Origin of the expansion mutation in myotonic dystrophy

Abstract

Myotonic dystrophy (DM) is caused by the expansion of a CTG trinucleotide repeat. The mutation is in complete linkage disequilibrium with a nearly two-allele insertion/deletion polymorphism, suggesting a single origin for the mutation or predisposing mutation. To trace this-ancestral event, we have studied the association of CTG repeat alleles in a normal population to alleles of the insertion/deletion polymorphism and of a (CA)n repeat marker 90 kilobases from the DM mutation. The results strongly suggest that the initial predisposing event(s) consisted of a transition from a (CTG)5 allele to an allele with 19 to 30 repeats. The heterogeneous class of (CTG)19-30 alleles which has an overall frequency of about 10%, may constitute a reservoir for recurrent DM mutations.

Evidence of cis-acting factors in replication-mediated trinucleotide repeat instability in primate cells

“…A similar location effect may explain DM1 founder chromosomes and their possible predisposition to CTG expansion 12,13 . The location of the human chromosomal replication origin that replicates the DM1 region is not known, and it may differ between individuals affected with DM1 and nonaffected individuals.…”

“…Complete allelic association between the DM1 expansion and several insertion/deletion polymorphisms flanking the repeat 12,13 show that a specific chromosomal background is associated with (CTG) n instability, which suggests that chromosomal context and ciselements may be required for expansion. The variable stability of similar CAG tract lengths at different disease loci provides further support for a role of flanking sequences 2,11,14,15 .…”

A multistep mutation mechanism drives the evolution of the CAG repeat at MJD/SCA3 locus

“…In MD, a multistep mechanism was also proposed, under which a very rare (possibly also a single one) transition had occurred from a (CTG) 5 allele to an allele with 19 to 30 repeats, whereas the heterogeneous class of (CTG) 19 -30 alleles was suggested as a reservoir for recurrent MD mutations. 32 On the other hand, in the case of SCA1 and SCA2, studying the distribution of interruptions within the tracts, it was suggested that the dynamic mutation of ATXN1 and ATXN2 genes initiated from the expansion of long pure repeat tracts without the prior loss of interruptions. 33 In conclusion, our results strongly support a multistep mutation model underlying the evolution of the CAG alleles at the MJD/SCA3 locus.…”

Genetic fitness in Huntington's Disease and Spinocerebellar Ataxia 1: a population genetics model for CAG repeat expansions

“…In diseases with a reduced genetic fitness, such as DM and FRAXA, a strong or complete linkage disequilibrium between the mutation and intraor extra-genic markers has been found (Imbert et al, 1993;Richards et al, 1992;Oudet et al, 1993). Under the assumption of mutation/ selection equilibrium, the expanded alleles lost at each generation should be replaced by new mutations which are unlikely to arise on a restricted set of haplotypes, unless the latter are in disequilibrium with factors predisposing to mutation.…”