Molecular and biochemical mechanisms of human iris color: A comprehensive review

Molecular and biochemical mechanisms of human iris color: A comprehensive review
Morteza Oladnabi,^1,* Saeed Dorgaleleh,² Karim Naghipoor,³ Farzad Dastaviz,⁴
1. Golestan University of Medical Sciences
2. Golestan University of Medical Sciences
3. Golestan university of Medical Sciences
4. Golestan university of Medical Sciences
Introduction: Abstract Eye color is determined as a polymorphism and polygenic trait. Brown is the most common eye color in the world, accounting for about 79%, blue eye color for about 8–10%, hazel for 5%, and green for 2%. Rare‐colored eyes include gray and red/ violet. Different factors are involved in determining eye color. The two most important factors are the iris pigment and the way light is scattered from the iris. Gene expression determines the iris pigmentation and how much melanin is present in the eye, which is the number of melanin subunits that identify eye color. The genes involved in the pigmentation of single‐nucleotide polymorphism (SNP) have a significant role; and even some genes are included only in the eye color through SNP. MicroRNAs also affect melanocyte synthesis, which is usually affected by the downregulation of essential genes involved in pigmentation. In this study, we assess the biochemical pathways of melanin synthesis, and the role of each gene in this pathway also has been examined in the signaling pathway that stimulates melanin synthesis.
Methods: REFERENCES Ambrosio, A. L., Boyle, J. A., Aradi, A. E., Christian, K. A., & Di Pietro, S. M. (2016). TPC2 controls pigmentation by regulating melanosome pH and size. Proceedings of the National Academy of Sciences of the United States of America, 113(20), 5622–5627. https://doi.org/10.1073/pnas.1600108113 Aoki, H., Yamada, Y., Hara, A., & Kunisada, T. (2009). Two distinct types of mouse melanocyte: Differential signaling requirement for the maintenance of non‐cutaneous and dermal versus epidermal melanocytes. Development, 136(15), 2511–2521. Caliebe, A., Harder, M., Schuett, R., Krawczak, M., Nebel, A., & von Wurmb‐Schwark, N. (2016). The more the merrier? How a few SNPs predict pigmentation phenotypes in the Northern German population. European Journal of Human Genetics, 24(5), 739–747. https://doi.org/ 10.1038/ejhg.2015.167 Chao, Y. K., Schludi, V., Chen, C. C., Butz, E., Nguyen, O. N. P., Muller, M., … Grimm, C. (2017). TPC2 polymorphisms associated with a hair pigmentation phenotype in humans result in gain of channel function by independent mechanisms. Proceedings of the National Academy of Sciences of the United States of America, 114(41), E8595–e8602. https://doi.org/10.1073/pnas.1705739114 d'Ischia, M., Wakamatsu, K., Cicoira, F., Di Mauro, E., Garcia‐Borron, J. C., Commo, S., … Meredith, P. (2015). Melanins and melanogenesis: From pigment cells to human health and technological applications. Pigment Cell & Melanoma Research, 28(5), 520–544. D'Mello, S. A., Finlay, G. J., Baguley, B. C., & Askarian‐Amiri, M. E. (2016). Signaling pathways in melanogenesis. International Journal of Molecular Sciences, 17(7), 1144. https://doi.org/10.3390/ijms17071144 Dynoodt, P., Mestdagh, P., van Peer, G., Vandesompele, J., Goossens, K., Peelman, L. J., … van Gele, M. J. (2013). Identification of miR‐145 as a key regulator of the pigmentary process. Journal of Investigative Dermatology, 133(1), 201–209. https://doi.org/10.1038/jid.2012.266 El‐Chemaly, S., & Young, L. R. (2016). Hermansky‐Pudlak syndrome. Clinics in Chest Medicine, 37(3), 505–511. https://doi.org/10.1016/j.ccm.2016. 04.012 Fattahi, Z., Beheshtian, M., Mohseni, M., Poustchi, H., Sellars, E., Nezhadi, S. H., … Najmabadi, H. (2019). Iranome: A catalog of genomic variations in the Iranian population. Human Mutation, 40(11), 1968–1984. https://doi.org/10.1002/humu.23880 Fracasso, N. C. A., de Andrade, E. S., Wiezel, C. E. V., Andrade, C. C. F., Zanao, L. R., da Silva, M. S., … Mendes‐Junior, C. T. (2017). Haplotypes from the SLC45A2 gene are associated with the presence of freckles and eye, hair and skin pigmentation in Brazil. Leg Med (Tokyo), 25, 43–51. https://doi.org/10.1016/j.legalmed.2016.12.013 Frudakis, T., Thomas, M., Gaskin, Z., Venkateswarlu, K., Chandra, K. S., Ginjupalli, S., … Ponnuswamy, K. N. (2003). Sequences associated with human iris pigmentation. Genetics, 165(4), 2071–2083. Ghanem, G., & Fabrice, J. (2011). Tyrosinase related protein 1 (TYRP1/ gp75) in human cutaneous melanoma. Molecular Oncology, 5(2), 150–155. https://doi.org/10.1016/j.molonc.2011.01.006 Guo, J., Zhang, J.‐F., Wang, W.‐M., Cheung, F. W., Lu, Y., Ng, C., … Liu, W. (2014). MicroRNA‐218 inhibits melanogenesis by directly suppressing microphthalmia‐associated transcription factor expression. RNA Biology, 11(6), 732–741. https://doi.org/10.4161/rna.28865 Hashemi, H., Pakzad, R., Yekta, A., Hasani, J., Asharlous, A., Ostadimoghaddam, H., … Shariati, R. (2019). Iris color distribution and its relation with refractive errors, amblyopia, and strabismus in children. Journal of Comprehensive Pediatrics, 10(3), e66099. Hearing, V. J. (2011). Determination of melanin synthetic pathways. Journal of Investigative Dermatology, 131(E1), E8–E11. Hurbain, I., Romao, M., Sextius, P., Bourreau, E., Marchal, C., Bernerd, F., … Raposo, G. (2018). Melanosome distribution in keratinocytes in different skin types: Melanosome clusters are not degradative organelles. Journal of Investigative Dermatology, 138(3), 647–656. https://doi.org/10.1016/j.jid.2017.09.039 Katsara, M.‐A., & Nothnagel, M. (2019). True colors: A literature review on the spatial distribution of eye and hair pigmentation. Forensic Science International: Genetics, 39, 109–118. Kayser, M., Liu, F., Janssens, A. C., Rivadeneira, F., Lao, O., van Duijn, K., … van Duijn, C. M. (2008). Three genome‐wide association studies and a linkage analysis identify HERC2 as a human iris color gene. American Journal of Human Genetics, 82(2), 411–423. https://doi.org/10.1016/j. ajhg.2007.10.003 Kim, K. H., Lee, T. R., & Cho, E. G. (2017). SH3BP4, a novel pigmentation gene, is inversely regulated by miR‐125b and MITF. Experimental & Molecular Medicine, 49(8), e367. https://doi.org/10.1038/emm. 2017.115 King, R. A., Pietsch, J., Fryer, J. P., Savage, S., Brott, M. J., Russell‐Eggitt, I., … Oetting, W. S. (2003). Tyrosinase gene mutations in oculocutaneous albinism 1 (OCA1): Definition of the phenotype. Human Genetics, 113(6), 502–513. Liu, F., Wollstein, A., Hysi, P. G., Ankra‐Badu, G. A., Spector, T. D., Park, D., … Kayser, M. (2010). Digital quantification of human eye color highlights genetic association of three new loci. PLOS Genetics, 6(5), e1000934. https://doi.org/10.1371/journal.pgen.1000934 Marín, O. (2013). Cellular and molecular mechanisms controlling the migration of neocortical interneurons. European Journal of Neuroscience, 38(1), 2019–2029. McNulty, J. C., Jackson, P. J., Thompson, D. A., Chai, B., Gantz, I., Barsh, G. S., … Millhauser, G. L. (2005). Structures of the agouti signaling protein. Journal of Molecular Biology, 346(4), 1059–1070. https://doi. org/10.1016/j.jmb.2004.12.030 Mehrjoo, Z., Fattahi, Z., Beheshtian, M., Mohseni, M., Poustchi, H., Ardalani, F., … Nothnagel, M. (2019). Distinct genetic variation and heterogeneity of the Iranian population. PLOS Genetics, 15(9), e1008385. https://doi.org/10.1371/journal.pgen.1008385 Mione, M., & Bosserhoff, A. (2015). MicroRNAs in melanocyte and melanoma biology. Pigment Cell & Melanoma Research, 28(3), 340–354. https://doi.org/10.1111/pcmr.12346 National Center for Biotechnology Information (NCBI). (2019a). ASIP, āgouti signaling protein [Homo sapiens (human)]. National Center for Biotechnology Information (NCBI). (2019b). DCT, dopachrome tautomerase [Homo sapiens (human)]. National Center for Biotechnology Information (NCBI). (2019c). HERC2, HECT and RLD domain containing E3 ubiquitin protein ligase 2 [Homo sapiens (human)]. National Center for Biotechnology Information (NCBI). (2019d). IRF4, interferon regulatory factor 4 [Homo sapiens (human)]. National Center for Biotechnology Information (NCBI). (2019e). KITLG, KIT ligand [Homo sapiens (human)]. National Center for Biotechnology Information (NCBI). (2019f). PMEL, premelanosome protein [Homo sapiens (human)]. National Center for Biotechnology Information (NCBI). (2019g). SH3BP4, SH3 domain binding protein 4 [Homo sapiens (human)]. National Center for Biotechnology Information (NCBI). (2019h). SLC24A5, solute carrier family 24 member 5 [Homo sapiens (human)]. National Center for Biotechnology Information (NCBI). (2019i). SLC45A2, solute carrier family 45 member 2 [Homo sapiens (human)]. National Center for Biotechnology Information (NCBI). (2019j). TPCN2, two pore segment channel 2 [Homo sapiens (human)]. National Center for Biotechnology Information (NCBI). (2019k). TYR, tyrosinase [Homo sapiens (human)]. National Center for Biotechnology Information (NCBI). (2019l). TYRP1, tyrosinase related protein 1 [Homo sapiens (human)]. National Center for Biotechnology Information (NCBI). (2019m). OCA2, melanosomal transmembrane protein [Homo sapiens (human)]. National Center for Biotechnology Information (NCBI). (2019n). MC1R, melanocortin 1 receptor [Homo sapiens (human)]. Noguchi, S., Kumazaki, M., Yasui, Y., Mori, T., Yamada, N., & Akao, Y. (2014). MicroRNA‐203 regulates melanosome transport and tyrosinase expression in melanoma cells by targeting kinesin superfamily protein 5b. The Journal of Investigative Dermatology, 124(2), 461–469. https://doi.org/10.1038/jid.2013.310 Di Pietro, S. M., & Dell'Angelica, E. C. (2005). The cell biology of Hermansky‐Pudlak syndrome: Recent advances. Traffic, 6(7), 525–533. https://doi.org/10.1111/j.1600-0854.2005.00299.x Pillaiyar, T., Manickam, M., & Jung, S.‐H. (2017). Recent development of signaling pathways inhibitors of melanogenesis. Cellular Signalling, 40, 99–115. https://doi.org/10.1016/j.cellsig.2017.09.004 Pospiech, E., Draus‐Barini, J., Kupiec, T., Wojas‐Pelc, A., & Branicki, W. (2011). Gene‐gene interactions contribute to eye colour variation in humans. Journal of Human Genetics, 56(6), 447–455. https://doi.org/ 10.1038/jhg.2011.38 Praetorius, C., Grill, C., Stacey, S. N., Metcalf, A. M., Gorkin, D. U., Robinson, K. C., … Steingrimsson, E. (2013). A polymorphism in IRF4 affects human pigmentation through a tyrosinase‐dependent MITF/ TFAP2A pathway. Cell, 155(5), 1022–1033. https://doi.org/10.1016/j. cell.2013.10.022 Qi, S., Liu, B., Zhang, J., Liu, X., Dong, C., & Fan, R. (2019). Knockdown of microRNA1435p by STTM technology affects eumelanin and pheomelanin production in melanocytes. Molecular Medicine Reports, 20(3), 2649–2656. https://doi.org/10.3892/mmr.2019.10492 Rambow, F., Bechadergue, A., Saintigny, G., Morizot, F., Mahe, C., & Larue, L. (2014). miR‐330‐5p targets tyrosinase and induces depigmentation. Journal of Investigative Dermatology, 134(11), 2846–2849. https://doi.org/10.1038/jid.2014.231 Raposo, G., & Marks, M. S. (2002). The dark side of lysosome‐related organelles: Specialization of the endocytic pathway for melanosome biogenesis. Traffic, 3(4), 237–248. Saleem, M. D. (2019). Biology of human melanocyte development, Piebaldism, and Waardenburg syndrome. Pediatric Dermatology, 36(1), 72–84. https://doi.org/10.1111/pde.13713 Sturm, R. A., & Frudakis, T. N. (2004). Eye colour: Portals into pigmentation genes and ancestry. Trends in Genetics, 20(8), 327–332. https://doi.org/10.1016/j.tig.2004.06.010 Sturm, R. A., & Larsson, M. (2009). Genetics of human iris colour and patterns. Pigment Cell & Melanoma Research, 22(5), 544–562. https:// doi.org/10.1111/j.1755-148X.2009.00606.x Sulem, P., Gudbjartsson, D. F., Stacey, S. N., Helgason, A., Rafnar, T., Magnusson, K. P., … Stefansson, K. (2007). Genetic determinants of hair, eye and skin pigmentation in Europeans. Nature Genetics, 39(12), 1443–1452. https://doi.org/10.1038/ng.2007.13 Sun, L., Hu, L., Zhang, P., Li, H., Sun, J., Wang, H., … Hu, J. (2018). Silencing of PMEL attenuates melanization via activating lysosomes and degradation of tyrosinase by lysosomes. Biochemical and Biophysical Research Communications, 503(4), 2536–2542. https://doi.org/10. 1016/j.bbrc.2018.07.012 Vaish, U., Kumar, A. A., Varshney, S., Ghosh, S., Sengupta, S., Sood, C., … Rani, R. (2019). Micro RNAs upregulated in Vitiligo skin play an important role in its aetiopathogenesis by altering TRP1 expression and keratinocyte‐melanocytes cross‐talk. Scientific Reports, 9(1), 10079. https://doi.org/10.1038/s41598-019-46529-6 Visser, M., Kayser, M., Grosveld, F., & Palstra, R. J. (2014). Genetic variation in regulatory DNA elements: The case of OCA2 transcriptional regulation. Pigment Cell & Melanoma Research, 27(2), 169–177. https://doi.org/10.1111/pcmr.12210 Wang, P., Li, Y., Hong, W., Zhen, J., Ren, J., Li, Z., & Xu, A. (2012). The changes of microRNA expression profiles and tyrosinase related proteins in MITF knocked down melanocytes. Molecular BioSystems, 8(11), 2924–2931. https://doi.org/10.1039/c2mb25228g Wei, A. H., Zang, D. J., Zhang, Z., Liu, X. Z., He, X., Yang, L., … Li, W. (2013). Exome sequencing identifies SLC24A5 as a candidate gene for nonsyndromic oculocutaneous albinism. Journal of Investigative Dermatology, 133(7), 1834–1840. https://doi.org/10.1038/jid.2013.49 Wielgus, A. R., & Sarna, T. (2005). Melanin in human irides of different color and age of donors. Pigment Cell Research, 18(6), 454–464. https://doi.org/10.1111/j.1600-0749.2005.00268.x Wolf Horrell, E. M., Boulanger, M. C., & D'Orazio, J. A., (2016). Melanocortin 1 receptor: Structure, function, and regulation. Frontiers in Genetics, 7. https://doi.org/10.3389/fgene.2016.00095 Zanna, P. T., Sanchez‐Laorden, B. L., Perez‐Oliva, A. B., Turpin, M. C., Herraiz, C., Jimenez‐Cervantes, C., & Garcia‐Borron, J. C. (2008). Mechanism of dimerization of the human melanocortin 1 receptor. Biochemical and Biophysical Research Communications, 368(2), 211–216. https://doi.org/10.1016/j.bbrc.2008.01.060 Zeigler‐Johnson, C., Panossian, S., Gueye, S. M., Jalloh, M., Ofori‐Adjei, D., & Kanetsky, P. A. (2004). Population differences in the frequency of the agouti signaling protein g.8818a>G polymorphism. Pigment Cell Research, 17(2), 185–187. https://doi.org/10.1111/j.1600-0749.2004. 00134.x
Results: In this study, has been assessed the number of genes found in various articles related to eye coloration. The expression of each of the genes examined in this study plays a role in the development of eye color. It affects the amount, size, pH, or pathways that influence melanin synthesis. One of the features of the genes involved in pigmentation is the high number of SNPs that affect specific SNP populations. In some countries, these SNPs are also used in forensic cases to diagnose people
Conclusion: Studying pigmentation in human is very important because the genes involved in pigmentation cause various diseases. This study further discusses eye color. We have about 80 different eye colors around the world, all of which are caused by the levels of eumelanin and pheomelanin. Changes in the amount of eumelanin and pheomelanin are influenced by genes that affect the biochemical pathway, signaling, or cellular and molecular structure issues of the melanogenic mechanism. In this study, has been assessed the number of genes found in various articles related to eye coloration. The expression of each of the genes examined in this study plays a role in the development of eye color. It affects the amount, size, pH, or pathways that influence melanin synthesis. One of the features of the genes involved in pigmentation is the high number of SNPs that affect specific SNP populations. In some countries, these SNPs are also used in forensic cases to diagnose people. Some genes such as HERC2 or CYPs are not pigmentation genes just because of their effect on eye color through the SNP in these genes. miR also has a significant impact on pigmentation through the expression of genes involved in the production of melanin. miR can increase or decrease the amount of melanin, which changes the amount of melanin to alter the balance of eumelanin and pheomelanin and produce different eye colors. The purpose of this study is to provide complete information on eye color determination.
Keywords: eumelanin, iris color, melanin pathway, pheomelanin, pigmentation gene