SNPs in each of the SNCGs were tested for association with skin pigmentation in 515 admixed Indigenous American and European individuals from regions of the Americas with high ground-level ultraviolet radiation. In addition to SLC24A5 and SLC45A2, genes previously associated with European/non-European differences in skin pigmentation, OPRM1 and EGFR were associated with variation in skin pigmentation in New World populations for the first time.

Keywords

Skin Pigmentation Single Nucleotide Polymorphism Array Pigmentation Gene Extended Haplotype Homozygosity Core Haplotype 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The authors would like to thank the individuals who volunteered their time to participate in this research and the anonymous reviewers for their comments. This project was funded by National Science Foundation Doctoral Dissertation Improvement Grant #0925976 and intramural Research and Graduate Studies Office and Hill Fellowships from Pennsylvania State University to EEQ. MB and MSt were funded by the Max Planck Society. YCK was funded by a Graduate Research Development grant from the University of New Mexico. The authors have no conflicts of interest to disclose.

Supplementary material

439_2011_1135_MOESM1_ESM.xls (942 kb)
Supplementary material 1 (XLS 942 kb)

References

  1. Akey JM, Zhang G, Zhang K et al (2002) Interrogating a high-density SNP map for signatures of natural selection. Genome Res 12:1805–1814. doi: 10.1101/gr.631202 PubMedCrossRefGoogle Scholar
  2. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics (Oxford, England) 21:263–265. doi: 10.1093/bioinformatics/bth457 CrossRefGoogle Scholar
  3. Bigham A, Bauchet M, Pinto D et al (2010) Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLoS Genetics 6:14CrossRefGoogle Scholar
  4. Bigliardi PL, Tobin DJ, Gaveriaux-Ruff C, Bigliardi-Qi M (2009) Opioids and the skin—where do we stand? Exp Dermatol 18:424–430. doi: 10.1111/j.1600-0625.2009.00844.x PubMedCrossRefGoogle Scholar
  5. Bonilla C, Parra EJ, Pfaff CL et al (2004) Admixture in the Hispanics of the San Luis Valley, Colorado, and its implications for complex trait gene mapping. Ann Hum Genet 68:139–153. doi: 10.1046/j.1529-8817.2003.00084.x PubMedCrossRefGoogle Scholar
  6. Bonilla C, Gutiérrez G, Parra EJ et al (2005) Admixture analysis of a rural population of the state of Guerrero, Mexico. Am J Phys Anthropol 128:861–869. doi: 10.1002/ajpa.20227 PubMedCrossRefGoogle Scholar
  7. Fejerman L, John EM, Huntsman S et al (2008) Genetic ancestry and risk of breast cancer among US Latinas. Cancer Res 68:9723. doi: 10.1158/0008-5472.CAN-08-2039 PubMedCrossRefGoogle Scholar
  8. Fitch KR, McGowan KA, van Raamsdonk CD et al (2003) Genetics of dark skin in mice. Genes Dev 17:214–228. doi: 10.1101/gad.1023703 PubMedCrossRefGoogle Scholar
  9. Harrow J, Denoeud F, Frankish A et al (2006) GENCODE: producing a reference annotation for ENCODE. Genome Biol 7(Suppl 1):S4.1–S4.9. doi: 10.1186/gb-2006-7-s1-s4 CrossRefGoogle Scholar
  10. Hirobe T (2011) How are proliferation and differentiation of melanocytes regulated? Pigment Cell Melanoma Res 24:462–478. doi: 10.1111/j.1755-148X.2011.00845.x PubMedCrossRefGoogle Scholar
  11. Ho H, Milenković T, Memisević V et al (2010) Protein interaction network topology uncovers melanogenesis regulatory network components within functional genomics datasets. BMC Syst Biol 4:84. doi: 10.1186/1752-0509-4-84 PubMedCrossRefGoogle Scholar
  12. Hoggart CJ, Shriver MD, Kittles RA et al (2004) Design and analysis of admixture mapping studies. American J Hum Genet 74:965–978. doi: 10.1086/420855 CrossRefGoogle Scholar
  13. Jablonski NG, Chaplin G (2000) The evolution of human skin coloration. J Hum Evol 39:57–106. doi: 10.1006/jhev.2000.0403 PubMedCrossRefGoogle Scholar
  14. Jablonski NG, Chaplin G (2010) Human skin pigmentation as an adaptation to UV radiation. Proc Natl Acad Sci 107(Suppl 2):8962–8968. doi: 10.1073/pnas.0914628107 PubMedCrossRefGoogle Scholar
  15. Johansson A, Gyllesnsten U (2008) Identification of local selective sweeps in human populations since the exodus from Africa. Hereditas 145:126–137. doi: 10.1111/j.2008.0018-0661.02054.x PubMedCrossRefGoogle Scholar
  16. Jost M, Kari C, Rodeck U (2000) The EGF receptor–an essential regulator of multiple epidermal functions. Eur J Dermatol 10:505–510PubMedGoogle Scholar
  17. Kent WJ, Sugnet CW, Furey TS et al (2002) The Human Genome Browser at UCSC. Genome Res 12:996–1006PubMedGoogle Scholar
  18. Klimentidis YC, Miller GF, Shriver MD (2009) Genetic admixture, self-reported ethnicity, self-estimated admixture, and skin pigmentation among Hispanics and Native Americans. Am J Phys Anthropol 138:375–383. doi: 10.1002/ajpa.20945 PubMedCrossRefGoogle Scholar
  19. Lamason RL, Mohideen M-APK, Mest JR et al (2005) SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science 310:1782–1786. doi: 10.1126/science.1116238 PubMedCrossRefGoogle Scholar
  20. Lao O, de Gruijter JM, van Duijn K et al (2007) Signatures of positive selection in genes associated with human skin pigmentation as revealed from analyses of single nucleotide polymorphisms. Ann Hum Genet 71:354–369. doi: 10.1111/j.1469-1809.2006.00341.x PubMedCrossRefGoogle Scholar
  21. Li JZ, Absher DM, Tang H et al (2008) Worldwide human relationships inferred from genome-wide patterns of variation. Science (New York) 319:1100–1104. doi: 10.1126/science.1153717 CrossRefGoogle Scholar
  22. Myles S, Tang K, Somel M et al (2008) Identification and analysis of genomic regions with large between-population differentiation in humans. Ann Hum Genet 72:99–110. doi: 10.1111/j.1469-1809.2007.00390.x PubMedGoogle Scholar
  23. Norton HL, Kittles RA, Parra E et al (2007) Genetic evidence for the convergent evolution of light skin in Europeans and East Asians. Molecular Biol Evol 24:710–722. doi: 10.1093/molbev/msl203 CrossRefGoogle Scholar
  24. Pickrell JK, Coop G, Novembre J et al (2009) Signals of recent positive selection in a worldwide sample of human populations. Genome Res 19:826–837. doi: 10.1101/gr.087577.108 PubMedCrossRefGoogle Scholar
  25. Relethford JH (1997) Hemispheric difference in human skin color. Am J Phys Anthropol 104:449–457. doi: 10.1002/(SICI)1096-8644(199712)104:4<449:AID-AJPA2>3.0.CO;2-N PubMedCrossRefGoogle Scholar
  26. Sabeti PC, Reich DE, Higgins JM et al (2002) Detecting recent positive selection in the human genome from haplotype structure. Nature 419:832–837. doi: 10.1038/nature01140 PubMedCrossRefGoogle Scholar
  27. Sabeti PC, Varilly P, Fry B et al (2007) Genome-wide detection and characterization of positive selection in human populations. Nature 449:913–918. doi: 10.1038/nature06250 PubMedCrossRefGoogle Scholar
  28. Schlötterer C, Dieringer D (2005) A novel test statistic for the identification of local selective sweeps based on microsatellite gene diversity. In: Nurminsky D (ed) Selective Sweep. Kluwer Academic/Plenum Publishers, New york, pp 55–64CrossRefGoogle Scholar
  29. Shriver MD, Kennedy GC, Parra EJ et al (2004) The genomic distribution of population substructure in four populations using 8, 525 autosomal SNPs. Human Genomics 1:274–286PubMedGoogle Scholar
  30. Simonin F, Gavériaux-Ruff C, Befort K et al (1995) kappa-Opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system. Proc Natl Acad Sci USA 92:7006–7010PubMedCrossRefGoogle Scholar
  31. Tajima F (1989) Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123:585–595PubMedGoogle Scholar
  32. The International HapMap Consortium (2003) The International HapMap Project. Nature 426:789–796. doi: 10.1038/nature02168 CrossRefGoogle Scholar
  33. Thong HY, Jee SH, Sun CC, Boissy R (2003) The patterns of melanosome distribution in keratinocytes of human skin as one determining factor of skin colour. Br J Dermatol 149:498–505PubMedCrossRefGoogle Scholar
  34. Voight BF, Kudaravalli S, Wen X, Pritchard JK (2006) A map of recent positive selection in the human genome. PLoS biology 4:e72. doi: 10.1371/journal.pbio.0040072 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Ellen E. Quillen
    • 1
    • 9
    Email author
  • Marc Bauchet
    • 2
  • Abigail W. Bigham
    • 3
  • Miguel E. Delgado-Burbano
    • 4
    • 5
  • Franz X. Faust
    • 6
  • Yann C. Klimentidis
    • 7
  • Xianyun Mao
    • 8
  • Mark Stoneking
    • 2
  • Mark D. Shriver
    • 1
  1. 1.Department of AnthropologyPennsylvania State UniversityUniversity ParkUSA
  2. 2.Department of Evolutionary GeneticsMax Planck Institute for Evolutionary AnthropologyLeipzigGermany
  3. 3.Department of AnthropologyUniversity of MichiganAnn ArborUSA
  4. 4.División Antropología, Facultad de Ciencias Naturales y MuseoUniversidad Nacional de La PlataLa PlataArgentina
  5. 5.Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)Buenos AiresArgentina
  6. 6.Department of AnthropologyUniversidad del CaucaPopayánColombia
  7. 7.Department of BiostatisticsUniversity of Alabama at BirminghamBirminghamUSA
  8. 8.Department of StatisticsPennsylvania State UniversityUniversity ParkUSA
  9. 9.Department of GeneticsTexas Biomedical Research InstituteSan AntonioUSA

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