1998), but mouse studies have suggested that 14 genes preferentially affect pigmentation in vertebrates (reviewed in Sturm et al. Although this could indicate that the SNPs are in LD with other phenotypically active loci, it may also be a reflection that variability in message transcription and/or turnover may explain part of the variability observed in human iris colors. You are using a browser version with limited support for CSS. For each gene, we inferred haplotypes and used contingency analyses to determine which haplotypes were statistically associated with iris colors. Alternatively, the mechanism for the associations could be LD with phenotypically active loci in nearby pigment genes. Human pigmentation genes break out into several biochemical pathways, including those for tyrosinase enzyme complex formation on the inner surface of the melanosome, hormonal and environmental regulation, melanoblast migration and differentiation, the intracellular routing of new proteins into the melanosome, and the proper transportation of the melanosomes from the body of the cell into the dendritic arms toward the keratinocytes. Genetic determinants of hair, eye and skin pigmentation in Europeans. What is the likely genotype of individual C-4? Even if the OCA2 gene contains the alleles for brown eyes, the SNP in intron 86 of HERC2 will prevent its expression. It was unclear from the outset whether we would have better success considering iris color in terms of four colors (blue, green, hazel, and brown) or in terms of groups of colors. In studies with HERC2 functions, deletions caused hypopigmentation even though the protein has nothing to do with pigmentation. PubMed A dominant allele of this gene (P) causes pigment to be deposited in the front of the iris, thus masking the blue to various degrees. Multiple SNPs were identified on chromosome 10q; the CYP2C8-10p23 region had 1 marginally associated SNP, and the neighboring region, CYP2C9-10p24, also had one. In other words, the distribution of SNPs among the various genes tested was not random. Last, we also showed that the associations between TYR haplotypes and iris colors were relatively weak, which is not inconsistent with results obtained by many others before us working in the field of oculocutaneous albinism who have failed to find strong associations in smaller samples. The strongest associations were observed for genes with SNPs that were marginally associated (Table 2) and most of the genes with marginal SNP associations had haplotypes and diplotypes (sometimes referred to as multilocus gene-wise genotypes or diploid pairs of haplotypes) positively (agonist) or negatively (antagonist) associated with at least one iris color (Table 3). The density of granules appears to reach genetically determined levels by early childhood and usually remains constant throughout later life, although a small minority of individuals exhibit changes in color during later stages of life (Bito et al. An individual with this disorder produces little or no pigment in their ocular melanocytes. Kayser, M., Liu, F., Janssens, A. C., Rivadeneira, F., Lao, O., van Duijn, K. et al. Other very minor genes are responsible for eye color production, such as agouti signaling protein, but they usually have miniscule effects.5, Finally, two major genes are responsible for eye color: HERC2 and OCA2. 1998; Flanagan et al. Although corrections for multiple testing left most of the SNP-level associations intact, a number of the associations we found did not pass the multiple-testing examination, but nonetheless we present them here to avoid possible type II error; the sequences may be weakly associated with iris colors and possibly relevant within a multiple-gene model for classification (i.e., epistasis). Although TYR does not code for color, a nonfunctioning TYR masks any other gene responsible for pigmentation. In other words, their SNPs were associated with iris colors only within the context of gene haplotypes or diplotypes. For some, associations with iris colors were found only within the context of diplotypes, but not at the level of the SNPs or the haplotype (i.e., SILV and GSTT2 genes located at 22q11.23). This is an example of a hihybrid crosses. record your observations. 1997; Smith et al. In the pheomelanin pathway, the presence of cysteine has a major role. Statistical methods: To test the departures from independence in allelic state within and between loci, we used the exact test, described in Zaykin et al. Specimens: Specimens for resequencing were obtained from the Coriell Institute in Camden, New Jersey. Eye color genes. trends Genet. However, it is yet to be completely understood. Fig. This provides an explanation why some babies develop their eye color, but skin pigmentation changes constantly throughout life. The mammalian iris has three main tissue layers, all pigmented with melanin: an anterior fibrovascular stroma; a middle smooth-muscle layer consisting of the circumferential sphincter muscle at . 1, 105110 (2007). Place the PTC paper on your tongue for a few seconds. 2) although some associations were found within nonpigmentation genes such as CYP2C8 at 10q23, CYP2C9 at 10q24, CYP1B1 at 2p21, and MAOA at Xp11.3. The most strongly associated of the marginally associated SNPs were from the OCA2, TYRP1, and AIM genes, in order of the strength of association, which is the same order as that provided using the number of marginally associated SNPs, rather than their strength. The pigment responsible for eye color is called melanin, which also affects skin color. OCA2 associations were by far the most significant of any gene or region we tested, while MYO5A SNPs were only weakly associated (but haplotypes and diplotypes more strongly). Eye color phenotypes demonstrate both epistasis and incomplete dominance. For this population a. Although the crystal structure has not been published for the P protein coded by OCA2, residue 419 is predicted to face the cytoplasmic portion of the lipid bilayer in one of the several transmembrane domains.14 Therefore, the SNP change that results in R419Q most likely affects the P protein in conformation. We also thank Robert White for his help with sample collection. Interactive effects of MC1R and OCA2 on melanoma risk phenotypes. Most traits are determined by more than one gene. (1986) and Shriver et al. Apart from representing the first comprehensive candidate gene study for variable iris pigmentation and constituting a first step toward developing a classification model for the inference of iris color from DNA, our results suggest that cryptic population structure might serve as a leverage tool for complex trait gene mapping if genomes are screened with the appropriate ancestry informative markers. As one might expect from the proximity of these two regions, CYP2C8-CYP2C9 marker pairs were found to be in tight LD with one another (P < 0.001 for each possible pair). One leads to eumelanin, a darker pigment (brown-black), and the other to pheomelanin, a light pigment (red-yellow). Most of the SNPs within a gene or region were in LD with others in that gene or region (|D| 0.05); only 32 SNP pairsin the MC1R (1 pair), OCA2 (27 pairs), TYR (2 pairs), and TYRP1 (2 pairs) geneswere found to be in linkage equilibrium (not shown). 1997). 1997), and other genes (reviewed by Sturm et al. Article A battery of genetic tests, of which one for the inference of iris color could be a part, could enable the construction of a more objective and science-based (partial) physical profile from crime-scene DNA, and an investigator using these tests would be less interested in the biological mechanism of the phenotype than in an ability to make an accurate inference of trait value. The Louisville twin study, Mutation in and lack of expression of tyrosinase-related protein-1 (TRP-1) in melanocytes from an individual with brown oculocutaneous albinism: a new subtype of albinism classified as OCA3., Characterization of melanocyte stimulating hormone variant alleles in twins with red hair, Melanocortin-1 receptor genotype is a risk factor for basal and squamous cell carcinoma, Estimation of the heritability of hair and iris color, Mapping the human CAS2 gene, the homologue of the mouse brown (b) locus, to human chromosome 9p22-pter, Excision of the DBA ecotropic provirus in dilute coat-color revertants of mice occurs by homologous recombination involving the viral LTRs, African origin of an intragenic deletion of the human P gene in tyrosinase positive oculocutaneous albinism, Estimation of carrier frequency of a 2.7 kb deletion allele of the P gene associated with OCA2 in African-Americans, Assignment of genes coding for brown iris colour (BEY2) and brown hair colour (HCL3) on chromosome 15q, Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation, A classifier for the SNP-based inference of ancestry, The mouse pink-eyed dilution gene: association with human Prader-Willi and Angelman syndromes, Molecular study of the Prader-Willi syndrome: deletion, RFLP, and phenotype analyses of 50 patients, Individual admixture estimates: disease associations and individual risk of diabetes and gallbladder disease among Mexican-Americans in Starr County, Texas, The color of the human iris: a review of morphologic correlates and of some conditions that affect iridial pigmentation, A cDNA encoding tyrosinase-related protein maps to the brown locus in mouse, A second tyrosinase-related protein, TRP-2, maps to and is mutated at the mouse slaty locus, A polymorphism in the Agouti signaling protein gene is associated with human pigmentation, An unusual pigment pattern in type I oculocutaneous albinism (OCA) resulting from a temperature-sensitive enzyme. A golden-brown iris indicates the mixture of both eumelanin and pheomelanin (produces the yellow color), and hazel is usually a mixture of brown and green or blue and green, depending on the shade. These genes are of the greatest importance for eye color.9, 10, 11, Numerous ubiquitin ligases are coded for throughout the body. We focused on human pigmentation and xenobiotic metabolism genes, selected on the basis of their gene identities, not their chromosomal position. .. Copeland N G, Hutchison K W, Jenkins N A. Durham-Pierre D, Gardner J M, Nakatsu Y, King R A, Francke U et al. For example, forensics investigators construct physical profiles using surprisingly unscientific means; only in rare cases are eye-witness accounts available, and in certain circumstances these accounts are subjective and unreliable. Forensic Sci Int: Genet. 5.01 In an experiment designed to study the inheritance of flower color in four-o'clocks, two plants with pink flowers were crossed. IRIS pigmentation is a complex genetic trait that has long interested geneticists, anthropologists, and the public at large. Study of a number of other TYR-positive OCA phenotypes has shown that, in addition to TYR, the oculocutaneous 2 (OCA2; Hamabe et al. When a T is replaced with a C in rs12913832 of intron 86, OCA2 transcription is depressed, resulting in a blue-eyed individual. 1997; Box et al. We sincerely thank the referees for their valuable suggestions for improvements on the earlier version of this article. Attached earlobes. Complete the table. ISSN 1435-232X (online) We identified numerous SNPs, haplotypes, and diplotypes (diploid pairs of haplotypes) within the OCA2, MYO5A, TYRP1, AIM, DCT, and TYR genes and the CYP1A2-15q22-ter, CYP1B1-2p21, CYP2C8-10q23, CYP2C9-10q24, and MAOA-Xp11.4 regions as significantly associated with iris colors. b) Give the genotype of an individual who is homozygous recessive for brown eye color. A pigment in the front part of the eye masks a blue layer at the back of the iris. Montserrat Rabago-Smith. ISSN 1434-5161 (print), Genotypephenotype associations and human eye color, Further insight into the global variability of the OCA2-HERC2 locus for human pigmentation from multiallelic markers, The distinctive geographic patterns of common pigmentation variants at the OCA2 gene, Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability, What colour are your eyes? Dopachrome tautomerase (13q32) and TYR-related protein 1 (9p23) will continue the pathway to form eumelanin.15 Therefore, if any of these proteins are not coded for correctly, the eumelanin production may be hindered, producing lighter eyes. Heterochromia, although not viewed as a severe disorder, affects many individuals. The disorder is characterized by different-colored irises or different colors within the iris. Hum Genet 123, 177187 (2008). Although there are about 16 different genes responsible for eye color, it is mostly attributed to two adjacent genes on chromosome 15, hect domain and RCC1-like domain-containing protein 2 (HERC2) and ocular albinism (that is, oculocutaneous albinism II (OCA2)). Genotype-phenotype correlations have been reported with specific mutations possibly associated with certain angle abnormalities. Decreased expression of OCA2 affects the pathway for melanosome maturation. During the first studies to classify genes for eye color, OCA2 was believed to be the dominating factor for eye color determination.3, 6, 7, 8 Within the last couple of years, HERC2, an ubiquitin ligase-coding region, has been linked more strongly to eye color. Aside from these two genes, the genes involved in melanogenesis and other minor genes also contain regions that account for eye color. HERC2/OCA2 rs12913832 and IRF4 rs12203592 influenced both eye colour and the number of iris pigmented lesions. We developed a program (T. Frudakis, M. Thomas, Z. Gaskin, K. Venkateswarlu, K. Suresh Chandra, S. Ginjupalli, S. Gunturi, S. Natrajan, V. K. Ponnuswamy and K. N. Ponnuswamy, unpublished results) to design resequencing primers in a manner respectful of homologous sequences in the genome, to ensure that we did not coamplify pseudogenes or amplify from within repeats. On the basis of population studies, scientists speculate that the blue-eyed mutation originated in peoples of Northern Europe (Scandinavian countries).