R. Gellibolian et al., TRIPLET REPEAT INSTABILITY AND DNA TOPOLOGY - AN EXPANSION MODEL-BASED ON STATISTICAL-MECHANICS, The Journal of biological chemistry, 272(27), 1997, pp. 16793-16797
The variance of writhe, the contribution of writhe to supercoiling, an
d the free energies of supercoiling were calculated for (CTG.CAG)(n) a
nd (CGG.CCG)(n) triplet repeat sequences (TRS) by statistical mechanic
s from the bending and torsional moduli previously determined, Expansi
ons of these sequences are inherited by non-mendelian transmission and
are linked with several hereditary neuromuscular diseases, The varian
ce of writhe was greater for the TRS than for random B-DNA, For random
B-DNA, (CGG)(n), and (CTG)(n), the contribution of writhe to supercoi
ling was 70, 78, and 79%, whereas the free energy of supercoiling at a
length of 10 kilobase pairs was 1040.RT, 760.RT, and 685.RT, respecti
vely, These data indicate that the TRS are preferential sites for the
partitioning of supercoiling, Calculations of the differences in free
energy of supercoiling between the TRS and random B-DNA revealed a loc
al minimum at similar to 520 base pairs, Human medical genetic studies
have shown that individuals carrying up to 180-200 copies of TRS (540
-600 base pairs, premutations) in the fragile X or myotonic dystrophy
gene loci are usually asymptomatic, whereas large expansions (>200 rep
eats, full mutations), which lead to disease, are observed in their of
fspring, Therefore, the length corresponding to the local minimum in f
ree energy of supercoiling correlates with the genetic breakpoint betw
een premutation and full mutation, We propose that (a) TRS instability
is mediated by DNA mispairing caused by the accumulation of supercoil
ing within the repeats, and (b) the expansions that take place at the
premutation to full mutation threshold are associated with increased m
ispairing caused by the optimal partitioning of writhe within the TRS
at this length.