Slipped structures in DNA triplet repeat sequences: Entropic contributions to genetic instabilities

Slipped DNA structures can occur in sequences with direct repeats. DNA triplet repeats, particularly (CTG)(n), (CGC)(n), and (GAA)(n), are known to be associated with several neurological diseases. Slippage is probably the cause of expansion of the number of repeats, a process called dynamic mutation, which is known to be the cause of the diseased state. Here it is shown that the conformational entropy associated with slippage is more destabilizing for long direct repeats (300-1000 base pairs) than shorter runs (10-30 base pairs), by about 2 kcal/mol. This contributes to the greater instability of longer sequences. Entropic considerations also favor the formation of simple bulges, rather than hairpin structures. A model is presented for dynamic mutations, and experimentally testable predictions are made that will allow the model to be tested.