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Normal variation at the myotonic dystrophy locus in global human populations.

Myotonic dystrophy (DM) is a dominant neuromuscular disease that results from an unstable CTG-repeat expansion in the 3' UTR of the myotonin kinase gene at 19q13.3. This repeat is normally polymorphic with a trimodal distribution reflecting 5-, 11-17-, and 19-30-repeat-length alleles. An absolute association between expanded CTG alleles and the 1-kb insertion allele of an intragenic polymorphism in Caucasians has led to the proposal that the 5-repeat allele gives rise to alleles of 19-30 repeats, from which expanded alleles are derived, a transition not involving the 11-17-repeat alleles. A survey of eight global populations confirms the stability of the 11-17-repeat alleles but shows disociation between the 1-kb insertion polymorphism and both the 5- and 19-30-repeat-length alleles. These data indicate more than one ancestral allele from which expanded alleles are derived and suggest that widely variable population frequencies of DM may reflect distinct frequencies of such predisposed alleles.