Structural basis for triplet repeat disorders: a computational analysis

Motivation: Over a dozen major degenerative disorders, including myotonic distrophy, Huntington's disease and fragile X syndrome result from unstable expansions of particular trinucleotides. Remarkably, only some of all the possible triplets, namely CAG/CTG, CGG/CCG and GAA/TTC, have been associated with the known pathological expansions This raises some basic questions at the DNA level. Why do particular triplets seem to be singed out? What is the mechanism for their expansion and how does it depend on the triplet itself? Could other triplets or longer repeats be involved in other diseases? Results: Using several different computational models of DNA structure, we show that the triplets involved in the pathological repeats generally fall into extreme classes. Thus, CAG/CTG repeats are particularly flexible, whereas GCC, CGG and GAA repeats appear to display both flexible and rigid (but curved) characteristics depending on the method of analysis. The fact that (1) trinucleotide repents often become increasingly unstable when they exceed a length of approximately 50 repeats, and (2) repented 12-mers display a similar increase in instability above 13 repeats, together suggest that approximately 150 bp is a general threshold length far repeat instability Since this is about the length of DNA wrapped up in a single nucleosome care particle, we speculate that chromatin structure may play an important role in the expansion mechanism. We furthermore suggest that expansion afa dodecamer repent, which we predict to have very high flexibility, may play a role in the pathogenesis of the neurodegenerative disorder multiple system atrophy (MSA). Contact: pfbaldi@ics.uci.edu, yves@netid.com, brunak@tbs.dtu.dk, gorm@cbs.dtu.dk.