SMALL SLIPPED REGISTER GENETIC INSTABILITIES IN ESCHERICHIA-COLI IN TRIPLET REPEAT SEQUENCES ASSOCIATED WITH HEREDITARY NEUROLOGICAL DISEASES

Genetic instability investigations on three triplet repeat sequences ( TRS) involved in human hereditary neurological diseases (CTG.CAG, CGG. CCG, and GAA.TTC) revealed a high frequency of small expansions or del etions in 3-base pair registers in Escherichia coli. The presence of G to A polymorphisms in the CTG.CAG sequences served as reporters for t he size and location of these instabilities. For the other two repeat sequences, length determinations confirmed the conclusions found for C TG.CAG. These studies were conducted in strains deficient in methyl-di rected mismatch repair or nucleotide excision repair in order to inves tigate the involvement of these postreplicative processes in the genet ic instabilities of these TRS. The observation that small and large in stabilities for (CTG.CAG)(175) fall into distinct size classes (1-8 re peats and approximate multiples of 41 repeats, respectively) leads to the conclusion that more than one DNA instability process is involved. The slippage of the complementary strands of the TRS is probably resp onsible for the small deletions and expansions in methyl-directed mism atch repair-deficient and nucleotide excision repair deficient cells. A model is proposed to explain the observed instabilities via strand m isalignment, incision, or excision, followed by DNA synthesis and liga tion. This slippage-repair mechanism may be responsible for the small expansions in type 1 hereditary neurological diseases involving polygl utamine expansions. Furthermore, these observations may relate to the high frequency of small deletions versus a lower frequency of large in stabilities observed in lymphoblastoid cells from myotonic dystrophy p atients.