Genetics of Eye Colour

Abstract

Human eye colour is a polygenic trait with a heritability of close to 100%, with seven leading factors explaining three‐quarters of the genetic variance: OCA2, TYR, TYRP1, IRF4, SLC45A2, SLC24A5 and SLC24A4. Many of these genes were already known to be mutated in oculocutaneous albinism, and all are involved in melanin biosynthesis, coding for key enzymes, transcription factors controlling expression of key enzymes or transporters that maintain the acidity of the melanosome interior. At least two of the variants of largest effect abrogate regulatory elements in the associated gene, causing changes in expression level. The differences in eye colour between different populations suggest strong selection, either on correlated traits such as skin colour or perhaps directly.

Key Concepts

  • Variation in eye colour is polygenic, with seven major genes explaining 75% of European population variance.
  • Blue eye colour is strongly predicted by a single nucleotide polymorphism near the OCA2 gene – this is the classical recessive gene inferred from family data. Intermediate eye colours such as hazels and greens are less well predicted.
  • Two of the major loci are in non‐coding regulatory regions, a pattern common to trait loci for other complex traits.
  • The large effect sizes make this an excellent model for the investigation of the architecture of gene action, especially gene‐by‐gene interactions (epistasis), as well as multi‐trait action (pleiotropy).
  • Iris pigmentation loci generally exhibit genomic evidence of strong Darwinian selection, and this may not be completely explained by pleiotropic effects on skin colour.

Keywords: iris colour; Darwinian selection; tyrosinase; oculocutaneous albinism; melanin; TYRP1 ; TYRP2 ; OCA2 ; IRF4 ; SLC45A2

Figure 1. Eye colour rating scale of (Martin ; Schultz ), modified from that of Martin. This was realised as a standardised series of glass eyes set in a handy foldout case.
Figure 2. Proportion of brown‐eyed individuals in samples from different European populations.
Figure 3. Eumelanin biosynthetic pathways.
Figure 4. Cartoon of iris structure.
close

References

Aoki K (2002) Sexual selection as a cause of human skin colour variation: Darwin's hypothesis revisited. Annals of Human Biology 29: 589–608.

Beckman L (1962) Assortative mating in man. Eugenics Review 54: 63–67.

Beleza S , Santos AM , McEvoy B , et al. (2013a) The timing of pigmentation lightening in Europeans. Molecular Biology and Evolution 30: 24–35.

Beleza S , Johnson NA , Candille SI , et al. (2013b) Genetic architecture of skin and eye color in an African‐European admixed population. PLoS Genetics 9: e1003372.

Bellono NW and Oancea EV (2014) Ion transport in pigmentation. Archives of Biochemistry and Biophysics 563: 35–41.

Bliss JM , Ford D , Swerdlow AJ , et al. (1995) Risk of cutaneous melanoma associated with pigmentation characteristics and freckling: systematic overview of 10 case–control studies. The International Melanoma Analysis Group (IMAGE). International Journal of Cancer 62: 367–376.

Corani A , Huijser A , Gustavsson T , et al. (2014) Superior photoprotective motifs and mechanisms in eumelanins uncovered. Journal of the American Chemical Society 136 (33): 11626–11635.

Darwin C (1871) The Descent of Man, and Selection in Relation to Sex. London: John Murray.

Denat L , Kadekaro AL , Marrot L , Leachman SA and Abdel‐Malek ZA (2014) Melanocytes as instigators and victims of oxidative stress. Journal of Investigative Dermatology 134: 1512–1518.

Diehl DL , Robin AL and Wand M (1991) The influence of iris pigmentation on the miotic effect of thymoxamine. American Journal of Ophthalmology 111: 351–355.

Di Stasio E , Maggi D , Berardesca E , et al. (2011) Blue eyes as a risk factor for type 1 diabetes. Diabetes/Metabolism Research and Reviews 27: 609–613.

Donnelly MP , Paschou P , Grigorenko E , et al. (2012) A global view of the OCA2‐HERC2 region and pigmentation. Human Genetics 131: 683–696.

Duffy DL , Montgomery GW , Chen W , et al. (2007) A three‐single‐nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye‐color variation. American Journal of Human Genetics 80: 241–252.

Duffy DL , Iles MM , Glass D , et al. (2010) IRF4 variants have age‐specific effects on nevus count and predispose to melanoma. American Journal of Human Genetics 87: 6–16.

Eiberg H and Mohr J (1996) Assignment of genes coding for brown eye colour (BEY2) and brown hair colour (HCL3) on chromosome 15q. European Journal of Human Genetics 4: 237–241.

Eiberg H , Troelsen J , Nielsen M , et al. (2008) Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression. Human Genetics 123: 177–187.

Eriksson N , Macpherson JM , Tung JY , et al. (2010) Web‐based, participant‐driven studies yield novel genetic associations for common traits. PLoS Genetics 6: e1000993.

Frost P (2014) The puzzle of European hair, eye, and skin color. Advances in Anthropology 4: 78–88.

Grant MD and Lauderdale DS (2002) Cohort effects in a genetically determined trait: eye colour among US whites. Annals of Human Biology 29: 657–666.

Grønskov K , Ek J and Brondum‐Nielsen K (2007) Oculocutaneous albinism. Orphanet Journal of Rare Diseases 2: 43.

Grønskov K , Dooley CM , Østergaard E , et al. (2013) Mutations in c10orf11, a melanocyte‐differentiation gene, cause autosomal‐recessive albinism. American Journal of Human Genetics 92: 415–421.

de Gruijter JM , Lao O , Vermeulen M , et al. (2011) Contrasting signals of positive selection in genes involved in human skin‐color variation from tests based on SNP scans and resequencing. Investigative Genetics 2: 24.

Hellström AR , Watt B , Fard SS , et al. (2011) Inactivation of Pmel alters melanosome shape but has only a subtle effect on visible pigmentation. PLoS Genetics 7: e1002285.

Hudjashov G , Villems R and Kivisild T (2013) Global patterns of diversity and selection in human tyrosinase gene. PLoS ONE 8: e74307.

Jagirdar K , Smit DJ , Ainger SA , et al. (2014) Molecular analysis of common polymorphisms within the human Tyrosinase locus and genetic association with pigmentation traits. Pigment Cell & Melanoma Research 27: 552–564.

Kamaraj B and Purohit R (2014) Mutational analysis of oculocutaneous albinism: a compact review. BioMed Research International 2014: 905472.

Kayser M , Liu F , Janssens ACJW , et al. (2008) Three genome‐wide association studies and a linkage analysis identify HERC2 as a human iris color gene. American Journal of Human Genetics 82: 411–423.

Lam MW and Baranoski GV (2006) A predictive light transport model for the human iris. Computer Graphics Forum 25: 359–368.

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.

Li L , Hu D‐N , Zhao H , et al. (2006) Uveal melanocytes do not respond to or express receptors for alpha‐melanocyte‐stimulating hormone. Investigative Ophthalmology & Visual Science 47: 4507–4512.

Liu F , Wollstein A , Hysi PG , et al. (2010) Digital quantification of human eye color highlights genetic association of three new loci. PLoS Genetics 6: e1000934.

Lucotte G and Yuasa I (2013) Near fixation of 374l allele frequencies of the skin pigmentation gene SLC45A2 in Africa. Biochemical Genetics 51: 655–665.

Mackey DA , Wilkinson CH , Kearns LS and Hewitt AW (2011) Classification of iris colour: review and refinement of a classification schema. Clinical & Experimental Ophthalmology 39: 462–471.

Martin R (1914) Lehrbuch der Anthropologia. Jena: Gustav Fischer.

Mitchell P , Smith W and Wang JJ (1998) Iris color, skin sun sensitivity, and age‐related maculopathy. The Blue Mountains Eye Study. Ophthalmology 105: 1359–1363.

Mitchell R , Rochtchina E , Lee A , et al. (2003) Iris color and intraocular pressure: the Blue Mountains Eye Study. American Journal of Ophthalmology 135: 384–386.

Morgan AM , Lo J and Fisher DE (2013) How does pheomelanin synthesis contribute to melanomagenesis? Two distinct mechanisms could explain the carcinogenicity of pheomelanin synthesis. Bioessays 35: 672–676.

Olivares C , Jiménez‐Cervantes C , Lozano JA , Solano F and García‐Borrón JC (2001) The 5,6‐dihydroxyindole‐2‐carboxylic acid (DHICA) oxidase activity of human tyrosinase. Biochemical Journal 354: 131–139.

Peles DN , Hong L , Hu D‐N , et al. (2009) Human iridal stroma melanosomes of varying pheomelanin contents possess a common eumelanic outer surface. Journal of Physical Chemistry B 113: 11346–11351.

Pośpiech E , Draus‐Barini J , Kupiec T , Wojas‐Pelc A and Branicki W (2011) Gene‐gene interactions contribute to eye colour variation in humans. Journal of Human Genetics 56: 447–455.

Praetorius C , Grill C , Stacey SN , et al. (2013) A polymorphism in IRF4 affects human pigmentation through a tyrosinase‐dependent MITF/TFAP2A pathway. Cell 155: 1022–1033.

Rajeevan H , Cheung K‐H , Gadagkar R , et al. (2005) ALFRED: an allele frequency database for microevolutionary studies. Evolutionary Bioinformatics Online 1: 1–10.

Rochin L , Hurbain I , Serneels L , et al. (2013) BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells. Proceedings of the National Academy of Sciences of the United States of America 110: 10658–10663.

Schultz BK (1930) Eine verbesserte Augenfarbental. Anthropologischer Anzeiger 6: 331–335.

Sturm RA (2009) Molecular genetics of human pigmentation diversity. Human Molecular Genetics 18: R9–R17.

Sturm RA , Duffy DL , Zhao ZZ , et al. (2008) A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue‐brown eye color. American Journal of Human Genetics 82: 424–431.

Sturm RA and Larsson M (2009) Genetics of human iris colour and patterns. Pigment Cell & Melanoma Research 22: 544–562.

Sturm RA and Duffy DL (2012) Human pigmentation genes under environmental selection. Genome Biology 13: 248.

Sulem P , Gudbjartsson DF , Stacey SN , et al. (2007) Genetic determinants of hair, eye and skin pigmentation in Europeans. Nature Genetics 39: 1443–1452.

Vercellini P , Buggio L , Somigliana E , et al. (2014) 'Behind blue eyes'†: the association between eye colour and deep infiltrating endometriosis. Human Reproduction 29 (10): 2171–2175.

Visser M , Kayser M , Grosveld F and Palstra R‐J (2014) Genetic variation in regulatory DNA elements: the case of OCA2 transcriptional regulation. Pigment Cell & Melanoma Research 27: 169–177.

Wagner AH , Anand VN , Wang W‐H , et al. (2013) Exon‐level expression profiling of ocular tissues. Experimental Eye Research 111: 105–111.

Walsh S , Liu F , Ballantyne KN , et al. (2011) IrisPlex: a sensitive DNA tool for accurate prediction of blue and brown eye colour in the absence of ancestry information. Forensic Science International: Genetics 5: 170–180.

Walsh S , Wollstein A , Liu F , et al. (2012) DNA‐based eye colour prediction across Europe with the IrisPlex system. Forensic Science International: Genetics 6: 330–340.

Wilde S , Timpson A , Kirsanow K , et al. (2014) Direct evidence for positive selection of skin, hair, and eye pigmentation in Europeans during the last 5,000 y. Proceedings of the National Academy of Sciences of the United States of America 111: 4832–4837.

Further Reading

Bonilla C , Ness AR , Wills AK , et al. (2014) Skin pigmentation, sun exposure and vitamin D levels in children of the Avon Longitudinal Study of Parents and Children. BMC Public Health 14: 597.

Candille SI , Absher DM , Beleza S , et al. (2012) Genome‐wide association studies of quantitatively measured skin, hair, and eye pigmentation in four European populations. PLoS ONE 7 (10): e48294.

Dynoodt P , Mestdagh P , Van Peer G , et al. (2013) Identification of miR‐145 as a key regulator of the pigmentary process. Journal of Investigative Dermatology 133 (1): 201–209.

Eagle RC Jr (1988) Iris pigmentation and pigmented lesions: an ultrastructural study. Transactions of the American Ophthalmological Society 86: 581–687.

Guenther CA , Tasic B , Luo L , Bedell MA and Kingsley DM (2014) A molecular basis for classic blond hair color in Europeans. Nature Genetics 46 (7): 748–752.

Jablonski NG and Chaplin G (2010) Colloquium paper: human skin pigmentation as an adaptation to UV radiation. Proceedings of the National Academy of Sciences of the United States of America 107 (Suppl. 2): 8962–8968.

Liu F , Wen B and Kayser M (2013) Colorful DNA polymorphisms in humans. Seminars in Cell & Developmental Biology 24 (6–7): 562–575.

Noguchi S , Kumazaki M , Yasui Y , et al. (2014) MicroRNA‐203 regulates melanosome transport and tyrosinase expression in melanoma cells by targeting kinesin superfamily protein 5b. Journal of Investigative Dermatology 134 (2): 461–469.

Olalde I , Allentoft ME , Sánchez‐Quinto F , et al. (2014) Derived immune and ancestral pigmentation alleles in a 7,000‐year‐old Mesolithic European. Nature 507 (7491): 225–228.

Zhang M , Song F , Liang L , et al. (2013) Genome‐wide association studies identify several new loci associated with pigmentation traits and skin cancer risk in European Americans. Human Molecular Genetics 22 (14): 2948–2959.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Duffy, David(Mar 2015) Genetics of Eye Colour. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024646]