Variant repeat mapping at the insulin minisatellite

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: