Human Molecular Genetics, 2000, Vol. 9, No. 5 713-723
© 2000 Oxford University Press
Allele diversity and germline mutation at the insulin minisatellite
Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, UK
Previous analysis of germline mutation at highly unstable GC-rich minisatellites with continuous allele size distributions revealed similar meiotic recombinational mechanisms operating at all loci investigated. The insulin minisatellite has been studied intensively due to its associations with diabetes, polycystic ovary syndrome, obesity and birth size. Its bimodal allele size distribution in Caucasians suggests a much lower mutation rate and possible differences in the mutation process compared with highly unstable minisatellites. Mutation at the insulin minisatellite therefore was studied both indirectly from allele diversity surveys and directly by recovering de novo mutants from sperm DNA. Structural analysis of variant repeat distributions in 876 alleles identified 189 different alleles, almost all of which could be assigned to one of three very distinct lineages. Variation within a lineage was minor and due mainly to the gain or loss of one or a few repeat units. These events most probably arise by mitotic replication slippage at a frequency of perhaps 10–3 per gamete. Sperm DNA analysis revealed a second class of mutation occurring at a frequency of ~2 x 10–5 that involved highly complex intra- and inter-allelic rearrangements very similar to those seen at unstable minisatellites. These complex rearrangements were not seen in somatic DNA and are probably meiotic in origin. Minisatellite homozygosity did not reduce the frequency of these mutants in sperm. The insulin minisatellite therefore appears to evolve by two distinct processes: one involving slippage-like events and the second resulting in complex recombinational turnover of allele structure.
+ To whom correspondence should be addressed. Tel: +44 116 252 3435; Fax: +44 116 252 3378; Email: ajj@le.ac.uk
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Mead, T. E. F. Webb, T. A. Campbell, J. Beck, J. M. Linehan, S. Rutherfoord, S. Joiner, J. D. F. Wadsworth, J. Heckmann, S. Wroe, et al. Inherited prion disease with 5-OPRI: Phenotype modification by repeat length and codon 129 Neurology, August 21, 2007; 69(8): 730 - 738. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 A. J. Jeffreys and R. Neumann Factors influencing recombination frequency and distribution in a human meiotic crossover hotspot Hum. Mol. Genet., August 1, 2005; 14(15): 2277 - 2287. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D.H. Stead, M. E. Hurles, and A. J. Jeffreys Global Haplotype Diversity in the Human Insulin Gene Region Genome Res., September 1, 2003; 13(9): 2101 - 2111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Vafiadis, H. Ounissi-Benkalha, M. Palumbo, R. Grabs, M. Rousseau, C. G. Goodyer, and C. Polychronakos Class III Alleles of the Variable Number of Tandem Repeat Insulin Polymorphism Associated with Silencing of Thymic Insulin Predispose to Type 1 Diabetes J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3705 - 3710. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D.H. Stead, J. Buard, J. A. Todd, and A. J. Jeffreys Influence of allele lineage on the role of the insulin minisatellite in susceptibility to type 1 diabetes Hum. Mol. Genet., December 1, 2000; 9(20): 2929 - 2935. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G.M. v. Overveld, R. J.F.L. Lemmers, G. Deidda, L. Sandkuijl, G. W. Padberg, R. R. Frants, and S. M. van der Maarel Interchromosomal repeat array interactions between chromosomes 4 and 10: a model for subtelomeric plasticity Hum. Mol. Genet., November 1, 2000; 9(19): 2879 - 2884. [Abstract] [Full Text] [PDF]
|
|