1932

Abstract

Human skin and hair color are visible traits that can vary dramatically within and across ethnic populations. The genetic makeup of these traits—including polymorphisms in the enzymes and signaling proteins involved in melanogenesis, and the vital role of ion transport mechanisms operating during the maturation and distribution of the melanosome—has provided new insights into the regulation of pigmentation. A large number of novel loci involved in the process have been recently discovered through four large-scale genome-wide association studies in Europeans, two large genetic studies of skin color in Africans, one study in Latin Americans, and functional testing in animal models. The responsible polymorphisms within these pigmentation genes appear at different population frequencies, can be used as ancestry-informative markers, and provide insight into the evolutionary selective forces that have acted to create this human diversity.

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2019-08-31
2024-10-07
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Literature Cited

  1. 1.
    1000 Genomes Proj. Consort 2015. A global reference for human genetic variation. Nature 526:68–74
    [Google Scholar]
  2. 2.
    Abdel-Malek Z, Swope VB, Suzuki I, Akcali C, Harriger MD et al. 1995. Mitogenic and melanogenic stimulation of normal human melanocytes by melanotropic peptides. PNAS 92:1789–93
    [Google Scholar]
  3. 3.
    Abe Y, Tamiya G, Nakamura T, Hozumi Y, Suzuki T 2013. Association of melanogenesis genes with skin color variation among Japanese females. J. Dermatol. Sci. 69:167–72
    [Google Scholar]
  4. 4.
    Adhikari K, Fontanil T, Cal S, Mendoza-Revilla J, Fuentes-Guajardo M et al. 2016. A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features. Nat. Commun. 7:10815
    [Google Scholar]
  5. 5.
    Adhikari K, Mendoza-Revilla J, Sohail A, Fuentes-Guajardo M, Lampert J et al. 2019. A GWAS in Latin Americans highlights the convergent evolution of lighter skin pigmentation in Eurasia. Nat. Commun. 10:358
    [Google Scholar]
  6. 6.
    Ainger SA, Yong XL, Wong SS, Skalamera D, Gabrielli B et al. 2014. DCT protects human melanocytic cells from UVR and ROS damage and increases cell viability. Exp. Dermatol. 23:916–21
    [Google Scholar]
  7. 7.
    Allentoft ME, Sikora M, Sjogren KG, Rasmussen S, Rasmussen M et al. 2015. Population genomics of Bronze Age Eurasia. Nature 522:167–72
    [Google Scholar]
  8. 8.
    Alonso S, Izagirre N, Smith-Zubiaga I, Gardeazabal J, Diaz-Ramon JL et al. 2008. Complex signatures of selection for the melanogenic loci TYR, TYRP1 and DCT in humans. BMC Evol. Biol. 8:74
    [Google Scholar]
  9. 9.
    Ambrosio AL, Boyle JA, Aradi AE, Christian KA, Di Pietro SM 2016. TPC2 controls pigmentation by regulating melanosome pH and size. PNAS 113:5622–27
    [Google Scholar]
  10. 10.
    Andersen JD, Pietroni C, Johansen P, Andersen MM, Pereira V et al. 2016. Importance of nonsynonymous OCA2 variants in human eye color prediction. Mol. Genet. Genom. Med. 4:420–30
    [Google Scholar]
  11. 11.
    Baron AE, Asdigian NL, Gonzalez V, Aalborg J, Terzian T et al. 2014. Interactions between ultraviolet light and MC1R and OCA2 variants are determinants of childhood nevus and freckle phenotypes. Cancer Epidemiol. Biomark. Prev. 23:2829–39
    [Google Scholar]
  12. 12.
    Baxter LL, Watkins-Chow DE, Pavan WJ, Loftus SK 2019. A curated gene list for expanding the horizons of pigmentation biology. Pigment Cell Melanoma Res 32:348–58
    [Google Scholar]
  13. 13.
    Beaumont KA, Shekar SN, Newton RA, James MR, Stow JL et al. 2007. Receptor function, dominant negative activity and phenotype correlations for MC1R variant alleles. Hum. Mol. Genet. 16:2249–60
    [Google Scholar]
  14. 14.
    Beaumont KA, Wong SS, Ainger SA, Liu YY, Patel MP et al. 2011. Melanocortin MC1 receptor in human genetics and model systems. Eur. J. Pharmacol. 660:103–10
    [Google Scholar]
  15. 15.
    Bellono NW, Escobar IE, Lefkovith AJ, Marks MS, Oancea E 2014. An intracellular anion channel critical for pigmentation. eLife 3:e04543
    [Google Scholar]
  16. 16.
    Bellono NW, Escobar IE, Oancea E 2016. A melanosomal two-pore sodium channel regulates pigmentation. Sci. Rep. 6:26570
    [Google Scholar]
  17. 17.
    Bellono NW, Oancea EV. 2014. Ion transport in pigmentation. Arch. Biochem. Biophys. 563:35–41
    [Google Scholar]
  18. 18.
    Bertolotto C, Lesueur F, Giuliano S, Strub T, de Lichy M et al. 2011. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 480:94–98
    [Google Scholar]
  19. 19.
    Bin BH, Bhin J, Yang SH, Shin M, Nam YJ et al. 2015. Membrane-associated transporter protein (MATP) regulates melanosomal pH and influences tyrosinase activity. PLOS ONE 10:e0129273
    [Google Scholar]
  20. 20.
    Binstock M, Hafeez F, Metchnikoff C, Arron ST 2014. Single-nucleotide polymorphisms in pigment genes and nonmelanoma skin cancer predisposition: a systematic review. Br. J. Dermatol. 171:713–21
    [Google Scholar]
  21. 21.
    Bonet C, Luciani F, Ottavi JF, Leclerc J, Jouenne FM et al. 2017. Deciphering the role of oncogenic MITFE318K in senescence delay and melanoma progression. J. Natl. Cancer Inst. 109:djw340
    [Google Scholar]
  22. 22.
    Bycroft C, Freeman C, Petkova D, Band G, Elliott LT et al. 2018. The UK Biobank resource with deep phenotyping and genomic data. Nature 562:203–9
    [Google Scholar]
  23. 23.
    Candille SI, Kaelin CB, Cattanach BM, Yu B, Thompson DA et al. 2007. A β-defensin mutation causes black coat color in domestic dogs. Science 318:1418–23
    [Google Scholar]
  24. 24.
    Cassady JL, Sturm RA. 1994. Sequence of the human dopachrome tautomerase-encoding TRP-2 cDNA. Gene 143:295–98
    [Google Scholar]
  25. 25.
    Chaitanya L, Breslin K, Zuniga S, Wirken L, Pospiech E et al. 2018. The HIrisPlex-S system for eye, hair and skin colour prediction from DNA: introduction and forensic developmental validation. Forensic Sci. Int. 35:123–35
    [Google Scholar]
  26. 26.
    Chao YK, Schludi V, Chen CC, Butz E, Nguyen ONP et al. 2017. TPC2 polymorphisms associated with a hair pigmentation phenotype in humans result in gain of channel function by independent mechanisms. PNAS 114:E8595–602
    [Google Scholar]
  27. 27.
    Cheli Y, Luciani F, Khaled M, Beuret L, Bille K et al. 2009. αMSH and cyclic AMP elevating agents control melanosome pH through a protein kinase A-independent mechanism. J. Biol. Chem. 284:18699–706
    [Google Scholar]
  28. 28.
    Chhabra Y, Yong HXL, Fane ME, Soogrim A, Lim W et al. 2018. Genetic variation in IRF4 expression modulates growth characteristics, tyrosinase expression and interferon-gamma response in melanocytic cells. Pigment Cell Melanoma Res 31:51–63
    [Google Scholar]
  29. 29.
    Chiang PW, Spector E, Tsai AC 2009. Oculocutaneous albinism spectrum. Am. J. Med. Genet. A 149A:1590–91
    [Google Scholar]
  30. 30.
    Chintala S, Li W, Lamoreux ML, Ito S, Wakamatsu K et al. 2005. Slc7a11 gene controls production of pheomelanin pigment and proliferation of cultured cells. PNAS 102:10964–69
    [Google Scholar]
  31. 31.
    Cook AL, Chen W, Thurber AE, Smit DJ, Smith AG et al. 2009. Analysis of cultured human melanocytes based on polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P loci. J. Investig. Dermatol. 129:392–405
    [Google Scholar]
  32. 32.
    Cooper CD. 2017. Insights from zebrafish on human pigment cell disease and treatment. Dev. Dyn. 246:889–96
    [Google Scholar]
  33. 33.
    Costin GE, Valencia JC, Vieira WD, Lamoreux ML, Hearing VJ 2003. Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4. J. Cell Sci. 116:3203–12
    [Google Scholar]
  34. 34.
    Crawford NG, Kelly DE, Hansen MEB, Beltrame MH, Fan S et al. 2017. Loci associated with skin pigmentation identified in African populations. Science 358:eaan8433
    [Google Scholar]
  35. 35.
    d'Ischia M, Wakamatsu K, Cicoira F, Di Mauro E, Garcia-Borron JC et al. 2015. Melanins and melanogenesis: from pigment cells to human health and technological applications. Pigment Cell Melanoma Res 28:520–44
    [Google Scholar]
  36. 36.
    Dannemann M, Kelso J. 2017. The contribution of Neanderthals to phenotypic variation in modern humans. Am. J. Hum. Genet. 101:578–89
    [Google Scholar]
  37. 37.
    del Marmol V, Ito S, Jackson I, Vachtenheim J, Berr P et al. 1993. TRP-1 expression correlates with eumelanogenesis in human pigment cells in culture. FEBS Lett 327:307–10
    [Google Scholar]
  38. 38.
    Ding Q, Hu Y, Xu S, Wang CC, Li H et al. 2014. Neanderthal origin of the haplotypes carrying the functional variant Val92Met in the MC1R in modern humans. Mol. Biol. Evol. 31:1994–2003
    [Google Scholar]
  39. 39.
    Donnelly MP, Paschou P, Grigorenko E, Gurwitz D, Barta C et al. 2012. A global view of the OCA2-HERC2 region and pigmentation. Hum. Genet. 131:683–96
    [Google Scholar]
  40. 40.
    Duffy DL. 2015. Genetics of eye colour. eLS Chichester, UK: Wiley & Sons https://doi.org/10.1002/9780470015902.a0024646
    [Crossref] [Google Scholar]
  41. 41.
    Duffy DL, Box NF, Chen W, Palmer JS, Montgomery GW et al. 2004. Interactive effects of MC1R and OCA2 on melanoma risk phenotypes. Hum. Mol. Genet. 13:447–61
    [Google Scholar]
  42. 42.
    Duffy DL, Iles MM, Glass D, Zhu G, Barrett JH et al. 2010. IRF4 variants have age-specific effects on nevus count and predispose to melanoma. Am. J. Hum. Genet. 87:6–16
    [Google Scholar]
  43. 43.
    Duffy DL, Jagirdar K, Lee KJ, McWhirter SR, McMeniman EK, et al. 2019. Genes determining nevus count and dermoscopic appearance in Australian melanoma cases and controls. J. Investig. Dermatol. In press
    [Google Scholar]
  44. 44.
    Duffy DL, Montgomery GW, Chen W, Zhao ZZ, Le L et al. 2007. A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation. Am. J. Hum. Genet. 80:241–52
    [Google Scholar]
  45. 45.
    Duffy DL, Zhao ZZ, Sturm RA, Hayward NK, Martin NG, Montgomery GW 2010. Multiple pigmentation gene polymorphisms account for a substantial proportion of risk of cutaneous malignant melanoma. J. Investig. Dermatol. 130:520–28
    [Google Scholar]
  46. 46.
    Duffy DL, Zhu G, Li X, Sanna M, Iles MM et al. 2018. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways. Nat. Commun. 9:4774
    [Google Scholar]
  47. 47.
    Durham-Pierre D, Gardner JM, Nakatsu Y, King RA, Francke U et al. 1994. African origin of an intragenic deletion of the human P gene in tyrosinase positive oculocutaneous albinism. Nat. Genet. 7:176–79
    [Google Scholar]
  48. 48.
    Eaton K, Edwards M, Krithika S, Cook G, Norton H, Parra EJ 2015. Association study confirms the role of two OCA2 polymorphisms in normal skin pigmentation variation in East Asian populations. Am. J. Hum. Biol. 27:520–25
    [Google Scholar]
  49. 49.
    Edwards M, Bigham A, Tan J, Li S, Gozdzik A et al. 2010. Association of the OCA2 polymorphism His615Arg with melanin content in east Asian populations: further evidence of convergent evolution of skin pigmentation. PLOS Genet 6:e1000867
    [Google Scholar]
  50. 50.
    eGTEx Proj 2017. Enhancing GTEx by bridging the gaps between genotype, gene expression, and disease. Nat. Genet. 49:1664–70
    [Google Scholar]
  51. 51.
    Eriksson N, Macpherson JM, Tung JY, Hon LS, Naughton B et al. 2010. Web-based, participant-driven studies yield novel genetic associations for common traits. PLOS Genet 6:e1000993
    [Google Scholar]
  52. 52.
    Garcia-Borron JC, Abdel-Malek Z, Jimenez-Cervantes C 2014. MC1R, the cAMP pathway, and the response to solar UV: extending the horizon beyond pigmentation. Pigment Cell Melanoma Res 27:699–720
    [Google Scholar]
  53. 53.
    Gerstenblith MR, Goldstein AM, Fargnoli MC, Peris K, Landi MT 2007. Comprehensive evaluation of allele frequency differences of MC1R variants across populations. Hum. Mutat. 28:495–505
    [Google Scholar]
  54. 54.
    Gibbs DC, Orlow I, Bramson JI, Kanetsky PA, Luo L et al. 2016. Association of interferon regulatory factor-4 polymorphism rs12203592 with divergent melanoma pathways. J. Natl. Cancer Inst. 108:djw004
    [Google Scholar]
  55. 55.
    Ginger RS, Askew SE, Ogborne RM, Wilson S, Ferdinando D et al. 2008. SLC24A5 encodes a trans-Golgi network protein with potassium-dependent sodium-calcium exchange activity that regulates human epidermal melanogenesis. J. Biol. Chem. 283:5486–95
    [Google Scholar]
  56. 56.
    Graf J, Hodgson R, van Daal A 2005. Single nucleotide polymorphisms in the MATP gene are associated with normal human pigmentation variation. Hum. Mutat. 25:278–84
    [Google Scholar]
  57. 57.
    Grønskov K, Dooley CM, Østergaard E, Kelsh RN, Hansen L et al. 2013. Mutations in C10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism. Am. J. Hum. Genet. 92:415–21
    [Google Scholar]
  58. 58.
    Gudbjartsson DF, Sulem P, Stacey SN, Goldstein AM, Rafnar T et al. 2008. ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nat. Genet. 40:886–91
    [Google Scholar]
  59. 59.
    Guenther CA, Tasic B, Luo L, Bedell MA, Kingsley DM 2014. A molecular basis for classic blond hair color in Europeans. Nat. Genet. 46:748–52
    [Google Scholar]
  60. 60.
    Guyonneau L, Murisier F, Rossier A, Moulin A, Beermann F 2004. Melanocytes and pigmentation are affected in dopachrome tautomerase knockout mice. Mol. Cell. Biol. 24:3396–403
    [Google Scholar]
  61. 61.
    Han J, Kraft P, Nan H, Guo Q, Chen C et al. 2008. A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation. PLOS Genet 4:e1000074
    [Google Scholar]
  62. 62.
    Huang X, Wang S, Jn L, He Y 2018. Dissecting historical changes of selective pressures in the evolution of human pigmentation. bioRxiv 253963. https://doi.org/10.1101/253963
    [Crossref]
  63. 63.
    Hysi PG, Valdes AM, Liu F, Furlotte NA, Evans DM et al. 2018. Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability. Nat. Genet. 50:652–56
    [Google Scholar]
  64. 64.
    Iliescu FM, Chaplin G, Rai N, Jacobs GS, Basu Mallick C et al. 2018. The influences of genes, the environment, and social factors on the evolution of skin color diversity in India. Am. J. Hum. Biol. 30:e23170
    [Google Scholar]
  65. 65.
    Ito S, Nakanishi Y, Valenzuela RK, Brilliant MH, Kolbe L, Wakamatsu K 2011. Usefulness of alkaline hydrogen peroxide oxidation to analyze eumelanin and pheomelanin in various tissue samples: application to chemical analysis of human hair melanins. Pigment Cell Melanoma Res 24:605–13
    [Google Scholar]
  66. 66.
    Ito S, Wakamatsu K. 2011. Diversity of human hair pigmentation as studied by chemical analysis of eumelanin and pheomelanin. J. Eur. Acad. Dermatol. Venereol. 25:1369–80
    [Google Scholar]
  67. 67.
    Jacobs LC, Hamer MA, Gunn DA, Deelen J, Lall JS et al. 2015. A genome-wide association study identifies the skin color genes IRF4, MC1R, ASIP, and BNC2 influencing facial pigmented spots. J. Investig. Dermatol 135:1735–42
    [Google Scholar]
  68. 68.
    Jacobs LC, Wollstein A, Lao O, Hofman A, Klaver CC et al. 2013. Comprehensive candidate gene study highlights UGT1A and BNC2 as new genes determining continuous skin color variation in Europeans. Hum. Genet. 132:147–58
    [Google Scholar]
  69. 69.
    Jagirdar K, Smit DJ, Ainger SA, Lee KJ, Brown DL et al. 2014. Molecular analysis of common polymorphisms within the human Tyrosinase locus and genetic association with pigmentation traits. Pigment Cell Melanoma Res 27:552–64
    [Google Scholar]
  70. 70.
    Jarrett SG, Wolf Horrell EM, Boulanger MC, D'Orazio JA 2015. Defining the contribution of MC1R physiological ligands to ATR phosphorylation at Ser435, a predictor of DNA repair in melanocytes. J. Investig. Dermatol. 135:3086–95
    [Google Scholar]
  71. 71.
    Jin Y, Ferrara T, Gowan K, Holcomb C, Rastrou M et al. 2012. Next-generation DNA re-sequencing identifies common variants of TYR and HLA-A that modulate the risk of generalized vitiligo via antigen presentation. J. Investig. Dermatol. 132:1730–33
    [Google Scholar]
  72. 72.
    Johanson HC, Chen W, Wicking C, Sturm RA 2010. Inheritance of a novel mutated allele of the OCA2 gene associated with high incidence of oculocutaneous albinism in a Polynesian community. J. Hum. Genet. 55:103–11
    [Google Scholar]
  73. 73.
    Jones P, Lucock M, Veysey M, Beckett E 2018. The vitamin D–folate hypothesis as an evolutionary model for skin pigmentation: an update and integration of current ideas. Nutrients 10:554
    [Google Scholar]
  74. 74.
    Jonnalagadda M, Bharti N, Patil Y, Ozarkar S, K SM et al. 2017. Identifying signatures of positive selection in pigmentation genes in two South Asian populations. Am. J. Hum. Biol. 29:e23012
    [Google Scholar]
  75. 75.
    Kasamatsu S, Hachiya A, Higuchi K, Ohuchi A, Kitahara T, Boissy RE 2008. Production of the soluble form of KIT, s-KIT, abolishes stem cell factor-induced melanogenesis in human melanocytes. J. Investig. Dermatol. 128:1763–72
    [Google Scholar]
  76. 76.
    Kausar T, Bhatti MA, Ali M, Shaikh RS, Ahmed ZM 2013. OCA5, a novel locus for non-syndromic oculocutaneous albinism, maps to chromosome 4q24. Clin. Genet. 84:91–93
    [Google Scholar]
  77. 77.
    Kenny EE, Timpson NJ, Sikora M, Yee MC, Moreno-Estrada A et al. 2012. Melanesian blond hair is caused by an amino acid change in TYRP1. Science 336:554
    [Google Scholar]
  78. 78.
    King RA, Willaert RK, Schmidt RM, Pietsch J, Savage S et al. 2003. MC1R mutations modify the classic phenotype of oculocutaneous albinism type 2 (OCA2). Am. J. Hum. Genet. 73:638–45
    [Google Scholar]
  79. 79.
    Kobayashi T, Hearing VJ. 2007. Direct interaction of tyrosinase with Tyrp1 to form heterodimeric complexes in vivo. J. Cell Sci. 120:4261–68
    [Google Scholar]
  80. 80.
    Krude H, Gruters A. 2000. Implications of proopiomelanocortin (POMC) mutations in humans: the POMC deficiency syndrome. Trends Endocrinol. Metab. 11:15–22
    [Google Scholar]
  81. 81.
    Lai X, Wichers HJ, Soler-Lopez M, Dijkstra BW 2017. Structure of human tyrosinase related protein 1 reveals a binuclear zinc active site important for melanogenesis. Angew. Chem. Int. Ed. 56:9812–15
    [Google Scholar]
  82. 82.
    Lai X, Wichers HJ, Soler-Lopez M, Dijkstra BW 2018. Structure and function of human tyrosinase and tyrosinase-related proteins. Chemistry 24:47–55
    [Google Scholar]
  83. 83.
    Laino AM, Berry EG, Jagirdar K, Lee KJ, Duffy DL et al. 2018. Iris pigmented lesions as a marker of cutaneous melanoma risk: an Australian case-control study. Br. J. Dermatol. 178:1119–27
    [Google Scholar]
  84. 84.
    Lamason RL, Mohideen MA, Mest JR, Wong AC, Norton HL et al. 2005. SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science 310:1782–86
    [Google Scholar]
  85. 85.
    Lao O, de Gruijter JM, van Duijn K, Navarro A, Kayser M 2007. Signatures of positive selection in genes associated with human skin pigmentation as revealed from analyses of single nucleotide polymorphisms. Ann. Hum. Genet. 71:354–69
    [Google Scholar]
  86. 86.
    Lasseaux E, Plaisant C, Michaud V, Pennamen P, Trimouille A et al. 2018. Molecular characterization of a series of 990 index patients with albinism. Pigment Cell Melanoma Res 31:466–74
    [Google Scholar]
  87. 87.
    Le Pape E, Passeron T, Giubellino A, Valencia JC, Wolber R, Hearing VJ 2009. Microarray analysis sheds light on the dedifferentiating role of agouti signal protein in murine melanocytes via the Mc1r. PNAS 106:1802–7
    [Google Scholar]
  88. 88.
    Le Pape E, Wakamatsu K, Ito S, Wolber R, Hearing VJ 2008. Regulation of eumelanin/pheomelanin synthesis and visible pigmentation in melanocytes by ligands of the melanocortin 1 receptor. Pigment Cell Melanoma Res 21:477–86
    [Google Scholar]
  89. 89.
    Leclerc J, Ballotti R, Bertolotto C 2017. Pathways from senescence to melanoma: focus on MITF sumoylation. Oncogene 36:6659–67
    [Google Scholar]
  90. 90.
    Lee ST, Nicholls RD, Jong MT, Fukai K, Spritz RA 1995. Organization and sequence of the human P gene and identification of a new family of transport proteins. Genomics 26:354–63
    [Google Scholar]
  91. 91.
    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E et al. 2016. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–91
    [Google Scholar]
  92. 92.
    Li CY, Gao TW, Wang G, Han ZY, Shen Z et al. 2004. The effect of antisense tyrosinase-related protein 1 on melanocytes and malignant melanoma cells. Br. J. Dermatol. 150:1081–90
    [Google Scholar]
  93. 93.
    Liem EB, Lin CM, Suleman MI, Doufas AG, Gregg RG et al. 2004. Anesthetic requirement is increased in redheads. Anesthesiology 101:279–83
    [Google Scholar]
  94. 94.
    Lin BD, Mbarek H, Willemsen G, Dolan CV, Fedko IO et al. 2015. Heritability and genome-wide association studies for hair color in a Dutch twin family based sample. Genes 6:559–76
    [Google Scholar]
  95. 95.
    Lin M, Siford RL, Martin AR, Nakagome S, Moller M et al. 2018. Rapid evolution of a skin-lightening allele in southern African KhoeSan. PNAS 115:13324–29
    [Google Scholar]
  96. 96.
    Liu F, Visser M, Duffy DL, Hysi PG, Jacobs LC et al. 2015. Genetics of skin color variation in Europeans: genome-wide association studies with functional follow-up. Hum. Genet. 134:823–35
    [Google Scholar]
  97. 97.
    Liu Y, Hong L, Wakamatsu K, Ito S, Adhyaru B et al. 2005. Comparison of structural and chemical properties of black and red human hair melanosomes. Photochem. Photobiol. 81:135–44
    [Google Scholar]
  98. 98.
    Maccioni L, Rachakonda PS, Scherer D, Bermejo JL, Planelles D et al. 2013. Variants at chromosome 20 (ASIP locus) and melanoma risk. Int. J. Cancer 132:42–54
    [Google Scholar]
  99. 99.
    Maronas O, Phillips C, Sochtig J, Gomez-Tato A, Cruz R et al. 2014. Development of a forensic skin colour predictive test. Forensic Sci. Int. 13:34–44
    [Google Scholar]
  100. 100.
    Martin AR, Lin M, Granka JM, Myrick JW, Liu X et al. 2017. An unexpectedly complex architecture for skin pigmentation in Africans. Cell 171:1340–53.e14
    [Google Scholar]
  101. 101.
    Miller CT, Beleza S, Pollen AA, Schluter D, Kittles RA et al. 2007. cis-Regulatory changes in Kit ligand expression and parallel evolution of pigmentation in sticklebacks and humans. Cell 131:1179–89
    [Google Scholar]
  102. 102.
    Mogil JS, Ritchie J, Smith SB, Strasburg K, Kaplan L et al. 2005. Melanocortin-1 receptor gene variants affect pain and μ-opioid analgesia in mice and humans. J. Med. Genet. 42:583–87
    [Google Scholar]
  103. 103.
    Montoliu L, Grønskov K, Wei AH, Martinez-García M, Fernández A et al. 2014. Increasing the complexity: new genes and new types of albinism. Pigment Cell Melanoma Res 27:11–18
    [Google Scholar]
  104. 104.
    Montoliu L, Kelsh RN. 2014. Do you have to be albino to be albino. ? Pigment Cell Melanoma Res 27:325–26
    [Google Scholar]
  105. 105.
    Morgan MD, Pairo-Castineira E, Rawlik K, Canela-Xandri O, Rees J et al. 2018. Genome-wide study of hair colour in UK Biobank explains most of the SNP heritability. Nat. Commun. 9:5271
    [Google Scholar]
  106. 106.
    Mort RL, Jackson IJ, Patton EE 2015. The melanocyte lineage in development and disease. Development 142:620–32
    [Google Scholar]
  107. 107.
    Morya VK, Dung NH, Singh BK, Lee HB, Kim EK 2014. Homology modelling and virtual screening of P-protein in a quest for novel antimelanogenic agent and in vitro assessments. Exp. Dermatol. 23:838–42
    [Google Scholar]
  108. 108.
    Mountjoy KG. 1994. The human melanocyte stimulating hormone receptor has evolved to become “super-sensitive” to melanocortin peptides. Mol. Cell. Endocrinol. 102:R7–11
    [Google Scholar]
  109. 109.
    Nan H, Kraft P, Qureshi AA, Guo Q, Chen C et al. 2009. Genome-wide association study of tanning phenotype in a population of European ancestry. J. Investig. Dermatol. 129:2250–57
    [Google Scholar]
  110. 110.
    Newton JM, Cohen-Barak O, Hagiwara N, Gardner JM, Davisson MT et al. 2001. Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4. Am. J. Hum. Genet. 69:981–88
    [Google Scholar]
  111. 111.
    Nguyen NT, Fisher DE. 2018. MITF and UV responses in skin: from pigmentation to addiction. Pigment Cell Melanoma Res 32:224–36
    [Google Scholar]
  112. 112.
    Nix MA, Kaelin CB, Ta T, Weis A, Morton GJ et al. 2013. Molecular and functional analysis of human β-defensin 3 action at melanocortin receptors. Chem. Biol. 20:784–95
    [Google Scholar]
  113. 113.
    Norman CS, O'Gorman L, Gibson J, Pengelly RJ, Baralle D et al. 2017. Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B). Sci. Rep. 7:4415
    [Google Scholar]
  114. 114.
    Norton HL, Correa EA, Koki G, Friedlaender JS 2014. Distribution of an allele associated with blond hair color across Northern Island Melanesia. Am. J. Phys. Anthropol. 153:653–62
    [Google Scholar]
  115. 115.
    Norton HL, Edwards M, Krithika S, Johnson M, Werren EA, Parra EJ 2016. Quantitative assessment of skin, hair, and iris variation in a diverse sample of individuals and associated genetic variation. Am. J. Phys. Anthropol. 160:570–81
    [Google Scholar]
  116. 116.
    Norton HL, Kittles RA, Parra E, McKeigue P, Mao X et al. 2007. Genetic evidence for the convergent evolution of light skin in Europeans and East Asians. Mol. Biol. Evol. 24:710–22
    [Google Scholar]
  117. 117.
    Oetting WS, Pietsch J, Brott MJ, Savage S, Fryer JP et al. 2009. The R402Q tyrosinase variant does not cause autosomal recessive ocular albinism. Am. J. Med. Genet. A 149A:466–69
    [Google Scholar]
  118. 118.
    Olalde I, Allentoft ME, Sanchez-Quinto F, Santpere G, Chiang CW et al. 2014. Derived immune and ancestral pigmentation alleles in a 7,000-year-old Mesolithic European. Nature 507:225–28
    [Google Scholar]
  119. 119.
    Park S, Morya VK, Nguyen DH, Singh BK, Lee HB, Kim EK 2015. Unrevealing the role of P-protein on melanosome biology and structure, using siRNA-mediated down regulation of OCA2. Mol. Cell Biochem. 403:61–71
    [Google Scholar]
  120. 120.
    Peng F, Zhu G, Hysi PG, Eller RJ, Chen Y et al. 2019. Genome-wide association studies identify multiple genetic loci influencing eyebrow color variation in Europeans. J. Investig. Dermatol. 139:1601–5
    [Google Scholar]
  121. 121.
    Phillips C. 2015. Forensic genetic analysis of bio-geographical ancestry. Forensic Sci. Int. 18:49–65
    [Google Scholar]
  122. 122.
    Picardo M, Cardinali G. 2011. The genetic determination of skin pigmentation: KITLG and the KITLG/c-Kit pathway as key players in the onset of human familial pigmentary diseases. J. Investig. Dermatol. 131:1182–85
    [Google Scholar]
  123. 123.
    Praetorius C, Grill C, Stacey SN, Metcalf AM, Gorkin DU et al. 2013. A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway. Cell 155:1022–33
    [Google Scholar]
  124. 124.
    Quillen EE, Norton HL, Parra EJ, Lona-Durazo F, Ang KC et al. 2019. Shades of complexity: new perspectives on the evolution and genetic architecture of human skin. Am. J. Phys. Anthropol. 168:S674–26
    [Google Scholar]
  125. 125.
    Raghunath A, Sambarey A, Sharma N, Mahadevan U, Chandra N 2015. A molecular systems approach to modelling human skin pigmentation: identifying underlying pathways and critical components. BMC Res. Notes 8:170
    [Google Scholar]
  126. 126.
    Ramagopalan SV, Knight M, Ebers GC, Knight JC 2007. Origins of magic: review of genetic and epigenetic effects. BMJ 335:1299–301
    [Google Scholar]
  127. 127.
    Robbins LS, Nadeau JH, Johnson KR, Kelly MA, Roselli-Rehfuss L et al. 1993. Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell 72:827–34
    [Google Scholar]
  128. 128.
    Rooryck C, Morice-Picard F, Elcioglu NH, Lacombe D, Taieb A, Arveiler B 2008. Molecular diagnosis of oculocutaneous albinism: new mutations in the OCA1–4 genes and practical aspects. Pigment Cell Melanoma Res 21:583–87
    [Google Scholar]
  129. 129.
    Schweizer RM, Durvasula A, Smith J, Vohr SH, Stahler DR et al. 2018. Natural selection and origin of a melanistic allele in North American gray wolves. Mol. Biol. Evol. 35:1190–209
    [Google Scholar]
  130. 130.
    Simon JD, Peles D, Wakamatsu K, Ito S 2009. Current challenges in understanding melanogenesis: bridging chemistry, biological control, morphology, and function. Pigment Cell Melanoma Res 22:563–79
    [Google Scholar]
  131. 131.
    Soejima M, Koda Y. 2007. Population differences of two coding SNPs in pigmentation-related genes SLC24A5 and SLC45A2. Int. J. . Legal Med 121:36–39
    [Google Scholar]
  132. 132.
    Soejima M, Tachida H, Ishida T, Sano A, Koda Y 2006. Evidence for recent positive selection at the human AIM1 locus in a European population. Mol. Biol. Evol. 23:179–88
    [Google Scholar]
  133. 133.
    Spritz RA, Fukai K, Holmes SA, Luande J 1995. Frequent intragenic deletion of the P gene in Tanzanian patients with type II oculocutaneous albinism (OCA2). Am. J. Hum. Genet. 56:1320–23
    [Google Scholar]
  134. 134.
    Staleva L, Manga P, Orlow SJ 2002. Pink-eyed dilution protein modulates arsenic sensitivity and intracellular glutathione metabolism. Mol. Biol. Cell 13:4206–20
    [Google Scholar]
  135. 135.
    Sturm RA. 2006. A golden age of human pigmentation genetics. Trends Genet 22:464–68
    [Google Scholar]
  136. 136.
    Sturm RA. 2009. Molecular genetics of human pigmentation diversity. Hum. Mol. Genet. 18:R9–17
    [Google Scholar]
  137. 137.
    Sturm RA, Duffy DL. 2012. Human pigmentation genes under environmental selection. Genome Biol 13:248
    [Google Scholar]
  138. 138.
    Sturm RA, Duffy DL. 2018. Towards the full spectrum of genes for human skin colour. Pigment Cell Melanoma Res 31:457–58
    [Google Scholar]
  139. 139.
    Sturm RA, Duffy DL, Box NF, Chen W, Smit DJ et al. 2003. The role of melanocortin-1 receptor polymorphism in skin cancer risk phenotypes. Pigment Cell Res 16:266–72
    [Google Scholar]
  140. 140.
    Sturm RA, Duffy DL, Zhao ZZ, Leite FP, Stark MS et al. 2008. A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color. Am. J. Hum. Genet. 82:424–31
    [Google Scholar]
  141. 141.
    Sturm RA, Fox C, McClenahan P, Jagirdar K, Ibarrola-Villava M et al. 2014. Phenotypic characterization of nevus and tumor patterns in MITF E318K mutation carrier melanoma patients. J. Investig. Dermatol. 134:141–49
    [Google Scholar]
  142. 142.
    Sturm RA, Larsson M. 2009. Genetics of human iris colour and patterns. Pigment Cell Melanoma Res 22:544–62
    [Google Scholar]
  143. 143.
    Sturm RA, O'Sullivan BJ, Box NF, Smith AG, Smit SE et al. 1995. Chromosomal structure of the human TYRP1 and TYRP2 loci and comparison of the tyrosinase-related protein gene family. Genomics 29:24–34
    [Google Scholar]
  144. 144.
    Sulem P, Gudbjartsson DF, Stacey SN, Helgason A, Rafnar T et al. 2007. Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat. Genet. 39:1443–52
    [Google Scholar]
  145. 145.
    Sulem P, Gudbjartsson DF, Stacey SN, Helgason A, Rafnar T et al. 2008. Two newly identified genetic determinants of pigmentation in Europeans. Nat. Genet. 40:835–37
    [Google Scholar]
  146. 146.
    Suzuki I, Cone RD, Im S, Nordlund J, Abdel-Malek ZA 1996. Binding of melanotropic hormones to the melanocortin receptor MC1R on human melanocytes stimulates proliferation and melanogenesis. Endocrinology 137:1627–33
    [Google Scholar]
  147. 147.
    Swope VB, Abdel-Malek ZA. 2018. MC1R: front and center in the bright side of dark eumelanin and DNA repair. Int. J. Mol. Sci. 19:2667
    [Google Scholar]
  148. 148.
    Swope VB, Jameson JA, McFarland KL, Supp DM, Miller WE et al. 2012. Defining MC1R regulation in human melanocytes by its agonist α-melanocortin and antagonists agouti signaling protein and β-defensin 3. J. Investig. Dermatol. 132:2255–62
    [Google Scholar]
  149. 149.
    Tagliabue E, Gandini S, Garcia-Borron JC, Maisonneuve P, Newton-Bishop J et al. 2016. Association of melanocortin-1 receptor variants with pigmentary traits in humans: a pooled analysis from the M-Skip Project. J. Investig. Dermatol. 136:1914–17
    [Google Scholar]
  150. 150.
    Visconti A, Duffy DL, Liu F, Zhu G, Wu W et al. 2018. Genome-wide association study in 176,678 Europeans reveals genetic loci for tanning response to sun exposure. Nat. Commun. 9:1684
    [Google Scholar]
  151. 151.
    Visser M, Kayser M, Grosveld F, Palstra RJ 2014. Genetic variation in regulatory DNA elements: the case of OCA2 transcriptional regulation. Pigment Cell Melanoma Res 27:169–77
    [Google Scholar]
  152. 152.
    Visser M, Kayser M, Palstra RJ 2012. HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter. Genome Res 22:446–55
    [Google Scholar]
  153. 153.
    Visser M, Palstra RJ, Kayser M 2014. Human skin color is influenced by an intergenic DNA polymorphism regulating transcription of the nearby BNC2 pigmentation gene. Hum. Mol. Genet. 23:5750–62
    [Google Scholar]
  154. 154.
    Wakamatsu K, Kavanagh R, Kadekaro AL, Terzieva S, Sturm RA et al. 2006. Diversity of pigmentation in cultured human melanocytes is due to differences in the type as well as quantity of melanin. Pigment Cell Res 19:154–62
    [Google Scholar]
  155. 155.
    Walsh S, Chaitanya L, Breslin K, Muralidharan C, Bronikowska A et al. 2017. Global skin colour prediction from DNA. Hum. Genet. 136:847–63
    [Google Scholar]
  156. 156.
    Wang Y, Zhao Y, Liu L, Zhang L, Xiao H et al. 2014. Inhibitory effects of imatinib mesylate on human epidermal melanocytes. Clin. Exp. Dermatol. 39:202–8
    [Google Scholar]
  157. 157.
    Wei AH, Zang DJ, Zhang Z, Liu XZ, He X et al. 2013. Exome sequencing identifies SLC24A5 as a candidate gene for nonsyndromic oculocutaneous albinism. J. Investig. Dermatol. 133:1834–40
    [Google Scholar]
  158. 158.
    Wu M, Hemesath TJ, Takemoto CM, Horstmann MA, Wells AG et al. 2000. c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi. Genes Dev 14:301–12
    [Google Scholar]
  159. 159.
    Yang Z, Zhong H, Chen J, Zhang X, Zhang H et al. 2016. A genetic mechanism for convergent skin lightening during recent human evolution. Mol. Biol. Evol. 33:1177–87
    [Google Scholar]
  160. 160.
    Yokoyama S, Woods SL, Boyle GM, Aoude LG, MacGregor S et al. 2011. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature 480:99–103
    [Google Scholar]
  161. 161.
    Zhang T, Choi J, Kovacs MA, Shi J, Xu M et al. 2018. Cell-type-specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes. Genome Res 28:1621–35
    [Google Scholar]
  162. 162.
    Zhou D, Ota K, Nardin C, Feldman M, Widman A et al. 2018. Mammalian pigmentation is regulated by a distinct cAMP-dependent mechanism that controls melanosome pH. Sci. Signal. 11:eaau7987
    [Google Scholar]
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