Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression

• Published in: Human genetics 2008-03, Vol.123 (2), p.177-187
• Main Authors: Eiberg, Hans, Troelsen, Jesper, Nielsen, Mette, Mikkelsen, Annemette, Mengel-From, Jonas, Kjaer, Klaus W., Hansen, Lars
• Format: Article
• Language: English
• Subjects: Adult; Albinism; Alleles; Analysis; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cells, Cultured; Chromosomes, Human, Pair 15 - genetics; Classical genetics, quantitative genetics, hybrids; Denmark; Eye Color - genetics; Female; Founder Effect; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - genetics; Gene Function; Genes; Genetic aspects; Genetic Linkage; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Genotype; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Hair Color - genetics; Haplotypes; Haplotypes - genetics; Human; Human Genetics; Humans; Lod Score; Luciferases - metabolism; Male; Membrane Transport Proteins - metabolism; Metabolic Diseases; Molecular Medicine; Mutation; Mutation - genetics; Original Investigation; Pedigree; Polymorphism, Single Nucleotide - genetics; Regulatory Sequences, Nucleic Acid - genetics; Surveys and Questionnaires
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-007-0460-x

The human eye color is a quantitative trait displaying multifactorial inheritance. Several studies have shown that the OCA2 locus is the major contributor to the human eye color variation. By linkage analysis of a large Danish family, we finemapped the blue eye color locus to a 166 Kbp region within the HERC2 gene. By association analyses, we identified two SNPs within this region that were perfectly associated with the blue and brown eye colors: rs12913832 and rs1129038. Of these, rs12913832 is located 21.152 bp upstream from the OCA2 promoter in a highly conserved sequence in intron 86 of HERC2 . The brown eye color allele of rs12913832 is highly conserved throughout a number of species. As shown by a Luciferase assays in cell cultures, the element significantly reduces the activity of the OCA2 promoter and electrophoretic mobility shift assays demonstrate that the two alleles bind different subsets of nuclear extracts. One single haplotype, represented by six polymorphic SNPs covering half of the 3′ end of the HERC2 gene, was found in 155 blue-eyed individuals from Denmark, and in 5 and 2 blue-eyed individuals from Turkey and Jordan, respectively. Hence, our data suggest a common founder mutation in an OCA2 inhibiting regulatory element as the cause of blue eye color in humans. In addition, an LOD score of Z  = 4.21 between hair color and D14S72 was obtained in the large family, indicating that RABGGTA is a candidate gene for hair color.