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technically not a trinucleotide repeat but does entail a multiple of three nucleotides that expands and contracts in similar fashion to trinucleotide repeats.

technically not a trinucleotide repeat but does entail a multiple of three nucleotides that expands and contracts in similar fashion to trinucleotide repeats.

bor hundreds or even thousands of copies. Mutations in which copies of a trinucleotide may increase greatly in number are called expanding trinucleotide repeats.

Expanding trinucleotide repeats have been found in several other human diseases (Table 17.1). The number of copies of the trinucleotide repeat often correlates with the severity or age of onset of the disease. The number of copies of the repeat also correlates with the instability of trinu-cleotide repeats—when more repeats are present, the probability of expansion to even more repeats increases. This instability leads to a phenomenon known as anticipation (see p. 000 in Chapter 5), in which diseases caused by trinucleotide-repeat expansions become more severe in each generation. Less commonly, the number of trinu-cleotide repeats may decrease within a family.

How an increase in the number of trinucleotides produces disease symptoms is not yet clear. In several of the diseases (e.g., Huntington disease), the trinucleotide CAG expands within the coding part of a gene, producing a toxic protein that has extra glutamine residues (the amino acid encoded by CAG). In other diseases (e.g., fragile-X syndrome and myotonic dystrophy), the repeat is outside the coding region of the gene and therefore must have some other mode of action. At least one disease (a rare type of epilepsy) has now been associated with an expanding repeat of a 12-bp sequence. Although this repeat is not a trinu-cleotide, it is included as a type of expanding trinucleotide because its repeat is a multiple of three.

The mechanism that leads to the expansion of trinu-cleotide repeats is still unclear. Strand slippage in DNA replication (see Figure 17.14) and crossing over between misaligned repeats (see Figure 17.15) are two possible sources of expansion. Single-stranded regions of some trinucleotide repeats are known to fold into hairpins (Figure 17.6) and other special DNA structures. Such structures may promote strand slippage in replication and may prevent these errors from being recognized and corrected, as described later in this chapter in the section on mismatch repair.

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