Genetic Architecture of Skin and Eye Color in an African-European Admixed Population

English version České info

Variation in human skin and eye color is substantial and especially apparent in admixed populations, yet the underlying genetic architecture is poorly understood because most genome-wide studies are based on individuals of European ancestry. We study pigmentary variation in 699 individuals from Cape Verde, where extensive West African/European admixture has given rise to a broad range in trait values and genomic ancestry proportions. We develop and apply a new approach for measuring eye color, and identify two major loci (HERC2[OCA2] P = 2.3×10⁻⁶², SLC24A5 P = 9.6×10⁻⁹) that account for both blue versus brown eye color and varying intensities of brown eye color. We identify four major loci (SLC24A5 P = 5.4×10⁻²⁷, TYR P = 1.1×10⁻⁹, APBA2[OCA2] P = 1.5×10⁻⁸, SLC45A2 P = 6×10⁻⁹) for skin color that together account for 35% of the total variance, but the genetic component with the largest effect (∼44%) is average genomic ancestry. Our results suggest that adjacent cis-acting regulatory loci for OCA2 explain the relationship between skin and eye color, and point to an underlying genetic architecture in which several genes of moderate effect act together with many genes of small effect to explain ∼70% of the estimated heritability.

Vyšlo v časopise: Genetic Architecture of Skin and Eye Color in an African-European Admixed Population. PLoS Genet 9(3): e32767. doi:10.1371/journal.pgen.1003372
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003372

Souhrn

Zdroje

1. JablonskiNG, ChaplinG (2000) The evolution of human skin coloration. J Hum Evol 39: 57–106.

2. ParraEJ (2007) Human pigmentation variation: evolution, genetic basis, and implications for public health. Am J Phys Anthropol (Suppl 45) 85–105.

3. Di RienzoA, HudsonRR (2005) An evolutionary framework for common diseases: the ancestral-susceptibility model. Trends Genet 21: 596–601.

4. SulemP, GudbjartssonDF, StaceySN, HelgasonA, RafnarT, et al. (2007) Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat Genet 39: 1443–1452.

5. SulemP, GudbjartssonDF, StaceySN, HelgasonA, RafnarT, et al. (2008) Two newly identified genetic determinants of pigmentation in Europeans. Nat Genet 40: 835–837.

6. HanJ, KraftP, NanH, GuoQ, ChenC, et al. (2008) A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation. PLoS Genet 4: e1000074 doi:10.1371/journal.pgen.1000074.

7. KayserM, LiuF, JanssensAC, RivadeneiraF, LaoO, et al. (2008) Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene. Am J Hum Genet 82: 411–423.

8. Liu F, Wollstein A, Hysi PG, Ankra-Badu GA, Spector TD, et al.. (2010) Digital quantification of human eye color highlights genetic association of three new loci. doi:10.1371/journal.pgen.1000934

9. StokowskiRP, PantPV, DaddT, FeredayA, HindsDA, et al. (2007) A genomewide association study of skin pigmentation in a South Asian population. Am J Hum Genet 81: 1119–1132.

10. SturmRA, DuffyDL, ZhaoZZ, LeiteFP, StarkMS, 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: 424–431.

11. ShriverMD, ParraEJ, DiosS, BonillaC, NortonH, et al. (2003) Skin pigmentation, biogeographical ancestry and admixture mapping. Hum Genet 112: 387–399.

12. BonillaC, BoxillLA, DonaldSA, WilliamsT, SylvesterN, et al. (2005) The 8818G allele of the agouti signaling protein (ASIP) gene is ancestral and is associated with darker skin color in African Americans. Hum Genet 116: 402–406.

13. LamasonRL, MohideenMA, MestJR, WongAC, NortonHL, et al. (2005) SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science 310: 1782–1786.

14. NortonHL, KittlesRA, ParraE, McKeigueP, MaoX, et al. (2007) Genetic evidence for the convergent evolution of light skin in Europeans and East Asians. Mol Biol Evol 24: 710–722.

15. MillerCT, BelezaS, PollenAA, SchluterD, KittlesRA, et al. (2007) cis-Regulatory changes in Kit ligand expression and parallel evolution of pigmentation in sticklebacks and humans. Cell 131: 1179–1189.

16. Baleno IC (2001) Povoamento e Formação da Sociedade. In: Albuquerque L, Santos, M.E., editor. História Geral de Cabo Verde. Lisbon, Praia: Instituto de Investigação Científica Tropical, Instituto Nacional de Investigação, Promoção e Património Culturais de Cabo Verde. pp. 125–177.

17. GoncalvesR, RosaA, FreitasA, FernandesA, KivisildT, et al. (2003) Y-chromosome lineages in Cabo Verde Islands witness the diverse geographic origin of its first male settlers. Hum Genet 113: 467–472.

18. SweetE, McDadeTW, KiefeCI, LiuK (2007) Relationships between skin color, income, and blood pressure among African Americans in the CARDIA Study. Am J Public Health 97: 2253–2259.

19. ConsortiumIH (2003) The International HapMap Project. Nature 426: 789–796.

20. TangH, PengJ, WangP, RischNJ (2005) Estimation of individual admixture: analytical and study design considerations. Genet Epidemiol 28: 289–301.

21. TangH, JorgensonE, GaddeM, KardiaSL, RaoDC, et al. (2006) Racial admixture and its impact on BMI and blood pressure in African and Mexican Americans. Hum Genet 119: 624–633.

22. KangHM, SulJH, ServiceSK, ZaitlenNA, KongSY, et al. (2010) Variance component model to account for sample structure in genome-wide association studies. Nat Genet 42: 348–354.

23. CandilleSI, AbsherDM, BauchetM, McEvoyB, BelezaS, et al. (2012) Genome-wide association studies of quantitatively measured skin, eye, and hair pigmentation in four European populations. PLoS ONE 7: e48294 doi:10.1371/journal.pone.0048294.

24. JohnsonNA, CoramMA, ShriverMD, RomieuI, BarshGS, et al. (2011) Ancestral components of admixed genomes in a Mexican cohort. PLoS Genet 7: e1002410 doi:10.1371/journal.pgen.1002410.

25. CostinGE, ValenciaJC, VieiraWD, LamoreuxML, HearingVJ (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: 3203–3212.

26. GingerRS, AskewSE, OgborneRM, WilsonS, FerdinandoD, 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: 5486–5495.

27. GrafJ, HodgsonR, van DaalA (2005) Single nucleotide polymorphisms in the MATP gene are associated with normal human pigmentation variation. Hum Mutat 25: 278–284.

28. NewtonJM, Cohen-BarakO, HagiwaraN, GardnerJM, DavissonMT, 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: 981–988.

29. FukamachiS, ShimadaA, ShimaA (2001) Mutations in the gene encoding B, a novel transporter protein, reduce melanin content in medaka. Nat Genet 28: 381–385.

30. SpritzRA, StrunkKM, GiebelLB, KingRA (1990) Detection of mutations in the tyrosinase gene in a patient with type IA oculocutaneous albinism. N Engl J Med 322: 1724–1728.

31. BrilliantMH (2001) The mouse p (pink-eyed dilution) and human P genes, oculocutaneous albinism type 2 (OCA2), and melanosomal pH. Pigment Cell Res 14: 86–93.

32. JacksonIJ (1994) Molecular and developmental genetics of mouse coat color. Annu Rev Genet 28: 189–217.

33. VisserM, KayserM, PalstraRJ (2012) HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter. Genome Res Epub ahead of print

34. McEvoyB, BelezaS, ShriverMD (2006) The genetic architecture of normal variation in human pigmentation: an evolutionary perspective and model. Hum Mol Genet 15 (Spec No 2) R176–81.

35. LaoO, de GruijterJM, van DuijnK, NavarroA, KayserM (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.

36. MylesS, SomelM, TangK, KelsoJ, StonekingM (2007) Identifying genes underlying skin pigmentation differences among human populations. Hum Genet 120: 613–621.

37. DonnellyMP, PaschouP, GrigorenkoE, GurwitzD, BartaC, et al. (2012) A global view of the OCA2-HERC2 region and pigmentation. Hum Genet 131: 683–696.

38. GrossmanSR, ShylakhterI, KarlssonEK, ByrneEH, MoralesS, et al. (2010) A composite of multiple signals distinguishes causal variants in regions of positive selection. Science 327: 883–886.

39. LiJZ, AbsherDM, TangH, SouthwickAM, CastoAM, et al. (2008) Worldwide human relationships inferred from genome-wide patterns of variation. Science 319: 1100–1104.

40. ByardPJ (1981) Quantitative genetics of human skin color. Am J Phys Anthropol 24: 123–137.

41. DuffyDL, MontgomeryGW, ChenW, ZhaoZZ, LeL, 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: 241–252.

42. SuAI, WiltshireT, BatalovS, LappH, ChingKA, et al. (2004) A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A 101: 6062–6067.

43. BiedererT, SudhofTC (2000) Mints as adaptors. Direct binding to neurexins and recruitment of munc18. J Biol Chem 275: 39803–39806.

44. NeedAC, GeD, WealeME, MaiaJ, FengS, et al. (2009) A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genet 5: e1000373 doi:10.1371/journal.pgen.1000373.

45. MakoffAJ, FlomenRH (2007) Detailed analysis of 15q11–q14 sequence corrects errors and gaps in the public access sequence to fully reveal large segmental duplications at breakpoints for Prader-Willi, Angelman, and inv dup(15) syndromes. Genome Biol 8: R114.

46. SpritzRA, BailinT, NichollsRD, LeeST, ParkSK, et al. (1997) Hypopigmentation in the Prader-Willi syndrome correlates with P gene deletion but not with haplotype of the hemizygous P allele. Am J Med Genet 71: 57–62.

47. PurcellS, NealeB, Todd-BrownK, ThomasL, FerreiraMA, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575.

48. Huber PJ (1981) Robust statistics. New York: John Wiley.

49. PriceAL, TandonA, PattersonN, BarnesKC, RafaelsN, et al. (2009) Sensitive detection of chromosomal segments of distinct ancestry in admixed populations. PLoS Genet 5: e1000519 doi:10.1371/journal.pgen.1000519.

50. PriceAL, PattersonNJ, PlengeRM, WeinblattME, ShadickNA, et al. (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38: 904–909.

51. TangH, SiegmundDO, JohnsonNA, RomieuI, LondonSJ (2010) Joint testing of genotype and ancestry association in admixed families. Genet Epidemiol 34: 783–791.

52. LiY, WillerCJ, DingJ, ScheetP, AbecasisGR (2010) MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34: 816–834.

53. BrowningBL, BrowningSR (2009) A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am J Hum Genet 84: 210–223.

54. YangJ, LeeSH, GoddardME, VisscherPM (2011) GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 88: 76–82.

55. BrowningSR, BrowningBL (2011) Population structure can inflate SNP-based heritability estimates. Am J Hum Genet 89: 191–3; author reply 193–5.