A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye colour

Sturm, Richard A., Duffy, David L., Zhao, Zhen Zhen, Leite, Fabio P.N., Stark, Mitchell S., Hayward, Nicholas K., Martin, Nicholas G. and Montgomery, Grant W. (2008) A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye colour. The American Journal of Human Genetics, 82 2: 424-431. doi:10.1016/j.ajhg.2007.11.005


Author Sturm, Richard A.
Duffy, David L.
Zhao, Zhen Zhen
Leite, Fabio P.N.
Stark, Mitchell S.
Hayward, Nicholas K.
Martin, Nicholas G.
Montgomery, Grant W.
Title A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye colour
Journal name The American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
1537-6605
Publication date 2008-02-08
Year available 2008
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2007.11.005
Volume 82
Issue 2
Start page 424
End page 431
Total pages 8
Editor C. C. Morton
Place of publication Cambridge, MA, United States
Publisher Cell Press
Collection year 2009
Language eng
Subject 060405 Gene Expression (incl. Microarray and other genome-wide approaches)
060401 Anthropological Genetics
920107 Hearing, Vision, Speech and Their Disorders
920117 Skin and Related Disorders
970106 Expanding Knowledge in the Biological Sciences
C1
Abstract We have previously demonstrated that haplotypes of three single nucleotide polymorphisms (SNPs) within the first intron of the OCA2 gene are extremely strongly associated with variation in human eye color. In the present work, we describe additional fine association mapping of eye color SNPs in the intergenic region upstream of OCA2 and within the neighboring HERC2 (hect domain and RLD2) gene. We screened an additional 92 SNPs in 300–3000 European individuals and found that a single SNP in intron 86 of HERC2, rs12913832, predicted eye color significantly better (ordinal logistic regression R2 = 0.68, association LOD = 444) than our previous best OCA2 haplotype. Comparison of sequence alignments of multiple species showed that this SNP lies in the center of a short highly conserved sequence and that the blue-eye-associated allele (frequency 78%) breaks up this conserved sequence, part of which forms a consensus binding site for the helicase-like transcription factor (HLTF). We were also able to demonstrate the OCA2 R419Q, rs1800407, coding SNP acts as a penetrance modifier of this new HERC2 SNP for eye color, and somewhat independently, of melanoma risk. We conclude that the conserved region around rs12913832 represents a regulatory region controlling constitutive expression of OCA2 and that the C allele at rs12913832 leads to decreased expression of OCA2, particularly within iris melanocytes, which we postulate to be the ultimate cause of blue eye color.
Q-Index Code C1
Q-Index Status Confirmed Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
School of Medicine Publications
School of Psychology Publications
 
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Created: Mon, 09 Mar 2009, 15:33:17 EST by Cody Mudgway on behalf of Institute for Molecular Bioscience