Association of Polymorphic Sites in the OCA2 Gene with Eye Colour Using the Tree Scanning Method

Abstract

SummaryA number of genes are considered to affect normal variation in human pigmentation. Recent studies have indicated that OCA2 is the crucial gene involved in the high variation of iris colour present among populations of European descent. In this study, eleven polymorphisms of the OCA2 gene were examined in search of their association with different pigment traits. The evolutionary tree scanning method indicated that the strongest phenotypic eye colour variation is associated with the branch defined by nonsynonymous change rs1800407, which refers to amino acid causing change Arg419Gln located in exon 13. Single SNP analysis indicated that allele 419Gln is associated with green/hazel iris colour (p < 0.001). According to tree scanning analysis, the proportion of eye colour variation explained by this nucleotide position is merely 4%. Thus, additional variation present in the OCA2 gene and perhaps some other pigment related genes must be taken into account in order to explain the high phenotypic variation in iris colour.

Gene–gene interactions contribute to eye colour variation in humans

“…The OCA2 gene encodes a protein that is an integral part of the melanosomal membrane and is responsible for regulation of pH inside the melanosome, [55][56][57] which, in consequence, has an influence on the activity of the enzyme tyrosinase, which has a crucial role in the synthesis of the pigment melanin. The important role of OCA2 in eye colour determination was confirmed in many studies, 11,13,28,31,[58][59][60][61] and further investigations revealed that regulation of OCA2 expression through the neighbouring HERC2 gene might have a crucial role. 16,20 A functional effect was assigned to the rs12913832 position located in a conservative segment of the intron 86 of the HERC2 gene, which contains transcription factor-binding sites.…”

“…Further studies confirmed the highest significance of rs12913832 in eye colour determination and also showed that in spite of strong linkage between HERC2 and OCA2, one position in the OCA2 gene; that is, rs1800407, remains independently associated with eye colour and has a modulatory role for rs12913832 in HERC2. 16,31 Our analyses showed that these two SNP positions were in strong LD and all the reconstructed haplotypes were found to be significantly associated with eye colour (Table 1). Moreover, both the SNPs were selected by ReliefF filtering in case of three from four eye colour models ( Table 1).…”

“…Except for rs3829241 and rs35264875-both in TPCN2, rs1015362 and rs4911414-both in ASIP and variation in MC1R, all the polymorphisms studied in this research have been reported to affect eye colour in humans. 13,14,16,18,19,25,28,31,32 As variables without a main effect can still be involved in significant interactions determining polygenic traits, we also considered (in our study) pigmentation-related polymorphisms that have not been associated with eye colour, but have been correlated with other pigmentation traits; that is, skin and hair colour. 18,19,21,54 Analysis conducted revealed three pairs of SNPs with significant interaction effects contributing to eye colour variation in the studied population.…”

“…The 24 (SNPs) located in 11 genes, which have been shown to be significantly associated with human pigmentation 10,13,14,16,18,19,[21][22][23][24][25][27][28][29][30][31][32] were genotyped in two multiplex minisequencing assays. The list of the studied polymorphisms is given in Supplementary Table 1.…”

Association of the SLC45A2 gene with physiological human hair colour variation

“…Many of their variants may cause serious pigmentation disorders, but at the same time other polymorphisms may be involved in physiological pigmentation variation. MC1R has been the subject of the most thorough studies, but initial results have also been replicated in various populations for such genes as ASIP, OCA2, and SLC45A2 (Rees 2004;Kanetsky et al 2002;Rebbeck et al 2002;Frudakis et al 2003;Bonilla et al 2005;Duffy et al 2007;Branicki et al 2008;Graf et al 2005;Fernandez et al 2008). The MC1R gene is one of the major pigmentation genes.…”