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 Google Scholar. 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? 2001) and that disparate regions of the TYR and other OCA genes are functionally distinct for determining the pigmentation in different tissues. Rinchik, E. M., Bultman, S. J., Horsthemke, B., Lee, S., Strunk, K. M., Spritz, R. A. et al. 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. Both genes are located on chromosome 15. 1997; Smith et al. Use two alleles per trait for the genotype. In other words, the distribution of SNPs among the various gene types was also not random. 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. & WojasPelc, A. Interactions between HERC2, OCA2, and MC1R may influence human pigmentation phenotype. This epistatic relationship demonstrates the significance of introns and how a single-base change greatly affects an aspect of the individual. 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. b) List the possible genotypes for an individual with pigmented iris but lacking a dimpled chin. The overlap among these SNP sets was high but not perfect. .. Lindsey J D, Jones H L, Hewitt E G, Angert M, Weinreb R N. Lyon M F, King T R, Gondo Y, Gardner J M, Nakatsu Y et al. 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). 2000). 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. .. Smith R, Healy E, Siddiqui S, Flanagan N, Steijlen P M et al. Fig. An intron in HERC2 contains the promoter region for OCA2, affecting its expression. Some phenotypes however, are determined by a single gene. MGG 1, 393394 (1908). 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. (d) List the possible genotypes of a blue eyed individual lacking a dimpled chin. 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. IRIS pigmentation is a complex genetic trait that has long interested geneticists, anthropologists, and the public at large. Liu, F., Wollstein, A., Hysi, P. G., Ankra-Badu, G. A., Spector, T. D., Park, D. et al. 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. If no haplotypes or diplotypes for a locus were found to be associated, only the SNP alleles are shown. 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. At the cellular level, variable iris color in healthy humans is the result of the differential deposition of melanin pigment granules within a fixed number of stromal melanocytes in the iris (Imesch et al. 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. 1999; Flanagan et al. 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 quantity and quality of melanin in the cytoplasm determines the observed color of the eye. Branicki, W., Brudnik, U. 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. Depending on how little pigment the melanocytes produce, albinism causes red or violet eyes. In addition, the evolutionary and population roles of the different expressions are significant. 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). 2003; data not shown). Decreased expression of OCA2 affects the pathway for melanosome maturation. 39, 14431452 (2007). homework 5 ans. It is around 12 . Angelman syndrome: three molecular classes identified with chromosome 15q11q13-specific DNA markers. 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. 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. Attached earlobes. 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. However, the results presented herein constitute a good first step toward solving what our results confirm is a very complex genetics problem. (2000). At the level of the haplotype, each gene or region had unique numbers and types of associations. (Abstr. Study of a number of other TYR-positive OCA phenotypes has shown that, in addition to TYR, the oculocutaneous 2 (OCA2; Hamabe et al. 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. In melanocyte-specific organelles known as melanosomes, two pathways for melanogenesis occur. Phenotypic Effect. CAS In all, 27 SNPs were significantly associated with iris pigmentation using at least one of the four criteria, and we refer to these as marginally associated. 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). Zaumseger, D., Rothschild, M. & Schneider, P. SNPs for the analysis of human pigmentation genes--A comparative study. Aside from HERC2 and OCA2, the other genes involved in melanin production have some regions that correlate to other eye colors.5 MC1R contains regions that increase the probability of obtaining green eyes. The solid figures represent albino individuals. Am J Hum Genet 80, 241252 (2007). What is your genotype for this trait? b) Give the genotype of an individual who is homozygous recessive for brown eye color. That is, the occurrence of an allele for eye pigmentation in a gamete has nobearing on which allele for chin form will occur in that same gamete. The possible changes in the DNA sequence are GCT to GTT and GCC to GTC. Genotype-phenotype correlations have been reported with specific mutations possibly associated with certain angle abnormalities. Indeed, the associations were observed to be generally stronger for the SNPs in the context of within-gene haplotypesa result that would not necessarily be obtained for individual SNPs spuriously associatedsuggesting that the gene sequences themselves are associated, not merely a spurious polymorphism within each gene. 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). A few disorders are associated with eye color. 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. as a function of BGA (Frudakis et al. CAS Use a lab partner to help you determine your phenotype for the traits listed. When there is no pigment in the front part of the eyes, then a blue layer at the back of the iris shows through, resulting in blue eyes. Eye color phenotypes demonstrate both epistasis and incomplete dominance. 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. In studies with HERC2 functions, deletions caused hypopigmentation even though the protein has nothing to do with pigmentation. Sturm, R., Duffy, D., Zhao, Z., Leite, F., Stark, M., Hayward, N. et al. 1997; Box et al. 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. For this population a. 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/). The rest were found in or around xenobiotic metabolism genes, which we have previously shown exhibit dramatic sequence variation, Candidate genes tested for sequence associations with human iris pigmentation. Interestingly, the number of genes in human DNA is not appreciably different from the number of genes in chimpanzees or mice. .. Schioth H B, Phillips S R, Rudzish R, Birch-Machin M A, Wikberg J E et al. Google Scholar. 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. 2002). OCA2 ranges from 15q11.2-12 and HERC 2 starts at 15q13. 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. Furthermore, with all genetic expression, aberration also occurs. lack pigment in skin (recessive) pigmented iris - pigments (dominant) hides blue/gray color of iris back layer ; attached earlobes - free earlobes dominant over attached earlobes ; hitchhiker's thumb - last joint of thumb bends back over 60 degrees . Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene. A change in rs1800407 causes a change in the protein, Arg419Gln, and a change from brown to blue eyes. 2001). 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. The first is that for most of the genes for which we identified marginally associated SNPs, multiple such SNPs were identified. 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. Eiberg, H., Troelsen, J., Nielsen, M., Mikkelsen, A., Mengel-From, J., Kjaer, K. et al. ., Oxford University Press is a department of the University of Oxford. E > e. ee. PubMed 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. Brilliant, M. The mouse p (pink-eyed dilution) and human P genes, ocular albinism type 2 (OCA2), and melanosomal pH. 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). Cassidy, S. B. 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. A genome scan for eye color in 502 twin families: most variation is due to a QTL on chromosome 15q. . Clearly work remains to be done, objectifying the collection of iris colors from subjects, enhancing the sample size so that epistatic interactions can be explored, possibly screening other regions of the genome not screened here, and modeling the sequences that we have described to enable classification of iris colors from DNA. .. 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. Article The eumelanin/pheomelanin switch triggered by the MC1R gene may account for some cases of this disorder. 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. PubMed Central Apart from representing the first comprehensive candidate gene study for variable iris pigmentation and constituting a first step toward developing a classification model for the inference of iris color from DNA, our results suggest that cryptic population structure might serve as a leverage tool for complex trait gene mapping if genomes are screened with the appropriate ancestry informative markers. 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. 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. In the case of TYR, melanin production will halt entirely, resulting in albinism in the entire body. Google Scholar. Nonetheless, the complexity of OCA phenotypes illustrates that TYR is not the only gene involved in iris pigmentation (Lee et al. Two major genes on chromosome 15 affect the quantity and quality of the melanin produced by melanogenesis. 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). 20, 327332 (2004). Lighter shades of brown and gray, a lighter shade of blue, show a mixture of two phenotypes where neither dominates completely. 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)). Duffy, D. L., Box, N. F., Chen, W., Palmer, J. S., Montgomery, G. W., James, M. R. et al. a) Give the genotype of an individual, who is homozygous dominant for Brown eye color, where "B" is the letter used to distinguish this trait. et al. 1, 105110 (2007). 1997), and other genes (reviewed by Sturm et al. PubMed Central .. 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. Box N F, Duffy D L, Irving R E, Russell A, Chen W et al. To obtain In other words, the distribution of SNPs among the various genes tested was not random. Sequences of the highest order of complexity within a locus found to be associated with iris colors. 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. & Driscoll, D. J. Prader-Willi syndrome. Hardy-Weinberg equilibrium P value, where a value <0.05 indicates that the alleles are not in equilibrium.