However, it is yet to be completely understood. .. Gardner J M, Nakatsu Y, Gondo Y, Lee S, Lyon M F et al. Redei, G. Encyclopedia of Genetics, Genomics, Proteomics, and Informatics, 3rd edn (Springer, New York City, NY, 2008). Decreased expression of OCA2 affects the pathway for melanosome maturation. Am J Hum Genet 82, 411423 (2008). In addition, the evolutionary and population roles of the different expressions are significant. Hum Mol Genet 13, 447461 (2004). We considered all 61 SNPs in Table 2, their haplotypes in Table 3, and their diplotypes (not shown). OCA2 contains regions for the numerous eye colors, but one SNP is a strong predictor for brown/blue eyes. For each gene, we inferred haplotypes and used contingency analyses to determine which haplotypes were statistically associated with iris colors. The little that isn't absorbed by the iris is reflected back, producing what we see as eye color. The mouse pink-eyed dilution gene: association with human Prader-Willi and Angelman Syndromes. Iris transillumination: The iris in albinism has little to no pigment to screen out stray light coming into the eye.On slit lamp exam, the examiner may detect speckled or diffuse transillumination defect. Heterochromia, although not viewed as a severe disorder, affects many individuals. 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. The solid figures represent albino individuals. 2001). Indeed, some, but not all, of our nonpigment gene SNPs are found in regions within the vicinity of pigmentation genes; CYP2C8 and CYP2C9 are located on chromosome 10 near the HPS1 and HPS2 pigmentation genes (which we did not test directly), CYP1A2 is located at 15q22ter on the same arm as OCA2 and MYO5A, CYP1B1 is located at 2p21 in the vicinity of the POMC gene at 2p23, and MAOA is located on the same arm of chromosome X (Xp11.411.3) as the OA1 pigmentation gene (which we also did not test directly). Pigment Cell Res 14, 8693 (2001). Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene. The first parent contains the mutation in the HERC2 intron in both alleles but possesses an allele with the coding for brown eyes. This epistatic relationship demonstrates the significance of introns and how a single-base change greatly affects an aspect of the individual. 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. 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. .. Kwon H Y, Bultman S J, Loffler C, Chen W-J, Furdon P J et al. CAS If you cannot taste anything, you do not possess the dominant allele. Alternatively, as a research tool, the common haplotypes that we have identified and the complex, biologically relevant contexts within which they are found may help researchers more accurately define risk factors for pigmentation-related diseases such as cataracts and melanoma. 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. Box N F, Duffy D L, Irving R E, Russell A, Chen W et al. When light passes through a large amount of melanin, most of the visible light is absorbed, and the little that is reflected back appears brown. Phakomatoses. (2000) with adjusted residuals to compensate for this risk. 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. For more extensively admixed individuals, we observed no correlation between higher levels (>33% but <50%) of Native American admixture and iris colors, although there was a weak association between higher levels of East Asian and sub-Saharan African admixture and darker iris colors (data not shown). European J Hum Genet 13, 913920 (2005). 2001), there appears to be only a minor dominance component for mammalian iris color determination (Brauer and Chopra 1978), and minimal correlation exists among skin, hair, and iris color within or between individuals of a given population. 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. . 1995; Koppula et al. Liu, F., Wollstein, A., Hysi, P. G., Ankra-Badu, G. A., Spector, T. D., Park, D. et al. HERC2/OCA2 rs12913832 and IRF4 rs12203592 influenced both eye colour and the number of iris pigmented lesions. 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. Further studies of this region and its sequence revealed that a change in one nucleotide, single-nucleotide polymorphism (SNP), regulates the binding site for the transcription of the OCA2 gene, altering its expression.9 The base changes from a thymine to a cytosine. In addition, we independently isolated the red hair/blue iris SNP alleles described by Valverde 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? Although we screened a large number of SNPs, some of the genes harbor a large number of candidate SNPs and we did not test them all. People with blue eyes have no pigment at all in this front layer, causing the fibers to scatter and absorb some of the longer wavelengths of light that come in. 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. genotype - all alleles present in the cell ; phenotype - physical appearance of a trait ; . (Abstr. On the basis of population studies, scientists speculate that the blue-eyed mutation originated in peoples of Northern Europe (Scandinavian countries). Article Diplotypes for these genes explain 15% of iris color variation. Of the 17 that did not, 6 were brown/hazel, 7 were green/hazel, and 4 were blue/green discrepancies although none were gross discrepancies such as brown/green, brown/blue, or hazel/blue. In the P protein, the mutation causes residue 419 to change from an arginine to a glutamine. Nat Genet. Predicting phenotype from genotype: normal pigmentation. Most traits are determined by more than one gene. 1994, 1996), tyrosinase-like protein (TYRP1; Abbott et al. Even at this level of complexity, the sequences from no single gene could be used to make reliable iris color inferences, which suggests an element of intergenic complexity (i.e., epistasis) for iris color determination as well. When multiple simultaneous hypotheses are tested at set P values, there is the possibility of enhanced type I error, so we used the correction procedure of Steenland et al. 2001; Sturm et al. For this population a. Although introns are usually viewed as superfluous DNA, intron 86 of HERC2 regulates the expression of OCA2. They help with hormone secretion, which affects the pituitary and can lead to dysfunction of the hypothalamus and other protein complexes. iris contact lenses, or a cosmetic iris implant inserted at the time of cataract surgery . In mice and humans where the P protein is nonfunctional, albinism occurs, indicating its crucial role in pigmentation.13, 14 The gene located 11.7kb from HERC2 requires 345kb, but it requires only 24 exons to produce a 110kDa protein with 838 residues. In the case of the mutation within HERC2, the expression of the P protein encoded by OCA2 decreases, effectively decreasing its effects in pigmentation. 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. Alleles for these latter SNPs were known to be informative for certain elements of population structure; 73 were selected from a screen of the human genome because they were exceptional ancestry informative markers (AIMs, based on high values) for Indo-European, sub-Saharan African, Native American, and East Asian biogeographical ancestry (BGA; Shriver et al. Relationship. For these genes we performed resequencing and of the genes discussed in this article, 113 SNPs were discovered in CYP1A2 (7 gene regions, 5 amplicons, 10 SNPs found), CYP2C8 (9 gene regions, 8 amplicons, 15 SNPs found), CYP2C9 (9 gene regions, 8 amplicons, 24 SNPs found), OCA2 (16 gene regions, 15 amplicons, 40 SNPs found), TYR (5 gene regions, 5 amplicons, 10 SNPs found), and TYRP1 (7 gene regions, 6 amplicons, 14 SNPs found). 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. The process that produces melanin, known as melanogenesis, requires numerous proteins. 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). Study of a number of other TYR-positive OCA phenotypes has shown that, in addition to TYR, the oculocutaneous 2 (OCA2; Hamabe et al. ), Molecular analysis of type I-A (tyrosine negative) oculocutaneous albinism, Molecular basis of type I (tyrosinase-related) oculocutaneous albinism: mutations and polymorphisms of the human tyrosinase gene, Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism, Altered expression of a novel adaptin leads to defective pigment granule biogenesis in the Drosophila iris color mutant garnet, P gene as an inherited biomarker of human eye color, Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function, Loss of function mutations of the human melanocortin 1 receptor are common and are associated with red hair, Molecular basis of dark-eyed albinism in the mouse, Skin pigmentation, biogeographical ancestry and admixture mapping, Melanocortin 1 receptor variants in an Irish population, Empirical Bayes adjustments for multiple results in hypothesis-generating or surveillance studies, A new statistical method for haplotype reconstruction from population data, Molecular analysis of two mouse dilute locus deletion mutations: spontaneous dilute lethal-20J and radiation-induced dilute prenatal lethal Aa2 alleles, Human pigmentation genes: identification, structure and consequences of polymorphic variation, Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans, A mutation in Rab27a causes the vesicle transport defects observed in ashen mice, Exact tests for association between alleles at arbitrary numbers of loci, This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (, Selection and Geography Shape Male Reproductive Tract Transcriptomes in Drosophila Melanogaster, From Multi-Allele Fish to Non-Standard Environments, How ZFIN Assigns Phenotypes, Human Disease Models, and Gene Expression Annotations to Genes, Genetic association models are robust to common population kinship estimation biases, 101 years ago: Hermann Muller's remarkable insight, https://doi.org/10.1093/genetics/165.4.2071, https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model, Receive exclusive offers and updates from Oxford Academic, Adaptor-related protein complex 3, -1 subunit, Adaptor-related protein complex 3, -1 subunit, Copyright 2023 Genetics Society of America. Tully, G. Genotype versus phenotype: human pigmentation. European J Genet 17, 317 (2009). 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 cysteine is not an essential amino acid and its deficiency rarely occurs, the lack of it halts the production of pheomelanin. .. Shriver M, Parra E, Dios S, Bonilla C, Norton H et al. Second, although a roughly equal number of pigmentation and nonpigmentation gene SNPs were tested, of the 34 marginally associated SNPs, 28 of them. Slider with three articles shown per slide. The decreased expression could account for incomplete dominance, as well. 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. (a) List all possible genotypes for an individual with pigmented iris and dimpled chin. Genetic determinants of hair, eye and skin pigmentation in Europeans. Similar to membrane-associated transporter protein, it transports melanosomes, but additionally, it controls their pH.3, 13 Therefore, the P protein encoded by OCA2 affects the amount and quality of melanin that deposits in melanocytes. What is the likely genotype of individual C-4? For these, it would seem more prudent to eliminate false positives downstream of SNP identification, such as from tests of higher-order association, using various other criteria, such as those described above, or possibly using the utility of the SNP for the generalization of a complex classification model when one is finally described. During pigment distribution in an infant, a diet low in cysteine or methionine, which it is synthesized from, would likely affect the color of the child's eyes until the amino acid is supplemented. Complete the table. Problems with just HERC2 lead to nerve tissue malfunctioning, small size and semi-sterility or sterility. 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). Others genes such as AIM, OCA2, and TYRP1 harbored haplotypes positively associated with brown but negatively associated with blue color (AIM haplotype 2; OCA2 haplotypes 2, 4, 45, 47; TYRP1 haplotype 4; Table 3) while others, such as the MYO5A, OCA2, TYRP1, and CYP2C8 genes located at 10q23, harbored haplotypes positively associated with one color but not negatively associated with any other color (MYO5A haplotype 5 and haplotype 10, OCA2 haplotype 19, TYRP1 haplotype 3, and CYP2C8 haplotype 1; Table 3). In the presence of cysteine, the reaction will proceed to form pheomelanin. The "P" allele produces the pigment which gives you eye color. 1991; Gardner et al. 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. 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. Producing multicolored irises, heterochromia stems from mutations in certain cells of the iris. Eiberg, H., Troelsen, J., Nielsen, M., Mikkelsen, A., Mengel-From, J., Kjaer, K. et al. Furthermore, with all genetic expression, aberration also occurs. We fixed significance levels at 5%, and the alleles of 20 SNPs were found to be associated with specific iris colors, 19 with iris color shades, 19 with blue/brown color comparisons, and 18 using the brown/not brown comparison. Individuals for whom iris color was ambiguous or had changed over the course of life were eliminated from the analysis. If you exhibit the dominant phenotype, use a dash to represent the second allele. A gene for the mouse pink-eyed dilution locus and for human type II oculocutaneous albinism. 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. A simple cross is provided in Figure 1: Blue-eyed Cross. We will explore some of these single gene traits in the laboratory. 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. Pigmented iris: If a person is homozygous recessive for eye color, there is no pigment in the front part of the eyes, and the blue color of the back of the iris shows through, giving blue eyes . b) Give the genotype of an individual who is homozygous recessive for brown eye color. Most of what we have learned about pigmentation since has been derived from molecular genetics studies of rare pigmentation defects in humans and model systems such as mouse and Drosophila. The first is that for most of the genes for which we identified marginally associated SNPs, multiple such SNPs were identified. 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. .. Smith R, Healy E, Siddiqui S, Flanagan N, Steijlen P M et al. In terms of disease, OCA2 and MC1R were linked to melanoma. With the help of dopachrome tautomerase and TYR-related protein 1, eumelanin, the darker pigment, is synthesized; with cysteine, pheomelanin, a yellow-red pigment, is produced. Haplotype order refers to the order of the SNPs in the haplotypes shown in Table 4 and described in the text. 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). 1997; Lloyd et al. Genotypes for these 754 candidate SNPs were scored for 851 European-derived individuals of self-reported iris colors (292 blue, 100 green, 186 hazel, and 273 brown). .. Hanis C, Chakraborty R, Ferrell R, Schull W. Jackson I J, Chambers D M, Tsukamoto K, Copeland N G, Gilbert D J et al. Over 300 SNPs for eye color have been identified on the gene, but classification of their results proved too arduous. 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. The change of this base from a C to a T causes a change from brown eyes to non-brown eyes (usually blue). E > e. ee. J Forensic Sci 55, 315322 (2010). P_ Pigmented Iris (Additional genes give specific color, e.g. 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. E-mail: Search for other works by this author on: The human homolog of the mouse brown gene maps to the short arm of chromosome 9 and extends the known region of homology with mouse chromosome 4, Interaction between the melanocortin-1 receptor and P genes contributes to inter-individual variation in skin pigmentation phenotypes in a Tibetan population, Discrete visual defects in pearl mutant mice, Human tyrosinase gene, mapped to chromosome 11 (q14-q21), defines second region of homology with mouse chromosome 7, Iris color changes past early childhood. As the eye color lightens, less melanin is present in the cells, reflecting more of the visible spectrum. 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). 1998), but mouse studies have suggested that 14 genes preferentially affect pigmentation in vertebrates (reviewed in Sturm et al. What is your genotype for this trait? 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. Digital quantification of human eye color highlights genetic association of three new loci. PubMed To an investigator interested in elucidating a biological mechanism, association due to population structure might not seem to be very satisfying, but when classification is the goal rather than the elucidation of a biological mechanism, it would seem to matter little why a marker is associated with a trait. One of these, the Arg305TRP SNP, was one of the 13 OCA2 SNPs that we found to be strongly associated with iris colors using all four of our color criteria, although its association was only the ninth strongest among the OCA2 SNPs that we identified and the eleventh strongest among all of the associated SNPs that we identified. Pedigree studies in the mid-1970s suggested that iris color variation is a function of two loci: a single locus responsible for depigmentation of the iris, not affecting skin or hair, and another pleiotropic gene for reduction of pigment in all tissues (Brues 1975). In the progeny from this cross, there were 42 plants with red flowers, 86 with pink flowers, and 39 with white flowers. 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. Only about half of the 61 SNPs that we identified were associated with iris colors independentlythe others were associated only in the context of haplotypes or diplotypes. 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. Google Scholar. Internet Explorer). (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. 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. However, this result would not have necessarily been obtained were we working with SNPs that were not truly 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. Once the pigment is produced, MC1R, membrane-associated transporter protein, and p proteins (OCA2) mature the melanosomes to be used in the cells. The colored area at the front of the eye is called the iris. 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. et al. Membrane-associated transporter protein and p protein oculocutaneous albinism II (OCA2) transport melanosomes for melanin maturation. 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. Green eyes require more pigment than blue and not much less than brown, and because the shades of hazel (brown with blue or green) are more versatile, hazel is still more popular than green. Am J Hum Genet 47, 149155 (1990). .. Newton J M, Cohen-Barak O, Hagiwara N, Gardner J M, Davisson M T et al. An intron in HERC2 contains the promoter region for OCA2, affecting its expression. 2003; T. Frudakis, Z. Gaskin, M. Thomas, V. Ponnuswamy, K. Venkateswarlu, S. Gunjupulli, C. Bonilla, E. Parra and M. Shriver, unpublished observations). The structure behind our results is unlikely to be of a crude (i.e., continental) nature; although two-thirds of our European-American samples were of significant (4%) BGA admixture, few correlations between structure measured on this level and iris colors were observed in this study. ., Oxford University Press is a department of the University of Oxford. Article 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. 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. 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). 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.