Genetic Epidemiology, Translational Neurogenomics, Psychiatric 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.
QIMR Home Page
GenEpi Home Page
About GenEpi
Publications
Contacts
Research
Staff Index
Collaborators
Software Tools
Computing Resources
Studies
Search
GenEpi Intranet
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
Cites Trends Genet. 2006 Sep;22(9):464-8 16857289
Cites J Biol Chem. 2006 Jul 21;281(29):20233-41 16648630
Cites Mol Hum Reprod. 2006 Nov;12(11):671-6 16973828
Cites Genome Res. 2006 Dec;16(12):1480-92 17038566
Cites Genome Res. 2006 Dec;16(12):1596-604 17053093
Cites Am J Hum Genet. 2007 Feb;80(2):241-52 17236130
Cites Genet Epidemiol. 2007 Jul;31(5):365-75 17326099
Cites Hum Genet. 2007 Nov;122(3-4):311-26 17619204
Cites PLoS Biol. 2007 Sep 4;5(10):e254 17803354
Cites Nat Genet. 2007 Dec;39(12):1443-52 17952075
Cites Mamm Genome. 1999 Sep;10(9):870-8 10441737
Cites Hum Mutat. 2000;15(2):166-72 10649493
Cites Hum Mutat. 1998;12(6):434 10671067
Cites Pigment Cell Res. 2001 Apr;14(2):86-93 11310796
Cites Am J Hum Genet. 2001 Oct;69(4):765-73 11500805
Cites Blood. 2002 Jan 1;99(1):348-56 11756191
Cites Int J Cancer. 2002 Jan 1;97(1):90-5 11774248
Cites Genome Res. 2002 Jun;12(6):996-1006 12045153
Cites Cancer Epidemiol Biomarkers Prev. 2002 Aug;11(8):782-4 12163334
Cites Mol Endocrinol. 2002 Sep;16(9):2101-12 12198246
Cites Am J Med Genet A. 2003 May 1;118A(4):402-3 12687678
Cites Genetics. 2003 Dec;165(4):2071-83 14704187
Cites Hum Mol Genet. 2004 Feb 15;13(4):447-61 14709592
Cites Genome Res. 2004 Apr;14(4):708-15 15060014
Cites Twin Res. 2004 Apr;7(2):197-210 15169604
Cites Trends Genet. 2004 Aug;20(8):327-32 15262401
Cites Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6968-72 1495987
Cites Science. 1992 Aug 21;257(5073):1121-4 1509264
Cites Am J Hum Genet. 1992 Oct;51(4):879-84 1415228
Cites Nature. 1993 Jan 7;361(6407):72-6 8421497
Cites J Biol Chem. 1995 Mar 3;270(9):4575-87 7876228
Cites Genomics. 1995 Mar 20;26(2):354-63 7601462
Cites Genet Epidemiol. 1995;12(2):109-27 7607413
Cites Genetics. 1995 Dec;141(4):1547-62 8601493
Cites Melanoma Res. 1996 Apr;6(2):155-65 8791274
Cites Eur J Hum Genet. 1996;4(4):237-41 8875191
Cites Dev Biol. 1997 Mar 15;183(2):166-82 9126292
Cites Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9436-41 9689098
Cites Mol Cell Biol. 1998 Dec;18(12):6930-8 9819381
Cites J Natl Cancer Inst. 1999 Mar 3;91(5):446-52 10070944
Cites J Biol Chem. 1999 Jul 9;274(28):19573-80 10391891
Cites Am J Hum Genet. 1999 Aug;65(2):483-92 10417291
Cites Bioinformatics. 2005 Jan 15;21(2):263-5 15297300
Cites Bioinformatics. 2005 Jul 1;21(13):2933-42 15860560
Cites Front Biosci. 2006;11:733-42 16146765
Cites Eur J Hum Genet. 2005 Aug;13(8):913-20 15889046
Cites Nature. 2005 Oct 27;437(7063):1299-320 16255080
Cites PLoS Biol. 2006 Mar;4(3):e72 16494531
Cites Behav Genet. 2006 Jan;36(1):12-7 16341609
Cites Genome Res. 2006 Jul;16(7):855-63 16769978
Cites Trends Mol Med. 2006 Sep;12(9):406-14 16899407
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
Designed by: GenEpi IT
Maintained by: GenEpi IT
Feedback: webmaster
Copyright © 2007 QIMR
For more information Contact Us
epiit@qimr.edu.au
Last Modified: Oct 15 2007