Myotonic dystrophy CTG repeats and the associated insertion/deletion polymorphism in human and primate populations

Myotonic dystrophy (DM) is associated with abnormal expansions of the CTG repeats in the 3' untranslated region of its gene. Previous studies in individuals of European origin demonstrated strong linkage disequilibrium between different CTG repeat length alleles and an Alu element insertion/deletion polymorphism in intron 8 of the DM gene: CTG11-13 chromosomes were almost exclusively associated with the deletion allele, while chromosomes with five or 19-30 repeats or disease chromosomes were only found on the insertion allele. One of the models suggested by these results proposed that the triplet repeats on insertion-associated chromosomes were particularly prone to mutation. Studies of other triplet repeat disorders have suggested that arrays of perfect repeats are more prone to instability than those that are interrupted. We have examined the evolution of this locus by typing a variety of primates and samples drawn from several different human populations for both CTG repeat length and the insertion/deletion polymorphism. DM gene sequences from different primates revealed inter- and intraspecies variability in the number of CTG repeats. Human chromosomes with five repeats or 11-13 repeats (the two major modes of the human CTG repeat distributions) showed no evidence of preferential stabilization of these repeat sizes by imperfect sequences. The insertion and deletion allele frequencies showed large interpopulation variation and the degree of association between these alleles and various CTG repeat lengths is not nearly as complete as was previously supposed. We have found deletion alleles carrying long normal (> 19) CTG repeats and insertion alleles associated with CTG11 - 13 in two african populations.(ABSTRACT TRUNCATED AT 250 WORDS)