LINKAGE DISEQUILIBRIUM IN THE INSULIN GENE REGION - SIZE VARIATION ATTHE 5' FLANKING POLYMORPHISM AND BIMODALITY AMONG CLASS-I ALLELES

The 5' flanking polymorphism (5'FP), a hypervariable region at the 5' end of the insulin gene, has ''class 1'' alleles (650-900 bp long) tha t are in positive linkage disequilibrium with insulin-dependent diabet es mellitus (IDDM). We report that precise sizing of the 5'FP yields a bimodal frequency distribution of class 1 allele lengths. Class 1 all eles belonging to the lower component (650-750 bp) of the bimodal dist ribution were somewhat more highly associated with IDDM than were alle les from the upper component (760-900 bp), but the difference was not statistically significant. We also examined 5'FP length variation in r elation to allelic variation at nearby polymorphisms. At biallelic RFL Ps on both sides of the 5'FP, we found that one allele exhibits near-t otal association with the upper component of the 5'FP class 1 distribu tion. Such associations represent a little-known but potentially wides pread form of linkage disequilibrium. In this type of disequilibrium, a flanking allele has near-complete association with a single mode of VNTR alleles whose lengths represent consecutive numbers of tandem rep eats (CNTR). Such extreme disequilibrium between a CNTR mode and flank ing alleles may originate and persist because length mutations at some VNTR loci usually add or delete only one or two repeat units.