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Human Genetics

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$B!G(Bs 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


 Hans Eiberg
Email: he@imbg.ku.dk

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$B!l(B 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.