Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
18252222
TITLE
A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color.
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 R(2) = 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.
DATE PUBLISHED
2008 Feb
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2007/09/21
revised 2007/11/19
accepted 2007/11/19
aheadofprint 2008/01/24
pubmed 2008/02/07 09:00
medline 2008/03/18 09:00
entrez 2008/02/07 09:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Sturm RA Sturm Richard A RA Institute for Molecular Bioscience, University of Queensland, Brisbane QLD 4072, Australia.
Duffy DL Duffy David L DL
Zhao ZZ Zhao Zhen Zhen ZZ
Leite FP Leite Fabio P N FP
Stark MS Stark Mitchell S MS
Hayward NK Hayward Nicholas K NK
Martin NG Martin Nicholas G NG
Montgomery GW Montgomery Grant W GW
INVESTIGATORS
JOURNAL
VOLUME: 82
ISSUE: 2
TITLE: American journal of human genetics
ISOABBREVIATION: Am. J. Hum. Genet.
YEAR: 2008
MONTH: Feb
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1537-6605
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Am J Hum Genet
COUNTRY: United States
ISSNLINKING: 0002-9297
NLMUNIQUEID: 0370475
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
CA88363 NCI NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adolescent
Base Sequence
Chromosome Mapping
Conserved Sequence genetics
DNA-Binding Proteins metabolism
Eye Color genetics
Gene Expression Regulation genetics
Gene Frequency genetics
Genotype genetics
Guanine Nucleotide Exchange Factors metabolism
Humans metabolism
Introns genetics
Lod Score genetics
Membrane Transport Proteins metabolism
Molecular Sequence Data metabolism
Polymorphism, Single Nucleotide genetics
Sequence Alignment genetics
Sequence Analysis, DNA genetics
Transcription Factors metabolism
Twins metabolism
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 DNA-Binding Proteins
0 Guanine Nucleotide Exchange Factors
0 HERC2 protein, human
0 HLTF protein, human
0 Membrane Transport Proteins
0 OCA2 protein, human
0 Transcription Factors
OTHER ID's
OTHERID SOURCE
PMC2427173 NLM