Genome Res. 13:2101-2111, 2003
©2003 by Cold Spring Harbor Laboratory Press; ISSN 1088-9051/03 $5.00
Letter
Global Haplotype Diversity in the Human Insulin Gene Region
John D.H. Stead1,3,4,
Matthew E. Hurles2 and
Alec J. Jeffreys1
1 Department of Genetics, University of Leicester, Leicester LE1 7RH,
UK
2 McDonald Institute for Archaeological Research, University of Cambridge,
Cambridge CB2 3ER, UK
The insulin minisatellite (INS VNTR) has been intensively analyzed
due to its associations with diseases including diabetes. We have previously
used patterns of variant repeat distribution in the minisatellite to
demonstrate that genetic diversity is unusually great in Africans compared to
non-Africans. Here we analyzed variation at 56 single nucleotide polymorphisms
(SNPs) flanking the minisatellite in individuals from six populations, and we
show that over 40% of the total genetic variance near the minisatellite is due
to differences between Africans and non-Africans, far higher than seen in most
genomic regions and consistent with differential selection acting on the
insulin gene region, most likely in the non-African ancestral population.
Linkage disequilibrium was lower in African populations, with evidence of
clustering of historical recombination events. Analysis of haplotypes from the
relatively nonrecombining region around the minisatellite revealed a
star-shaped phylogeny with lineages radiating from an ancestral
African-specific haplotype. These haplotypes confirmed that minisatellite
lineages defined by variant repeat distributions are monophyletic in origin.
These analyses provide a framework for a cladistic approach to future disease
association studies of the insulin region within both African and non-African
populations, and they identify SNPs which can be rapidly analyzed as surrogate
markers for minisatellite lineage.
[Supplemental material is available online at www.genome.org and at the
authors' Web site; http://www. leicester.ac.uk/genetics/ajj/insulin. The
sequence data from this study have been submitted to GenBank under accession
nos.: human AY138589, AY138590; chimpanzee AY137496, AY137497; gorilla
AY137498, AY137499, AY137500; orangutan AY137501, AY137502, AY137503. The SNP
data from this study have been submitted to dbSNP. The following individuals
kindly provided reagents, samples, or unpublished information as indicated in
the paper: J.Clegg and Y.Dubrova.]
Article and publication are at
http://www.genome.org/cgi/doi/10.1101/gr.948003.
3 Corresponding author.
E-MAIL
jdstead{at}umich.edu;
FAX (734) 647-4130.
4 Present address: Mental Health Research Institute, University of
Michigan, Ann Arbor, MI 48109, USA.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
T. Awata, E. Kawasaki, H. Ikegami, T. Kobayashi, T. Maruyama, K. Nakanishi, A. Shimada, H. Iizuka, S. Kurihara, M. Osaki, et al.
Insulin Gene/IDDM2 Locus in Japanese Type 1 Diabetes: Contribution of Class I Alleles and Influence of Class I Subdivision in Susceptibility to Type 1 Diabetes
J. Clin. Endocrinol. Metab.,
May 1, 2007;
92(5):
1791 - 1795.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Marchand and C. Polychronakos
Evaluation of Polymorphic Splicing in the Mechanism of the Association of the Insulin Gene With Diabetes
Diabetes,
March 1, 2007;
56(3):
709 - 713.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. N. M. Day, S. Rodriguez, J. Kralovicova, P. J. Wood, I. Vorechovsky, and T. R. Gaunt
Questioning INS VNTR role in obesity and diabetes: subclasses tag IGF2-INS-TH haplotypes; and -23HphI as a STEP (splicing and translational efficiency polymorphism)
Physiol Genomics,
December 13, 2006;
28(1):
113 - 113.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Le Fur, C. Auffray, F. Letourneur, C. Cruaud, C. Le Stunff, and P. Bougneres
Heterogeneity of class I INS VNTR allele association with insulin secretion in obese children
Physiol Genomics,
May 16, 2006;
25(3):
480 - 484.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Kralovicova, T. R. Gaunt, S. Rodriguez, P. J. Wood, I. N.M. Day, and I. Vorechovsky
Variants in the Human Insulin Gene That Affect Pre-mRNA Splicing: Is -23HphI a Functional Single Nucleotide Polymorphism at IDDM2?
Diabetes,
January 1, 2006;
55(1):
260 - 264.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. A. Rana, N. D. Ebenezer, A. R. Webster, A. R. Linares, D. B. Whitehouse, S. Povey, and A. J. Hardcastle
Recombination hotspots and block structure of linkage disequilibrium in the human genome exemplified by detailed analysis of PGM1 on 1p31
Hum. Mol. Genet.,
December 15, 2004;
13(24):
3089 - 3102.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. J. Barratt, F. Payne, C. E. Lowe, R. Hermann, B. C. Healy, D. Harold, P. Concannon, N. Gharani, M. I. McCarthy, M. G. Olavesen, et al.
Remapping the Insulin Gene/IDDM2 Locus in Type 1 Diabetes
Diabetes,
July 1, 2004;
53(7):
1884 - 1889.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Le Lay, T.-a. Matsuoka, E. Henderson, and R. Stein
Identification of a Novel PDX-1 Binding Site in the Human Insulin Gene Enhancer
J. Biol. Chem.,
May 21, 2004;
279(21):
22228 - 22235.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Rodriguez, T. R. Gaunt, S. D. O'Dell, X.-h. Chen, D. Gu, E. Hawe, G. J. Miller, S. E. Humphries, and I. N.M. Day
Haplotypic analyses of the IGF2-INS-TH gene cluster in relation to cardiovascular risk traits
Hum. Mol. Genet.,
April 1, 2004;
13(7):
715 - 725.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
