Unequal homologous exchange One proposed but highly unlikely mechanism that plays a role in trinucleotide<unk>  transmission occurs during meiotic or mitotic recombination. It is suggested that during these processes it is possible for a homologous repeat misalignment, commonly known for causing alpha-globin locus deletions, causes the meiotic instability of a<unk> . This process is unlikely to contribute to the transmission and presence of<unk> s due to differences in<unk>  mechanisms.<unk> s typically favor<unk> s of the CAG region but, in order for the unequal homologous exchange to be a plausible suggestion, these repeats would have to go through<unk>  and contraction events at the same time. In addition, numerous diseases that result from transmitted<unk> s, such as Fragile X syndrome, involve unstable trinucleotide repeats on the X chromosome that cannot be explained by meiotic recombination. Research has shown that although unequal homologous recombination is unlikely to be the sole cause of transmitted<unk> s, this homologous recombination likely plays a minor role in the length of some<unk> s. DNA replication DNA replication errors are predicted to be the main perpetrator of<unk>  transmission in many predicted models due to the difficulty of<unk>  (TRE). TREs have been shown to occur during DNA replication in both in vitro and in vivo studies, allowing for these long tracts of triplet repeats to assemble rapidly in different mechanisms that can result in either small scale or large scale<unk> s. Small scale<unk> s These<unk> s can occur through either strand slippage or flap ligation. Okazaki fragments are a key element of the proposed error in DNA replication. It is suggested that the small size of Okazaki fragments, typically between 150 and 200 nucleotides long, makes them more likely to fall off or “slip” off the lagging strand, which creates room for trinucleotide repeats to attach to the lagging strand copy. In addition to this possibility of<unk>  changes occurring due to slippage of Okazaki fragments, the ability of CG-rich<unk>  sequences to form a special hairpin, toroid, and triplex DNA structures contributes to this model, suggesting error occurs during DNA replication. Hairpin structures can form as a result of the freedom of the lagging strand during DNA replication and are typically observed to form in extremely long trinucleotide repeat sequences. Research has found that this hairpin formation depends on the orientation of the trinucleotide repeats within each CAG/CTG trinucleotide strand. Strands that have duplex formation by CTG repeats in the leading strand are observed to result in extra repeats, while those without CTG repeats in the leading strand result in repeat deletions. These intermediates can pause activity of the replication fork based on their interaction with DNA polymerases through strand slippage. Contractions occur when the replication fork skips over the intermediate on the Okazaki fragment.<unk> s occur when the fork reverses and restarts, which forms a chicken-foot structure. This structure results in the unstable intermediate forming on the nascent leading strand, leading to further TRE. Furthermore, this intermediate can avoid mismatch repair due to its affinity for the MSH-2-MSH3 complex, which stabilizes the hairpin instead of repairing it. In non-dividing cells, a process called flap-ligation can be responsible for TRE. 8-oxo-guanine DNA glycosylase removes a guanine and forms a nick in the sequence. The coding strand then forms a flap due to displacement, which prevents removal by an endonuclease. When the repair process finishes for either mechanism, the length of the<unk>  is equivalent to the number of triplet repeats involved in the formation of the hairpin intermediate. Large scale<unk> s Two mechanisms have been proposed for large scale repeats: template switching and break-induced replication. Template switching, a mechanism for large scale GAA repeats that can double the number of triplet repeats, has been proposed. GAA repeats expand when their repeat length is greater than the Okazaki fragment's length. These repeats are involved in the stalling of the replication fork as these repeats form a triplex when the 5’ flap of TTC repeats fold back. Okazaki fragment synthesis continues when the template is switched to the nascent leading strand. The Okazaki fragment eventually ligates back to the 5’ flap, which results in TRE. A different mechanism, based on break-induced replication, has been proposed for large scale CAG repeats and can also occur in non-dividing cells. At first, this mechanism follows the same process as the small scale strand slippage mechanism until replication fork reversal. An endonuclease then cleaves the chicken-foot structure, which results in a one-ended double strand break. The CAG repeat of this broken daughter strand forms a hairpin and invades the CAG strand on the sister chromatid, which results in<unk>  of this repeat in a migrating D-loop DNA synthesis. This synthesis continues until it reaches the replication fork and is cleaved, which results in an expanded sister chromatid.
Trinucleotide repeat expansion
Trinucleotide repeat disorder
Copy number variation
Ribosomopathy
Postzygotic mutation
Chromosomal translocation
Mitochondrial toxicity
Creatine transporter defect