Gardner, J., Nakatsu, Y., Gondo, Y., Lee, S., Lyon, M., King, R. et al. and JavaScript. 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. Half of the associated SNPs were located on chromosome 15, which corresponds with results that others have previously obtained from linkage analysis. There are thought to be about 20,000 genes in human DNA. The "P" allele produces the pigment which gives you eye color. 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. These analyses resulted in the identification of 61 SNPs in 16 genes/chromosomal regions associated with iris colors on one level or another; details for each and whether the SNP is marginally associated or associated within the context of the haplotype and/or diplotype are shown in Table 2. . b) List the possible genotypes for an individual with pigmented iris but lacking a dimpled chin. Indeed, one of those for which the evidence of lack of HWE was the strongest was validated as a legitimate SNP through direct DNA sequencing (data not shown). Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene. & WojasPelc, A. Interactions between HERC2, OCA2, and MC1R may influence human pigmentation phenotype. (2001) haplotype reconstruction method. 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). The chromosomal distribution of the SNPs that were significantly associated in a marginal sense was found to be independent of the distribution of SNPs actually surveyed, indicating that the associations were not merely a function of SNP sampling and the same was true for the distribution of all the SNPs shown in Table 2 (data not shown). Slider with three articles shown per slide. A simple cross is provided in Figure 1: Blue-eyed Cross. We thank D. C. Rao, Director of the Division of Biostatistics, Washington University, St. Louis, for help preparing this manuscript; Mark Shriver, Department of Anthropology and Human Genetics at The Pennsylvania State University for his help with the biogeographical ancestry admixture aspect of the project; and Murray Brilliant, professor of Pediatrics and Molecular and Cellular Biology at the University of Arizona for their kind advice and support of our work. His wife Jenny has free earlobes and . Tony Frudakis, Matthew Thomas, Zach Gaskin, K Venkateswarlu, K Suresh Chandra, Siva Ginjupalli, Sitaram Gunturi, Sivamani Natrajan, Viswanathan K Ponnuswamy, K N Ponnuswamy, Sequences Associated With Human Iris Pigmentation, Genetics, Volume 165, Issue 4, 1 December 2003, Pages 20712083, https://doi.org/10.1093/genetics/165.4.2071. Article ), 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. Each of these genes is part of the main (TYR) human pigmentation pathway. In Drosophila, iris pigmentation defects have been ascribed to mutations in >85 loci contributing to a variety of cellular processes in melanocytes (Ooi et al. 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. For R2 computation, we used the following function: Adj-R2 = 1 [n/(n p)](1 R2), where n is the model degrees of freedom and n p is the error degrees of freedom. Legal. (d) List the possible genotypes of a blue eyed individual lacking a dimpled chin. Alternatively, the mechanism for the associations could be LD with phenotypically active loci in nearby pigment genes. genotype - all alleles present in the cell ; phenotype - physical appearance of a trait ; . In the rest of the body, the melanin is secreted from the cells. Aside from these two genes, the genes involved in melanogenesis and other minor genes also contain regions that account for eye color. When this work is more fully developed, it may be possible to assign an iris color to an individual sample with reasonable certainty, and surely in this case the results herein will have some tangible value for the field of forensic science. Genotypes were subject to several quality controls: two scientists independently pass/fail inspected the calls, requiring an overall UHT signal intensity >1000 for >95% of genotypes and clear signal differential between the averages for each genotype class (i.e., clear genotype clustering in two-dimensional space using the UHT analysis software). The eumelanin/pheomelanin switch triggered by the MC1R gene may account for some cases of this disorder. 1998; Flanagan et al. The distances between these loci associated with iris colors and neighboring pigmentation genes is far greater than the average extent of LD in the genome, and if it is the case that these associations are through LD, it would seem that, again, population structure would need to be invoked as an explanation. Teaching the genetics of eye colour & colour vision. Multiple SNPs were also identified on chromosome 2; the C/C genotype for the POMC SNP located at 2p23 was associated with blue iris color (Table 3) and a CYP1B1-2p21-region SNP was also marginally associated at the level of iris shade (Table 2), as well as within the context of a 2-SNP haplotype (Table 3). PCR amplification was accomplished using pfu Turbo polymerase according to the manufacturer's guidelines (Stratagene, La Jolla, CA). The SNPs between the 2p21 and 2p23 regions were also in LD (P < 0.01). 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. 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. Although our results independently verified findings for OCA2, ASIP, and MC1R, they also show that several other pigmentation genes harbor alleles associated with the natural distribution of iris colors (TYRP1, AIM, MYO5A, and DCT). .. Frudakis T, Venkateswarlu K, Thomas M J, Gaskin Z, Ginjupalli S et al. A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation. Relationship. The sequences for most of these genes vary significantly as a function of population structure (Frudakis et al. 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. .. Ooi C E, Moreira J E, DellAngelica E C, Poy G, Wassarman D A et al. 1992; Durham-Pierre et al. 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. Petunias with genotype R1R1 are red flowered, R1R2 are pink flowered and R2R2 are white flowered. as a function of BGA (Frudakis et al. With the revelation of this epistatic relationship, it helps to prove that it can, and does, happen. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. 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. Sturm, R., Duffy, D., Zhao, Z., Leite, F., Stark, M., Hayward, N. et al. The gene contains a main coding region for brown eyes (BEY2 15q11-15) and hazel eyes (BEY1).3, 5 Other SNPs result in blue and green eyes. Predicting phenotype from genotype: normal pigmentation. IRIS pigmentation is a complex genetic trait that has long interested geneticists, anthropologists, and the public at large. Before screening these genotypes for association with iris colors, we used the 73 nonxenobiotic metabolism AIMs to determine BGA admixture proportions for each sample and we tested for correlation between BGA admixture and iris colors. Now, that color depends on the kind and density of melanin a person is born with. Disorders in the HERC regions of chromosome 15 cause PraderWilli or Angelman's syndrome. The remaining SNPs had values and chi-square P values that were not significant on any level of intragenic complexity. A gene for the mouse pink-eyed dilution locus and for human type II oculocutaneous albinism. Once the pigment is produced, MC1R, membrane-associated transporter protein, and p proteins (OCA2) mature the melanosomes to be used in the cells. 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. 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. The SNP, rs12913832, causes a phenotype change from brown to blue eyes, respectively. Place the PTC paper on your tongue for a few seconds. ., Oxford University Press is a department of the University of Oxford. Asterisks represent P values that remained significant after the correction for multiple tests and P values in italic are those that were statistically significant (P 0.05). .. Durham-Pierre D, King R A, Naber J M, Laken S, Brilliant M H. Flanagan N, Healy E, Ray A, Philips S, Todd C et al. MYO5A alleles were not found to be in LD with those of OCA2, suggesting that these results were independently obtained and that Eiberg and Mohr's results may have been a reflection of the activity of two separate genes. Kayser, M., Liu, F., Janssens, A. C., Rivadeneira, F., Lao, O., van Duijn, K. et al. Although such an error is tolerable for identifying sequences marginally associated with iris colors, the use of the sequences described herein for iris color classification would therefore likely require digitally quantified iris colors (which we have begun to accumulate and will present elsewhere). Jannot, A- S., Meziani, R., Bertrand, G., Gerard, B., Descamps, V., Archibaud, A. et al. The second parent has a non-mutated HERC2 allele but does not have the coding for brown eyes in the OCA2 gene. From the chi-square and adjusted residuals, we found 43 haplotypes for 16 different loci to be either positively (agonist) or negatively (antagonist) associated with iris colors (Table 3). Valenzuela, R., Henderson, M., Walsh, M., Garrison, N., Kelch, J., Cohen-Barak, O. et al. Individuals for whom iris color was ambiguous or had changed over the course of life were eliminated from the analysis. Since most of the SNPs identified from this approach localized to discrete genes or chromosomal regions, we grouped all of the SNPs from each locus and tested inferred haplotypes for association with iris colors using contingency analysis. 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). 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. Some individuals may express two phenotypesone in each eyeor a complete lack of pigmentation, ocular albinism. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. Although research on pigment mutants has made clear that a small subset of genes is largely responsible for catastrophic pigmentation defects in mice and humans, it remains unclear whether or how common single-nucleotide polymorphisms (SNPs) in these genes contribute toward (or are linked to) natural variation in human iris color. E_ Free earlobes. Pigment Cell Res 14, 8693 (2001). Of course, identifying markers in LD with phenotypically active loci (or the phenotypically active loci themselves) would provide for more accurate classification (as well as for a better understanding of biological mechanism), but the hunt for these elusive loci in heterogeneous populations is still impractical because LD extends only for a few kilobases and the economics of genome-wide scans in heterogeneous samples with full LD coverage are out of reach for most labs. Human Earlobe attachment. The colored area at the front of the eye is called the iris. 2. (2003) within the context of a software program we developed for this purpose, which will be presented elsewhere (T. Frudakis, Z. Gaskin, M. Thomas, V. Ponnuswamy, K. Venkateswarlu, S. Gunjupulli, C. Bonilla, E. Parra and M. Shriver, personal communication). The pedigree in the accompanying illustration shows the inheritance of albinism, a homozygous recessive condition resulting in a total lack of pigment. This is an example of a hihybrid crosses. Both genes are located on chromosome 15. Although cysteine is not an essential amino acid and its deficiency rarely occurs, the lack of it halts the production of pheomelanin. Although most TYR-negative OCA patients are completely depigmented, dark-iris albino mice (C44H) and their human type IB oculocutaneous counterparts exhibit a lack of pigment in all tissues except for the iris (Schmidt and Beermann 1994). .. Robbins L S, Nadeau J H, Johnson K R, Kelly M A, Roselli-Rehfuss L et al. 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. An ASIP polymorphism is reported to be associated with both brown iris and hair color (Kanetsky et al. Sequences associated with human iris pigmentation. The traditional view was correct in which an allele that codes for brown is dominant over green or blue, and green takes precedence over blue.2, Melanocytes in the stroma and anterior layers of the eye hold melanin in their cytoplasms. Provided by the Springer Nature SharedIt content-sharing initiative, Graefe's Archive for Clinical and Experimental Ophthalmology (2022), Cellular and Molecular Life Sciences (2016), Journal of Human Genetics (J Hum Genet) Diplotypes for these 61 alleles explained most of the iris color variance in our sample; the lowest amount was explained at the level of the SNP, suggesting an element of intragenic complexity to iris color determination (i.e., dominance). Problems with just HERC2 lead to nerve tissue malfunctioning, small size and semi-sterility or sterility. 1996), melanocortin receptor (MC1R; Robbins et al. We focused on human pigmentation and xenobiotic metabolism genes, selected on the basis of their gene identities, not their chromosomal position. Pigmented iris A person with the B allele has brown eyes. 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). . Last, we thank the reviewers of this manuscript who suggested a number of important improvements. .. Newton J M, Cohen-Barak O, Hagiwara N, Gardner J M, Davisson M T et al. To take advantage of each of these four methods, we considered all of them when screening SNPs for associations; we calculated the value, chi square, and exact test P values for (a) all four colors, (b) shades, using light (blue and green) vs. dark (hazel and brown), (c) blue vs. brown, and (d) brown vs. not brown (blue, green, and hazel) groupings. Google Scholar. For example, unlike human hair color (Sturm et al. PLoS Genet 6, e1000934 (2010). In the meantime, to ensure continued support, we are displaying the site without styles Am J Hum Genet 82, 424431 (2008). Our results show that a surprisingly large number of polymorphisms in a large number of genes are associated with iris colors, suggesting that the genetics of iris color pigmentation are quite complex. Haplotype order refers to the order of the SNPs in the haplotypes shown in Table 4 and described in the text. (1995). However, it is yet to be completely understood. This also explains why deletions within HERC2 would cause a decrease in melanin without interacting with the P protein itself. The P values we obtained for this particular SNP association (P = 0.010.05, depending on the color criteria) were less significant than those described (P = 0.002) by Rebbeck et al. Biogeographical ancestry admixture proportions were determined using the methods of Hanis et al. Google Scholar. 2002). Donors checked a box for blue, green, hazel, brown, black, or unknown/not clear iris colors, and each had the opportunity to identify whether iris color had changed over the course of their lives or whether the color of each iris was different. 2001) are necessary for normal human iris pigmentation. 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)). 1997), and other genes (reviewed by Sturm et al. In the most elementary form, the inheritance of eye color is classified as a Mendelian trait.1 On the basis of the observation of more than two phenotypes, eye color has a more complex pattern of inheritance. Article (2000) with adjusted residuals to compensate for this risk. The front layer of the iris (called the stroma) can make eyes appear brown, blue or green. In other words, the distribution of SNPs among the various genes tested was not random. b) Give the genotype of an individual who is homozygous recessive for brown eye color. 2003; data not shown). The most strongly associated 68 genotypes of the 543 genotypes observed for the 16 genes/regions, on the basis of chi-square-adjusted residuals, explained 13% of the variation (last row in Table 4). 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Zhu, G., Evans, D., Duffy, D., Montgomery, G., Medland, S., Gillespie, N. A. et al. A few of the genes/regions not harboring a marginally associated SNP had haplotypes and diplotypes positively and/or negatively associated with iris colors (ASIP gene, 1 haplotype; MC1R gene, 2 haplotypes; Tables 2 and 3). 37.10 Cosmetic iris implant. https://doi.org/10.1038/jhg.2010.126, DOI: https://doi.org/10.1038/jhg.2010.126. Most traits are determined by more than one gene. 2001; Sturm et al. One method of grouping colors is light = blue + green and dark = hazel + brown, and this grouping would seem to more clearly distinguish individuals with respect to the detectible level of eumelanin (brown pigment). Melanocortin 1 receptor (MC1R) instructs a melanocyte to switch production between eumelanin and pheomelanin.3, 4, 5 Therefore, these two proteins affect the quality and quantity of the melanin in the cell. In fact, study of the transmission genetics for pigmentation traits in humans and various model systems suggests that variable pigmentation is a function of multiple heritable factors whose interactions appear to be quite complex (Brauer and Chopra 1978; Bito et al. .. Hanis C, Chakraborty R, Ferrell R, Schull W. Jackson I J, Chambers D M, Tsukamoto K, Copeland N G, Gilbert D J et al. PraderWilli syndrome is inherited from the paternal side whereas Angelman's comes from the maternal side.16, 17, 18, 19 These syndromes result in hypopigmentation, along with delayed development, seizures and child-like behavior patterns.10, 12. Sequences of the highest order of complexity within a locus found to be associated with iris colors. To identify SNP loci associated with variable human pigmentation, we genotyped for 754 SNPs: 335 SNPs within pigmentation genes (AP3B1, ASIP, DCT, MC1R, OCA2, SILV, TYR, TYRP1, MYO5A, POMC, AIM, AP3D1, and RAB; Table 1), and 419 other SNPs distributed throughout the genome. 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?