The insulin minisatellite or variable number of tandem repeats locus (INS VNTR) (OMIM: 125852) has been associated with a range of phenotypes, including susceptibility to type 1 diabetes (OMIM: 222100), type 2 diabetes (OMIM: 125853), polycystic ovary syndrome (OMIM: 184700) and infant birth size.
We have been conducting a series of studies to determine levels of variation within and surrounding the insulin minisatellite, in addition to characterising the mechanisms responsible for de novo minisatellite mutation.
Minisatellites are regions of repetitive DNA with repeats units of typically 10-100 bp in length tandemly repeated 10-1000 times. The number of repeats and therefore the overall length of the minisatellite varies between alleles which often makes minisatellites highly variable within a population. In addition to length variation, not all repeat units are identical. Minor sequence variations between repeat units results in a range of variant repeat units throughout a minisatellite array. Characterisation of the distribution of variant repeat units produces highly informative maps of minisatellite structure which allow similarities and differences between alleles to be examined in far more detail simply analysing the lengths of alleles.
We have extensively analysed variant repeat distribution within alleles of the insulin minisatellite using the technique of minisatellite variant repeat mapping by PCR (MVR-PCR) (Jeffreys et al., 1991). Details of how this technique was applied specifically to the insulin minisatellite can be found in the Introduction to MVR-PCR at the insulin minisatellite.
Our initial studies of the insulin minisatellite focussed on two objectives.
The first was to characterise de novo mutation events detected both within the germline (sperm) and soma (blood). Over 150 mutation events were detected using the technique of size-enrichment small pool PCR (Jeffreys and Neumann, 1997) and their structures mapped by MVR-PCR (Stead and Jeffreys, 2000). Variant repeat maps of all mutant alleles are presented on our Mutation analysis page.
The second objective was to characterise variation at the insulin minisatellite within a population from the UK (Stead and Jeffreys, 2000) and examine the relationship between minisatellite allele structure and susceptibility to type 1 diabetes (Stead et al., 2000). In this study, we analysed 876 alleles from 219 affected sib-pair families. The structures of all alleles from this cohort can be viewed on our UK allele diversity page.
More recently, we have substantially extended these analyses by characterising diversity within the minisatellite in a range of populations throughout the world, in addition to examining the relationship between minisatellite structure and susceptibility to type 2 diabetes within a cohort from Southern India.
The full range of alleles analysed by MVR-PCR is as follows:
|Population Associated disease Number of alleles
UK T1D Type 1 diabetes 876
South India Type 2 diabetes 329
UK None 204
Kazakhstan None 80
Japan None 118
Ivory Coast None 156
Zimbabwe None 138
Kenya None 84
MVR codes of all alleles from all populations can be found on the following pages:
MVR codes of Class I alleles
MVR codes of Class III alleles
MVR codes of African-specific lineages
We have also been characterising variation within regions flanking the minisatellite. Within a 7.4 kb region surrounding the minisatellite we identified 56 polymorphisms (some of which were previously published elsewhere) and analysed these polymorphisms on 378 African chromosomes, plus 378 non-African chromosomes, all of which have also been characterised at the insulin minisatellite. Details of this study can be found on our Analysis of flanking polymorphisms pages.
These pages provide supplementary information for the following publications:
Global haplotype diversity in the human insulin gene region. Stead, J.D.H., Hurles, M.E. and Jeffreys, A.J. Genome Res. 13, 2101-11 (2003)
Structural analysis of insulin minisatellite alleles reveals unusually large differences in diversity between Africans and non-Africans. Stead, J.D.H. and Jeffreys, A.J. Am. J. Hum. Genet. 71, 1273-84 (2002)
Influence of allele lineage on the role of the insulin minisatellite in susceptibility to type 1 diabetes. Stead, J.D.H., Buard, J., Todd, J.A. and Jeffreys, A.J. Hum. Mol. Genet., 9, 2929-2935 (2000).
Allele diversity and germline mutation at the insulin minisatellite. Stead, J.D.H. and Jeffreys, A.J. Hum. Mol. Genet., 9, 713-723 (2000).If you refer to these data, please cite the relevant publication.