iris contact lenses, or a cosmetic iris implant inserted at the time of cataract surgery . 5.01 In an experiment designed to study the inheritance of flower color in four-o'clocks, two plants with pink flowers were crossed. 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). P_ Pigmented Iris (Additional genes give specific color, e.g. 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. Linkage disequilibrium (LD) for pairs of SNPs within a gene was determined using the Zaykin exact test and a cutoff value of |D| 0.05 (P value < 0.05; Zaykin et al. 20, 327332 (2004). The mouse pink-eyed dilution gene: association with human Prader-Willi and Angelman Syndromes. 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). The first step, however, is to define the complement of loci that on a sequence level explain variance in trait value and, of these, those that do so in a marginal or penetrant sense will be the easiest to find. Trace your probable genotype from trait 1 through trait 5 until you . .. Copeland N G, Hutchison K W, Jenkins N A. Durham-Pierre D, Gardner J M, Nakatsu Y, King R A, Francke U et al. 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. Most of the haplotypes were even more dramatically associated with iris colors in a multiracial sample (data not shown), because many of the SNPs comprising them are good AIMs and variants associated with darker iris colors were enriched in those ancestral, The common haplotypes and diplotypes for the 16 iris color genes discussed in the text. The SNPs between the 2p21 and 2p23 regions were also in LD (P < 0.01). 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; Smith et al. To form eumelanin, dopachrome tautomerase, TYR, and TYR-related protein 1 complete the chemical pathway from dopaquinone.3, Although the aforementioned proteins are responsible for the production of melanin, once it has been produced in the melanosomes, other proteins are responsible for melanin maturation. If you have no pigment you have either blue or gray eyes. Eiberg, H., Troelsen, J., Nielsen, M., Mikkelsen, A., Mengel-From, J., Kjaer, K. et al. PubMed Many more genes affect brown and blue more than the other eye colors. We have applied a nonsystematic, hypothesis-driven genome-screening approach to identify various SNPs, haplotypes, and diplotypes marginally (i.e., independently) associated with iris color variation. (Abstr. In addition, we independently isolated the red hair/blue iris SNP alleles described by Valverde 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. 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. The colored area at the front of the eye is called the iris. 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. 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). It is inherited or caused by somatic mutations within the cells.2 In addition, it can be caused by the inactivation of particular genes within the cells. 39, 14431452 (2007). 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). Decreased expression of OCA2 affects the pathway for melanosome maturation. PubMedGoogle Scholar. 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. Eye color is determined by the pattern of brown and red pigment, collagen fibers, and the topography of the iris. 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). .. Steenland K, Bray I, Greenland S, Boffetta P. Strobel M C, Seperack P K, Copeland N G, Jenkins N A. Valverde P, Healy E, Jackson I, Rees J L, Thody A J. Wilson S M, Yip R, Swing D A, OSullivan T N, Zhang Y et al. trends Genet. 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. For example, skin color and height are determined by many genes. Pigmented irises. One SNP has been studied to show a large significance for eye color. It is toward this goal that we have performed the present study. & WojasPelc, A. Interactions between HERC2, OCA2, and MC1R may influence human pigmentation phenotype. 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. Corresponding author: DNAPrint Genomics, 900 Cocoanut Ave., Sarasota, FL 34236. 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) 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. Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. For example, dissection of the oculocutaneous albinism (OCA) trait in humans has shown that many pigmentation defects are due to lesions in the TYR gene, resulting in their designation as TYR-negative OCAs (Oetting and King 1991, 1992, 1993, 1999; see albinism database at http://www.cbc.umn.edu/tad/). Nine were not and of these 2 were of relatively low frequency with weak evidence for disquilibrium (P value close to 0.05). 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? The little that isn't absorbed by the iris is reflected back, producing what we see as eye color. 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 Drosophila, iris pigmentation defects have been ascribed to mutations in >85 loci contributing to a variety of cellular processes in melanocytes (Ooi et al. 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. A dark iris pigment (green/brown/black) is dominant over the light pigmentation. Article Rinchik, E. M., Bultman, S. J., Horsthemke, B., Lee, S., Strunk, K. M., Spritz, R. A. et al. 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. (2001) haplotype reconstruction method. Haplotypes were inferred using the Stephens et al. Google Scholar. We also thank Robert White for his help with sample collection. 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. . Interestingly, the number of genes in human DNA is not appreciably different from the number of genes in chimpanzees or mice. 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). B_ genotype for the phenotype of brown eyes (dash indicates second allele could be B or b which means a genotype of BB or Bb) 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). The promoter region for OCA2 is located within the HERC2 gene. Genotype-phenotype correlations have been reported with specific mutations possibly associated with certain angle abnormalities. Linkage studies have implicated certain pigmentation genes as specifically relevant for pigmentation phenotypes, and most of the pigmentation gene SNPs that we identified clustered to certain genes such as OCA2, MYO5A, TYRP1, and AIM. (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). Blue Iris (non-pigmented) MG-3: Jeremy has attached earlobes and pigmented irises. Aside from these two genes, the genes involved in melanogenesis and other minor genes also contain regions that account for eye color. For most of the genes, multilocus gene-wise genotype sequences were more strongly associated with iris colors than were haplotypes or SNP alleles. The most common, which the OCA2 gene is named for, is oculocutaneous albinism. Correspondence to 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). 2000), and adaptin 3B (AP3B) loci (Ooi et al. The remaining SNPs had values and chi-square P values that were not significant on any level of intragenic complexity. In addition, the evolutionary and population roles of the different expressions are significant. However, the results presented herein constitute a good first step toward solving what our results confirm is a very complex genetics problem. 1991; Gardner et al. 2001) and that disparate regions of the TYR and other OCA genes are functionally distinct for determining the pigmentation in different tissues. Zhu, G., Evans, D., Duffy, D., Montgomery, G., Medland, S., Gillespie, N. A. et al. This same phenomenon is the reason why the pupil appears black. 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. Brilliant, M. The mouse p (pink-eyed dilution) and human P genes, ocular albinism type 2 (OCA2), and melanosomal pH. Eumelanin (brown pigment) is a light-absorbing polymer synthesized in specialized melanocyte lysosomes called melanosomes. Angelman syndrome: three molecular classes identified with chromosome 15q11q13-specific DNA markers. CAS 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. 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. 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. Although introns are usually viewed as superfluous DNA, intron 86 of HERC2 regulates the expression of OCA2. 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). Human Earlobe attachment. Duffy, D. L., Box, N. F., Chen, W., Palmer, J. S., Montgomery, G. W., James, M. R. et al. 1998; Schioth et al. PubMed Central We selected those for which at least two instances of PHRED identified variants that scored 24, and each of these SNPs discovered through resequencing were used for genotyping. Resequencing for these genes was performed by amplifying the proximal promoter (average 700 bp upstream of transcription start site), each exon (average size 1400 bp), the 5 and 3 ends of each intron (including the intron-exon junctions, average size 100 bp), and 3 untranslated region (UTR; average size 700 bp) sequences from a multi-ethnic panel of 672 individuals (450 individuals from the Coriell Institute's DNA Polymorphism Discovery Resource, 96 additional European Americans, 96 African Americans, 10 Pacific Islanders, 10 Japanese, and 10 Chinese; these 672 individuals represented a set of samples separate from that used for the association study described herein). Similar to a lack of TYR, other conditions cause ocular albinism. .. Bito L Z, Matheny A, Cruickshanks K J, Nondahl D M, Carino O B. Boissy R E, Zhao H, Oetting W S, Austin L M, Wildenberg S C et al. If no haplotypes or diplotypes for a locus were found to be associated, only the SNP alleles are shown. 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. Use two alleles per trait for the genotype. .. Shriver M, Parra E, Dios S, Bonilla C, Norton H et al. Each human somatic cell has 46 chromosomes in its nucleus. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in 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. .. Gardner J M, Nakatsu Y, Gondo Y, Lee S, Lyon M F et al. In the absence of melanin brown pigment, the iris is blue. 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. Problems with just HERC2 lead to nerve tissue malfunctioning, small size and semi-sterility or sterility. .. Hamabe J, Fukushima Y, Harada N, Abe K, Matsuo N et al. (2002) recently described two OCA2 coding changes associated with darker iris colors. 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. Legal. Use a lab partner to help you determine your phenotype for the traits listed. The large HERC2 gene requires 211kb and 93 exons that codes for a 528kDa protein made of 4834 residues.12. 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. Half of the associated SNPs were located on chromosome 15, which corresponds with results that others have previously obtained from linkage analysis. Melanin undergoes a packaging process and if large amounts of P protein are not available to process and transport it, the quality of the darker pigment is compromised and lighter shades will result.14 Demonstrating epistasis, the HERC2 gene affects the results produced by the OCA2 gene. Hurst, C. C. On the inheritance of eye colour in man. .. Newton J M, Cohen-Barak O, Hagiwara N, Gardner J M, Davisson M T et al. Eye colors are green, hazel, brown or black. https://doi.org/10.1038/jhg.2010.126, DOI: https://doi.org/10.1038/jhg.2010.126. 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). Twin Res 7, 197210 (2004). Am J Hum Genet 47, 149155 (1990). By analyzing the DNA from a crime scene, the general phenotypic traits of the suspect may be pieced together.21, 22, 23 Tully suggests that it may help eliminate particular groups of suspects in circumstances with few leads. 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. For example, unlike human hair color (Sturm et al. The two rounds were necessary due to the fact that many of the genes we queried were members of gene families, the SNPs resided in regions of sequence homology, and our genotyping platform required short (100 bp) amplicons. However, it is yet to be completely understood. 2003) and it is possible that alleles for these SNPs are associated with elements of population structure that correlate with iris colors. Forensic Sci Int: Genet. His wife Jenny has free earlobes and . Rebbeck et al. (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. 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). 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). 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. This is an example of a hihybrid crosses. We also acknowledge previous National Science Foundation support under grant numbers 1246120, 1525057, and 1413739. (gray/blue). 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. 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. 2001). Edridge Green Lecture RCOphth Annual Congress Glasgow May 2019, A GWAS in Latin Americans highlights the convergent evolution of lighter skin pigmentation in Eurasia, A multiethnic genome-wide analysis of 44,039 individuals identifies 41 new loci associated with central corneal thickness, A large Canadian cohort provides insights into the genetic architecture of human hair colour, Environment and culture shape both the colour lexicon and the genetics of colour perception, A systematic review of skin ageing genes: gene pleiotropy and genes on the chromosomal band 16q24.3 may drive skin ageing, White matter variability, cognition, and disorders: a systematic review, Quantitative changes in iris vasculature and blood flow in patients with different refractive errors, The Effect of Ambient Light Conditions on Quantitative Pupillometry, Functional and pathological relevance of HERC family proteins: a decade later. E > e. ee. They help with hormone secretion, which affects the pituitary and can lead to dysfunction of the hypothalamus and other protein complexes. MGG 1, 393394 (1908). . 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. Phakomatoses. Zaumseger, D., Rothschild, M. & Schneider, P. SNPs for the analysis of human pigmentation genes--A comparative study. Gardner, J., Nakatsu, Y., Gondo, Y., Lee, S., Lyon, M., King, R. et al. 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. If you exhibit the dominant phenotype, use a dash to represent the second allele. Genetic determinants of hair, eye and skin pigmentation in Europeans. 3. . ), 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. CAS 2002). Eye color genes. Frequency of the minor allele and the major and minor allele nucleotide. In the meantime, to ensure continued support, we are displaying the site without styles Google Scholar. Sulem, P., Gudbjartsson, D., Stacey, S., Helgason, A., Rafnar, T., Magnusson, K. P. et al. Attached earlobes. 1996), melanocortin receptor (MC1R; Robbins et al. Diplotypes for these genes explain 15% of iris color variation. Both genes are located on chromosome 15. Also, if an allele does code for brown, the individual will have brown eyes, except for cases where a critical gene is turned off. Redei, G. Encyclopedia of Genetics, Genomics, Proteomics, and Informatics, 3rd edn (Springer, New York City, NY, 2008). Red and violet eyes come from a lack of pigment. Producing multicolored irises, heterochromia stems from mutations in certain cells of the iris. PubMed Central 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 . .. Kanetsky P, Swoyer J, Panossian S, Holmes R, Guerry D et al. Slider with three articles shown per slide. J Forensic Sci 55, 315322 (2010). The front layer of the iris (called the stroma) can make eyes appear brown, blue or green.