Allele Variations in OCA2 gene (pink-eyed-dilution locus) are associated with genetic susceptibility to melanoma. 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)). This same phenomenon is the reason why the pupil appears black. We sincerely thank the referees for their valuable suggestions for improvements on the earlier version of this article. 1999; Flanagan et al. PHRED-qualified sequences were imported into the CLUSTAL X alignment program and the output of this was used with a second program that we developed (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K. Venkateswarlu, K. Suresh Chandra, S. Ginjupalli, S. Gunturi, S. Natrajan, V. K. Ponnuswamy and K. N. Ponnuswamy, unpublished results) to identify quality-validated discrepancies between sequences. E > e. ee. P_ Pigmented Iris (Additional genes give specific color, e.g. Third, when applied to a sample including individuals of multiple ancestries, the linear and nonlinear variables from these and the other genes combined performed even better than when applied just to individuals of majority European ancestry (not shown). 5.01 In an experiment designed to study the inheritance of flower color in four-o'clocks, two plants with pink flowers were crossed. Although TYR does not code for color, a nonfunctioning TYR masks any other gene responsible for pigmentation. Angelman syndrome: three molecular classes identified with chromosome 15q11q13-specific DNA markers. In studies with HERC2 functions, deletions caused hypopigmentation even though the protein has nothing to do with pigmentation. If no haplotypes were found to be associated for a locus but diplotypes were found to be associated, both the haplotypes and the diplotypes are shown. Aside from the fact that many of the SNPs we identified were significant after imposing the Steenland correction for multiple testing, there are three lines of evidence that the SNPs we have identified are not spuriously associated. 2003; data not shown). Interactive effects of MC1R and OCA2 on melanoma risk phenotypes. For these subjects, we obtained digital photographs of the right iris, where subjects peered into a box at one end at the camera at the other end to standardize lighting conditions and distance and from which a judge assigned the sample to a color group. Finally, in addition to the OCA2 (15q11.2q12) and MYO5A (15q21) sequences, a single SNP (15q22ter) was also implicated on chromosome 15q, but SNPs between each of these three loci were not found to be in LD (data not shown). The sequences we have identified constitute a good first step toward developing a classifier model for the inference of iris colors from DNA, and the nature of some of these as markers of population structure might have implications for the design of other complex trait gene-mapping studies. Box N F, Duffy D L, Irving R E, Russell A, Chen W et al. In other words, the distribution of SNPs among the various genes tested was not random. 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. 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. PubMedGoogle Scholar. 2000). In the absence of melanin brown pigment, the iris is blue. Most of the SNPs that we identified were on chromosome 15, which Eiberg and Mohr (1996) described from linkage analyses as the primary chromosome for the determination of brownness. As suggested by these authors, the candidate gene within the interval containing this locus (BEY2) is most likely the OCA2 gene, although the MYO5A gene is also present within this interval and, as shown here, associated with iris colors. An individual that is homozygous W is much more likely to have blue iris, exhibiting odds 77.25-times larger than the odds of having blue irises of a genotype other than W/W (P < 0.0001). Hum Genet 123, 177187 (2008). Eye color results from varying degrees of melanin produced in the melanocytes of the iris. All of the major sequences (count 13) for each locus with at least one significantly associated sequence are shown. This condition is pronounced in people who produce little to no pigment throughout their entire body, but it can be localized to the eyes.2 When they produce no pigment at all, it is usually due to a nonfunctioning TYR.10 With this condition, a complete lack of pigment produces red eyes, and a small amount of pigment may produce violet eyes. Phakomatoses. Chromosome 15q harbored the majority (14/27) of the SNPs that were marginally associated with iris colors, and all but one of these 14 were found in two different genes: OCA2 and MYO5A (Table 2). .. Shriver M, Parra E, Dios S, Bonilla C, Norton H et al. Abbott C, Jackson I J, Carritt B, Povey S. Akey J M, Wang H, Xiong M, Wu H, Liu W et al. The exact nature and density Although eye color is usually modeled as a simple, Mendelian trait, further research and observation has indicated that eye color does not follow the classical paths of inheritance. White, D., Rabago-Smith, M. Genotypephenotype associations and human eye color. However, the penetrance of each of these alleles appears to be low and, in general, they appear to explain but a very small amount of the overall variation in iris colors within the human population (Spritz 1995). id List the possible genotypes of a blue eyed, dimple chinned individual. Article We considered all 61 SNPs in Table 2, their haplotypes in Table 3, and their diplotypes (not shown). (2002), although it should be noted that we did not observe this gene association at the level of the SNP as they did; one of the ASIP SNPs that we identified (marker 861, Table 2) is the 8818 G-A SNP transversion that they described to be associated with brown iris colors, but from our study the association was with hazel color at the level of the haplotype. 1998), but mouse studies have suggested that 14 genes preferentially affect pigmentation in vertebrates (reviewed in Sturm et al. The range in eye color, from blue to hazel to brown (see figure one), depends on the level of melanin pigment stored in the melanosome "packets" in the melanocytes of the iris. Eye color is determined by the pattern of brown and red pigment, collagen fibers, and the topography of the iris. (Abstr. 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. Amplification products were subcloned into the pTOPO (Invitrogen, San Diego) sequencing vector and 96 insert-positive colonies were grown for plasmid DNA isolation (the use of 670 individuals for the amplification step reduced the likelihood of an individual contributing more than once to this subset of 96 selected). SNP discovery: We obtained candidate SNPs from the National Center for Biotechnology Information (NCBI) Single Nucleotide Polymorphism Database (dbSNP), which generally provided more candidate SNPs than were possible to genotype. ), Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur, Identification of common polymorphisms in the coding sequence of the human MSH receptor (MCIR) with possible biological effects, Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans, Pigmentation genes: the tyrosinase gene family and the pmel 17 gene family, Molecular basis of mouse Himalayan mutation, A melanocyte-specific gene, Pmel 17, maps near the silver coat color locus on mouse chromosome 10 and is in a syntenic region on human chromosome 12, Molecular structure and chromosomal mapping of the human homolog of the agouti gene, Diverse mutations of the P gene among African-Americans with type II (tyrosinase-positive) oculocutaneous albinism (OCA2), Induction of tyrosinase gene transcription in human iris organ cultures exposed to latanoprost, Not just pretty eyes: Drosophila eye-colour mutations and lysosomal delivery, Genetic and molecular analysis of recessive alleles at the pink-eyed dilution (p) locus of the mouse, Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4, Mutations within the promoter region of the tyrosinase gene in type I (tyrosinase-related) oculocutaneous albinism. We identified 5 additional genes (ASIP, MC1R, POMC, and SILV) and one additional region (GSTT2-22q11.23) with haplotype and/or diplotypes, but not individual SNP alleles associated with iris colors. For most of the genes, multilocus gene-wise genotype sequences were more strongly associated with iris colors than were haplotypes or SNP alleles. In addition, for 103 of the subjects, iris colors were reported using a number from 1 to 11 as well, where 1 is the darkest brown/black and 11 is the lightest blue, identified using a color placard. 2001). Blue is confined mostly to people who originated from Europe.11 Green eyes permeate the lowest amount of the population (excluding the disorders), probably due to the lack of coding for it within the genome. SNPs for the MC1R (16q24), SILV (12q13), and TYR (11q) genes and for the MAOA-Xp11.411.3 and GSTT2-22q11.23 regions were also found to be associated at the level of the haplotype (Tables 3 and 4), although these were the only regions of these chromosomes for which associations were found. To obtain The SNPs between the 2p21 and 2p23 regions were also in LD (P < 0.01). Blue Iris (non-pigmented) MG-3: Jeremy has attached earlobes and pigmented irises. Relationship. Lastly, disorders involved in eye color include ocular albinism and heterochromia. .. Krude H, Biebermann H, Luck W, Horn R, Brabant G et al. Cassidy, S. B. E_ Free earlobes. Despite the color of the eye, the number of melanocytes does not differ. To determine the extent to which extant iris color variation could be explained by various models, we calculated R2 values for SNPs, haplotypes, and multilocus genotype data by first assigning the phenotypic value for blue eye color as 1, green eye color as 2, hazel eye color as 3, and brown eye color as 4. The recessive allele (b) encodes blue eyes. Having little effect on eye color, many of them deal primarily with hair and skin pigmentation. Tully, G. Genotype versus phenotype: human pigmentation. The MC1R gene harbored haplotypes associated only with green color in our sample and the POMC gene harbored a single SNP with genotypes weakly associated with iris colors (no significant haplotypes or diplotypes were found). In humans, eye color is determined by the amount of light that reflects off the iris, a muscular structure that controls how much light enters the eye. Most of the marginally associated SNPs were found within the pigmentation genes OCA2 (n = 10), TYRP1 (n = 4), AIM (n = 3), MYO5A (n = 2), and DCT (n =, SNPs marginally (independently) associated with iris pigmentation and SNPs associated only within the context of haplotypes and/or diplotypes. Specimens for genotyping were of self-reported European descent, of different age, sex, hair, iris, and skin shades and they were collected using informed consent guidelines under Investigational Review Board guidance. Valenzuela, R., Henderson, M., Walsh, M., Garrison, N., Kelch, J., Cohen-Barak, O. et al. Interestingly, the number of genes in human DNA is not appreciably different from the number of genes in chimpanzees or mice. We also identified associations in the ASIP gene, which supports previous work by Kanetsky et al. Since most individuals of non-European or minority European descent exhibit low variability in iris colors (on average of darker shade than individuals of European descent), this improvement may not seem surprising. Pigment Cell Res 14, 8693 (2001). BLAST searches confirmed the specificity of all primers used. Nat Genet. .. Copeland N G, Hutchison K W, Jenkins N A. Durham-Pierre D, Gardner J M, Nakatsu Y, King R A, Francke U et al. As different genes may be transcribed in various cells, certain cells will produce more pigment or a different type of pigment than other adjacent cells. as a function of BGA (Frudakis et al. The red appearance is the reflection of the eye's blood vessels. (gray/blue). Frudakis, T., Thomas, M., Gaskin, Z., Venkateswarlu, K., Chandra, K. S., Ginjupalli, S. et al. Already, some researchers have started studying hues and saturations. Number of times the haplotype was observed in our sample of 851. groups of the world that are of darker average iris color (Frudakis et al. Genotype-phenotype correlations have been reported with specific mutations possibly associated with certain angle abnormalities. 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). The disorder is characterized by different-colored irises or different colors within the iris. Eumelanin (brown pigment) is a light-absorbing polymer synthesized in specialized melanocyte lysosomes called melanosomes. Although cysteine is not an essential amino acid and its deficiency rarely occurs, the lack of it halts the production of pheomelanin. Human Iris Color. Some phenotypes however, are determined by a single gene. .. Ooi C E, Moreira J E, DellAngelica E C, Poy G, Wassarman D A et al. (1997), suggesting that these sequences are indeed associated with iris pigmentation as suggested by these authors, although we note that the associations described by these authors were with blue irises and at the level of the SNP, while those that we observed were with green irises and apparent only at the level of the haplotypes and diplotypes. Google Scholar. Science 257, 1121 (1992). However, this result would not have necessarily been obtained were we working with SNPs that were not truly associated with iris colors. 1991; Boissy et al. Genetics 165, 20712083 (2003). Individuals for whom iris color was ambiguous or had changed over the course of life were eliminated from the analysis. 3. . OCA2 contains regions for the numerous eye colors, but one SNP is a strong predictor for brown/blue eyes. Sequences associated with human iris pigmentation. 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. Question: In albinism (a recessive disorder), the formation of melanin, a dark skin pigment, are blocked so that albinos have extremely light skin and hair. Complete the table. Eumelanin (brown pigment) is a light-absorbing polymer synthesized in specialized melanocyte lysosomes called melanosomes. 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. Phenotypic Effect. Each chromosome contains thousands of individual genes. His wife Jenny has free earlobes and . We did not confine this higher-order analysis to those genes with marginal SNP associations, but we grouped all of the high-frequency SNPs tested for each gene. & WojasPelc, A. Interactions between HERC2, OCA2, and MC1R may influence human pigmentation phenotype. The pedigree in the accompanying illustration shows the inheritance of albinism, a homozygous recessive condition resulting in a total lack of pigment. 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). Rinchik, E. M., Bultman, S. J., Horsthemke, B., Lee, S., Strunk, K. M., Spritz, R. A. et al. Supplement Series 1, 544546 (2008). We sequenced with an ABI3700 using PE Applied Biosystems BDT chemistry and we deposited the sequences into a commercial relational database system (iFINCH, Geospiza, Seattle). A few disorders are associated with eye color. PubMed Central Tyrosinase (TYR), the enzyme responsible for pigment production in the body, starts the synthesis of both types of melanin by catalyzing a reaction between tyrosine and dopa, forming dopaquinone. .. Hanis C, Chakraborty R, Ferrell R, Schull W. Jackson I J, Chambers D M, Tsukamoto K, Copeland N G, Gilbert D J et al. 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? This gene is often referred to as the red-headed gene because of its prevalent expression in people with red hair and green eyes.4 Dopachrome tautomerase also contains regions for hazel and green eyes.5 Regions for brown eyes dominate the effects of these genes, though. An ASIP polymorphism is reported to be associated with both brown iris and hair color (Kanetsky et al. These observations suggest that the genetic determinants for pigmentation in the various tissues are distinct and that these determinants have been subject to a common set of systematic and evolutionary forces that have shaped their distribution in world populations. Without cysteine, the synthesis cannot be carried out. 2000), and adaptin 3B (AP3B) loci (Ooi et al. Flower-color pigments are synthesized by gene action in two separate pigment-producing biochemical pathways. (2001) haplotype reconstruction method. This test showed that each of our 851 Caucasian samples was of majority Indo-European BGA, and although 58% of the samples were of significant (>4%) non-Indo-European BGA admixture, there was no correlation among low levels (<33%) of East Asian, sub-Saharan African, or Native American admixture and iris colors. Sturm, R. & Frudakis, T. Eye Colour: portals into pigmentation genes and ancestry. . The minor allele frequency for most of these SNPs was relatively high (average F minor allele = 0.22) and most of them were in Hardy-Weinberg equilibrium (HWE; those for which HWE P > 0.05, 28/34; Table 3). Haplotype order refers to the order of the SNPs in the haplotypes shown in Table 4 and described in the text. Nonetheless, the complexity of OCA phenotypes illustrates that TYR is not the only gene involved in iris pigmentation (Lee et al. Although introns are usually viewed as superfluous DNA, intron 86 of HERC2 regulates the expression of OCA2. Two major genes on chromosome 15 affect the quantity and quality of the melanin produced by melanogenesis. Although TYR is centrally important for this process, pigmentation in animals is not simply a Mendelian function of TYR or of any other single protein product or gene sequence. PubMed Central (2000) with adjusted residuals to compensate for this risk. In this pedigree use "A" to represent the dominant allele and "a" for the recessive allele.A When there is too little pigment to produce a strong blue color, the red reflections interact with the small amount of blue, producing a violet color.3, The biological process for producing melanin, melanogenesis, involves numerous protein interactions. Producing multicolored irises, heterochromia stems from mutations in certain cells of the iris. 2002). (Abstr. Philippe Suarez, Karine Baumer & Diana Hall, Kenneth K. Kidd, Andrew J. Pakstis, William C. Speed, Pirro G. Hysi, Ana M. Valdes, Timothy D. Spector, Kaustubh Adhikari, Javier Mendoza-Revilla, Andrs Ruiz-Linares, Hlne Choquet, Ronald B. Melles, Eric Jorgenson, Frida Lona-Durazo, Marla Mendes, Esteban J. Parra, Mathilde Josserand, Emma Meeussen, Dan Dediu, Journal of Human Genetics 2003; T. Frudakis, Z. Gaskin, M. Thomas, V. Ponnuswamy, K. Venkateswarlu, S. Gunjupulli, C. Bonilla, E. Parra and M. Shriver, unpublished observations). Rather, it seems likely that the structure behind our results is of a finer, more cryptic nature, such as ethnicity or even within-ethnic-group structure. Google Scholar. Incomplete dominance shows in individuals with lighter shades of brown and hazel. (82%) were in pigmentation genes. In the presence of cysteine, the reaction will proceed to form pheomelanin. 1998; Schioth et al. iris contact lenses, or a cosmetic iris implant inserted at the time of cataract surgery .