What it means to have a mutation and what role mutations play in Huntington’s disease.
Why is it that the longer a parent’s CAG repeat region is, the higher the likelihood of expansion?
In order to know the exact answer to this question, we must know the exact mechanism of expansion. Since researchers are not yet completely sure what this mechanism (or combination of mechanisms) is, we can only hypothesize from the probable mechanisms why more CAGs correspond to a greater likelihood of expansion. The most probable mechanism for expansion, the hairpin-mediated polymerase slippage model, offers two explanations for why longer CAG repeat regions correspond to a greater likelihood of expansion. First, the longer the CAG repeat region is, the more slippage sites there are. Thus, more CAGs mean an increased chance of slippage and therefore an increased chance of expansion (if indeed this model is the true one). Second, the longer the repeat region, the larger, more stable, and more probable hairpin formation becomes. Since hairpins help stabilize the energy change in the DNA that is caused by slippage, larger, more stable, and more probable hairpin formation may lead to a greater likelihood of slippage and thus a greater likelihood of expansion. However, it should again be emphasized that, although this model is a popular theory, it has not been proven as the exact mechanism of expansion. Thus, although it explains the relationship well, this does not mean that it is necessarily the 100% true answer to the question.
As for the unequal crossing over model, it does not appear to offer any reasonable answer to the question.
Last Modified: 1-28-04
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