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Interactions Between HERC2, OCA2 and MC1R May Influence Human Pigmentation Phenotype
Open accessAbstract
Summary: Human pigmentation is a polygenic trait which may be shaped by different kinds of gene–gene interactions. Recent studies have revealed that interactive effects between HERC2 and OCA2 may be responsible for blue eye colour determination in humans. Here we performed a population association study, examining important polymorphisms within the HERC2 and OCA2 genes. Furthermore, pooling these results with genotyping data for MC1R, ASIP and SLC45A2 obtained for the same population sample we also analysed potential genetic interactions affecting variation in eye, hair and skin colour. Our results confirmed the association of HERC2 rs12913832 with eye colour and showed that this SNP is also significantly associated with skin and hair colouration. It is also concluded that OCA2 rs1800407 is independently associated with eye colour. Finally, using various approaches we were able to show that there is an interaction between MC1R and HERC2 in determination of skin and hair colour in the studied population sample.
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“However, although there is strong evidence that the derived HERC2 rs12913832 G allele is recessive (36), it is less clear whether the SLC45A2 and TYR derived alleles are codominant, recessive, or dominant (22, 35).”
From Direct evidence for positive selection of skin, hair, and eye pigmentation in Europeans during the last 5,000 y (2014) · cites this paper as [36]
In the citing paper
“The derived allele of another SNP at OCA2, rs1800407, has been associated with green/hazel eyes in Europeans (Branicki et al. 2009).”
From A global view of the OCA2-HERC2 region and pigmentation (2012) · cites this paper as Branicki et al. 2009
Citations
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MethodInfluentialEpistasis: what it means, what it doesn't mean, and statistical methods to detect it in humans
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“In statistical terms, epistasis can be described as a deviation from an additive model explaining a connection between various gene variants and a particular complex trait (Cordell, 2002; Moore, 2003).”
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“Other authors have also suggested epistatic effects affecting the human pigmentation phenotype (Pastorino et al., 2004; Sulem et al., 2007).”
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BackgroundGenome Organization, Function, and Imprinting in Prader-Willi and Angelman Syndromes
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“Although HERC2 is not a pigmentary gene, it has been linked to Prader-Willi and Angelman syndromes, which are very often associated with hypopigmentation (Nicholls & Knepper, 2001).”
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“Han et al. (2008) also reported that rs12913832 shows significant, independent association with hair colour and tanning ability.”
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Bennett, D. C., & Lamoreux, M. L. (2003) · Pigment Cell Research · doi:10.1034/j.1600-0749.2003.00067.x · Cited by 486 · cited 1×
“Pigmentation is presumed to be under the control of 120 genes (Bennett & Lamoreux, 2003), which may act at different stages of the complex process of melanin formation, transportation and packaging.”
BackgroundGenetics of hair and skin color
Rees, J. L. (2003) · Annual Review of Genetics · doi:10.1146/annurev.genet.37.110801.143233 · Cited by 485 · cited 3×
“Some non-synonymous mutations within MC1R, known as major function mutations (R) have been proved to decrease eumelanin production and thus lead to the typical phenotype of red hair colour and fair skin (Rees, 2003).”
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“Detailed analysis of this region revealed transcription factor binding sites, which supported the hypothesis that it may be involved in transcription regulation of the OCA2 gene (Sturm et al., 2008).”
BackgroundResultInfluentialTwo newly identified genetic determinants of pigmentation in Europeans
Sulem, P., Gudbjartsson, D. F., Stacey, S. N., Helgason, A., Rafnar, T., Jakobsdottir, M., Steinberg, S., Gudjonsson, S. A., Palsson, A., Thorleifsson, G., et al. (2008) · Nature Genetics · doi:10.1038/ng.160 · Cited by 368 · cited 1×
“Recent research conducted on human pigmentation has enabled the discovery of many new genes and gene variants involved in eye, skin and hair colouration (Sulem et al., 2007; Han et al., 2008; Kayser et al., 2008; Sturm et al., 2008; Sulem et al., 2008).”
BackgroundThe evolution of human skin and skin color
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“Since human pigmentation might have been affected during the course of human evolution by various selective pressures, it is also a subject of research conducted in evolutionary biology (Jablonski, 2004).”
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“Using mobility shift assay they were also able to show that two variants of rs12913832 reveal a different protein binding pattern and thus possibly differ in affinity for nuclear factors (Eiberg et al., 2008).”
BackgroundMethodResultInfluentialThe Genetics of Sun Sensitivity in Humans
Rees, J. L. (2004) · The American Journal of Human Genetics · doi:10.1086/425285 · Cited by 294 · cited 1×
“Pigmentation phenotype is, in conjunction with a high level of UV exposure, considered a significant contributor to melanoma and non-melanoma skin cancers and thus is widely studied in medical genetics (Rees, 2004).”
BackgroundKayser, M., Liu, F., Janssens, A. C. J. W., Rivadeneira, F., Lao, O., van Duijn, K., Vermeulen, M., Arp, P., Jhamai, M. M., van IJcken, W. F. J., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2007.10.003 · Cited by 260 · cited 7×
“…OCA2 26017833 1.00000 Duffy et al., 2007 0.0528 T C rs12913832 HERC2 26039213 0.88406 Sturm et al., 2008 0.2281 T C rs916977 HERC2 26186959 0.84149 Kayser et al., 2008 0.1482 a – formerly rs11855019; b – formerly rs6497268; MAF – minor allele frequency; HWE – Hardy-Weinberg equilibrium. for…”
BackgroundResultInfluentialComputational analysis of gene-gene interactions using multifactor dimensionality reduction
Moore, J. H. (2004) · Expert Review of Molecular Diagnostics · doi:10.1586/14737159.4.6.795 · Cited by 242 · cited 1×
“The models with the highest BA and CV consistency were considered the best for the purposes of this research (Hahn et al., 2003; Moore, 2004).”
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“freckle and mole number (Duffy et al., 2007), thus its involvement in pigmentation seems to be possible.”
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“populations of European origin (Graf et al., 2005; Fernandez et al., 2008; Han et al., 2008).”
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“The product of the OCA2 gene is thought to be involved in transportation of tyrosine – the crucial substrate in the process of melanogenesis (Lee et al., 1995).”
BackgroundDetection of Gene × Gene Interactions in Genome-Wide Association Studies of Human Population Data
Musani, S. K., Shriner, D., Liu, N., Feng, R., Coffey, C. S., Yi, N., Tiwari, H. K., & Allison, D. B. (2007) · Human Heredity · doi:10.1159/000099179 · Cited by 168
Sequences associated with human iris pigmentation
Frudakis, T., Thomas, M., Gaskin, Z., Venkateswarlu, K., Chandra, K. S., Ginjupalli, S., Gunturi, S., Natrajan, S., Ponnuswamy, V. K., & Ponnuswamy, K. N. (2003) · Genetics · doi:10.1093/genetics/165.4.2071 · Cited by 153
A Genome Scan for Eye Color in 502 Twin Families: Most Variation is due to a QTL on Chromosome 15q
Zhu, G., Evans, D. M., Duffy, D. L., Montgomery, G. W., Medland, S. E., Gillespie, N. A., Ewen, K. R., Jewell, M., Liew, Y., Hayward, N. K., et al. (2004) · Twin Research · doi:10.1375/twin.7.2.197 · Cited by 119 · cited 1×
“2-12) was previously considered a major eye colour gene (Frudakis et al., 2003; Zhu et al., 2004).”
BackgroundSLC45A2: a novel malignant melanoma-associated gene
Fernández, L. P., Milne, R. L., Pita, G., Avilés, J. A., Lázaro, P., Benitez, J. J., & Ribas, G. (2008) · Human Mutation · doi:10.1002/humu.20804 · Cited by 115 · cited 2×
“populations of European origin (Graf et al., 2005; Fernandez et al., 2008; Han et al., 2008).”
BackgroundP gene as an inherited biomarker of human eye color.
Rebbeck, T. R., Kanetsky, P. A., Walker, A. H., Holmes, R., Halpern, A. C., Schuchter, L. M., Elder, D. E., & Guerry, D. (2002) · PubMed · Cited by 96
Association of the SLC45A2 gene with physiological human hair colour variation
Branicki, W., Brudnik, U., Draus‐Barini, J., Kupiec, T., & Wojas‐Pelc, A. (2008) · Journal of Human Genetics · doi:10.1007/s10038-008-0338-3 · Cited by 86 · cited 15×
“Gene–gene interactions between five genes, namely HERC2 (genotypic data from this study), OCA2 (this study and Branicki et al., 2008a), MC1R, ASIP (extended data from Brudnik et al., 2008), and SLC45A2 (Branicki et al., 2008b) were tested in this population sample using both the multifactor…”
BackgroundMethodResultInfluentialSelf-citationAkey, J. M., Wang, H., Xiong, M., Wu, H., Liu, W., Shriver, M. D., & Jin, L. (2001) · Human Genetics · doi:10.1007/s004390100524 · Cited by 67 · cited 2×
“Akey et al. (2001) reported an interactive effect of MC1R and OCA2 influencing skin features.”
BackgroundGenotype versus phenotype: Human pigmentation
Tully, G. (2007) · Forensic Science International Genetics · doi:10.1016/j.fsigen.2007.01.005 · Cited by 60 · cited 1×
“Moreover, eye, hair and skin colour prediction has been proposed to have potential use in forensic genetics (Tully, 2007).”
BackgroundP gene mutations associated with oculocutaneous albinism type II (OCA2)
Oetting, W. S., Garrett, S. S., Brott, M. J., & King, R. A. (2005) · Human Mutation · doi:10.1002/humu.9318 · Cited by 59 · cited 5×
“There are significant intrapopulation differences in human pigmentation among individuals of European ancestry.”
BackgroundInfluentialStructure of the Highly Conserved HERC2 Gene and of Multiple Partially Duplicated Paralogs in HumanPreprint
Ji, Y., Rebert, N. A., Joslin, J. M., Higgins, M. J., Schultz, R. A., & Nicholls, R. D. (2000) · Genome Research · doi:10.1101/gr.10.3.319 · Cited by 57 · cited 1×
“Due to a significant sequence homology across mammalian and invertebrate species, HERC2 is considered a highly conserved gene (Ji et al., 2000).”
BackgroundMolecular Photofitting: Predicting Ancestry and Phenotype Using DNA
Frudakis, T. N., & Shriver, M. D. (2007) · Cited by 55
Novel MC1R variants in Ligurian melanoma patients and controls
Pastorino, L., Cusano, R., Bruno, W., Lantieri, F., Origone, P., Barile, M., Gliori, S., Shepherd, G. A., Sturm, R. A., & Bianchi‐Scarrà, G. (2004) · Human Mutation · doi:10.1002/humu.9253 · Cited by 50 · cited 2×
“Other authors have also suggested epistatic effects affecting the human pigmentation phenotype (Pastorino et al., 2004; Sulem et al., 2007).”
BackgroundWalkowicz, M. J., Ji, Y., Ren, X., Horsthemke, B., Russell, L. B., Johnson, D. K., Rinchik, E. M., Nicholls, R. D., & Stubbs, L. J. (1999) · Mammalian Genome · doi:10.1007/s003359901106 · Cited by 35 · cited 1×
“Interactive effects between HERC2 and OCA2 were postulated years ago based on results obtained from studies on the mouse species model (Walkowicz et al., 1999).”
BackgroundAssociation of Polymorphic Sites in the OCA2 Gene with Eye Colour Using the Tree Scanning Method
Branicki, W., Brudnik, U., Kupiec, T., Wolañska‐Nowak, P., Szczerbińska, A., & Wojas‐Pelc, A. (2007) · Annals of Human Genetics · doi:10.1111/j.1469-1809.2007.00407.x · Cited by 34 · cited 15×
“Gene–gene interactions between five genes, namely HERC2 (genotypic data from this study), OCA2 (this study and Branicki et al., 2008a), MC1R, ASIP (extended data from Brudnik et al., 2008), and SLC45A2 (Branicki et al., 2008b) were tested in this population sample using both the multifactor…”
BackgroundMethodResultInfluentialSelf-citationBrudnik, U., Branicki, W., Wojas‐Pelc, A., & Kanas, P. (2008) · Experimental Dermatology · doi:10.1111/j.1600-0625.2008.00760.x · Cited by 33 · cited 1×
“…between five genes, namely HERC2 (genotypic data from this study), OCA2 (this study and Branicki et al., 2008a), MC1R, ASIP (extended data from Brudnik et al., 2008), and SLC45A2 (Branicki et al., 2008b) were tested in this population sample using both the multifactor dimensionality…”
MethodSelf-citationApplication of multi‐locus analytical methods to identify interacting loci in case‐control studies
Vermeulen, S. H. H. M., den Heijer, M., Sham, P. C., & Knight, J. (2007) · Annals of Human Genetics · doi:10.1111/j.1469-1809.2007.00360.x · Cited by 18 · cited 2×
“The MDR method already has an important place in the field of research on epistasis (e.g. Musani et al., 2007; Vermeulen et al., 2007).”
Method
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Kayser, M. (2015) · Forensic Science International Genetics · doi:10.1016/j.fsigen.2015.02.003 · Cited by 475
“Such interaction between SNPs from the same and/or different pigmentation genes has been found already, particularly for eye color [32,33,43,44].”
BackgroundVisser, M., Kayser, M., & Palstra, R.-J. T. S. (2012) · Genome Research · doi:10.1101/gr.128652.111 · Cited by 278
“The SNP rs12913832 is highly associated with human eye (Eiberg et al. 2008; Sturm et al. 2008; Liu et al. 2009, 2010), hair (Han et al. 2008; Branicki et al. 2009, 2011), and skin (Branicki et al. 2009; Valenzuela et al. 2010; Spichenok et al. 2011) color variation.”
BackgroundWilde, S., Timpson, A., Kirsanow, K., Kaiser, E., Kayser, M., Unterländer, M., Hollfelder, N., Potekhina, I. D., Schier, W., Thomas, M. G., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1316513111 · Cited by 257
“However, although there is strong evidence that the derived HERC2 rs12913832 G allele is recessive (36), it is less clear whether the SLC45A2 and TYR derived alleles are codominant, recessive, or dominant (22, 35).”
BackgroundInfluentialGenetics of human iris colour and patterns
Sturm, R. A., & Larsson, M. (2009) · Pigment Cell & Melanoma Research · doi:10.1111/j.1755-148x.2009.00606.x · Cited by 239
Metadata
- Authors
- Branicki, W., Brudnik, U., & Wojas‐Pelc, A.
- Affiliations
- Jagiellonian University (PL)
- Corresponding author
- Branicki, Wojciech
- Venue
- Annals of Human Genetics
- Publisher
- Wiley
- Published
- 2009-02-17
- Volume
- 73
- Issue
- 2
- Pages
- 160-170
- ISSN
- 0003-4800 (ISSN-L)
- 1469-1809
- OpenAlex
- W2037117670
- Cited by
- 108
- References
- 40
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 2 · 2020: 5 · 2019: 4 · 2018: 7 · 2017: 5 · 2016: 4 · 2015: 8 · 2014: 10 · 2013: 11 · 2012: 9
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- green
- ruj.uj.edu.pl
- Licence
- Locations
- Annals of Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- Jagiellonian University Repository (Jagiellonian University) (submittedVersion, cc-by-nc-nd)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Keywords
- human pigmentation, HERC2, OCA2, MC1R, gene-gene interaction, epistasis, eye color, skin colour, hair color, ASIP, SLC45A2, polygenic traits
- MeSH terms
- Antigens, Neoplasm, Epistasis, Genetic, Eye Color, Female, Hair Color, Humans, Male, Poland, Skin Pigmentation, Logistic Models, Polymorphism, Single Nucleotide, Guanine Nucleotide Exchange Factors, Membrane Transport Proteins, Receptor, Melanocortin, Type 1, Ubiquitin-Protein Ligases, Agouti Signaling Protein
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