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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
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Original Investigation
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
Hans Eiberg1  , Jesper Troelsen1, Mette Nielsen1, Annemette Mikkelsen1, Jonas Mengel-From2, Klaus W. Kjaer1, 3 and Lars Hansen1, 3
| (1) |
Department of Cellular and Molecular Medicine, Section IV Build. 24.4, Panum Institute, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark |
| (2) |
Institute of Forensic Genetics, University of Copenhagen, Fredrik V’s vej 11, 2100 Copenhagen, Denmark |
| (3) |
The Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark |
Received: 31 October 2007 Accepted: 18 December 2007 Published online: 3 January 2008
Abstract 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.
Electronic supplementary material The online version of this article (doi:10.1007/s00439-007-0460-x) contains supplementary material, which is available to authorized users.
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