Figure 4.

Proposed model for the roles of Msh2 and Msh6 in Hdh^Q111 CAG repeat intergenerational instability.

The length of the expanded HD CAG repeat (HD CAGexp) inherited from fathers is determined by the combined influences of two Msh2-dependent mechanisms: Msh2 mediates expansions and Msh2-Msh6 dimers protect against contractions. A) In mice wild-type for both Msh2 and Msh6 (Msh2^+/+/; Msh6^+/+) expansion (light blue ‘+’ arrow) and inhibition of contraction (red ‘-’ inhibitory symbol) both occur. B) In mice lacking Msh2 (Msh2^-/-; Msh6^+/+) both mechanisms are abolished, the net result being an increased contraction frequency (bold type). C) In mice lacking one Msh6 allele (Msh2^+/+; Msh6^+/-) contraction frequency is increased (bold type) as a result of reduced Msh2-Msh6 inhibition (pink‘-’ inhibitory symbol) while expansions are unaffected. D) In mice lacking two Msh6 alleles (Msh2^+/+; Msh6^-/-) contraction frequency is increased (bold type) due to loss of Msh2-Msh6 inhibition. However, this is compensated by an increase in expansions (dark blue ‘+’ arrow and bold type), as in the absence of Msh6 the balance of Msh2-dependent pathways is shifted in favor of those that mediate expansions.