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Overall Structure and General Mechanism of Triplet Repeat Expansion

A triplet repeat consists of the same 3 nucleotides being repeated in a sequence. The most common and well-known triplet rpeats are CAG, GCG, CTG, CGG, and GAA (4). Because these repeats are so dynamic, the length of these repeats can vary within an individual’s different tissues (4). In terms of location, these triplet repeats can be found in both coding and non-coding regions. These repetitive sequences lead to instability amongst the DNA strands, which results in DNA slippage during replication (7). During DNA replication, the strand being synthesized can misalign with its template strand due to the dynamic nature and flexibility of these triplet repeats.  This slippage allows for the strand to loop out and find a stable intermediate amongst itself through base pairing, forming a secondary structure known as a hairpin. After the hairpin forms, the primer realigns with the 3’ end of the newly synthesized strand and continue the synthesis, leading to triplet repeat expansion (7). The structure of the hairpin is based on a stem and a loop. In these repeats, the stem will maximize the number of Watson-Crick base pairing interactions. In CTG and CAG repeats, the number of nucleotides present in the loop depends on if the number of triplet repeats is odd or even. An even number of repeats forms a tetraloop structure, while an odd number leads to the formation of a triloop (8,9). In CAG repeats, more triplet repeats are associated with increased stability of the hairpin (7).