The high resolution haplotype analysis and origin of the myotonic dystrophy mutation.

Abstract

The objective of this thesis was to determine the origin of the myotonic dystrophy (DM) mutation. I have used PCR-based assays of nine polymorphisms spanning a physical distance of 30 kb, within and immediately flanking the DM kinase gene, in order to examine patterns of allelic association with respect to the DM mutation. Four main haplotypes (A-D) were observed in the normal population using these nine markers at the DM locus. Significantly, DM is in complete association with haplotype A, the most common haplotype in the normal population. Our data suggest the presence of two founding chromosomes: one containing a stretch of five contiguous Alu elements (the progenitor for haplotype A) and the other in which three of these have been deleted (the progenitor for haplotypes B, C and D). Individuals with haplotype A displayed the full spectrum of (CTG)$\sb{\rm n}$ number, ranging from 5 to 35 repeats. The (CTG)$\sb5$ alleles as well as alleles with greater than 19 repeats are exclusively linked to haplotype A. In contrast, alleles in which the three Alu elements are deleted possess only (CTG)$\sb{11-14}$ repeats. Although the inference that the loss of the three Alu repeats may confer increased stability on the (CTG)$\sb{\rm n}$ repeat is speculative, the narrow size range of the (CTG)$\sb{\rm n}$ repeat on chromosomes in which the Alu elements have been deleted, relative to the variation seen on normal chromosomes with the DM haplotype (i.e. haplotype A), is striking. (Abstract shortened by UMI.)