Unravelling the role of DNA on its own instability within the Huntington’s disease locus

Huntington's disease (HD) is a rare neurodegenerative disorder caused by a mutation in the HUNTIGTIN (HTT) gene. In patients, the HTT gene contains an abnormally elongated stretch of CAG repeats which, when exceeding 35 repeats, produces a defective form of HTT protein. The length of the inherited CAGs can further increase in patient’s tissues (e.g. in brain neurons) during life. In humans, the pure CAG repeats terminates with a CAA-CAG, thereby generating a trait within the HD locus formed by: 
CAG-CAG-CAG-CAG-CAG-CAG-CAG(n)-CAA-CAG 
However, patients have been identified who carry a CAG instead of a CAA at the penultimate position of the HD locus, to generate this other sequence: 
CAG-CAG-CAG-CAG-CAG-CAG-CAG(n)-CAG-CAG
Other patients instead carry a duplication of the two terminal triplets that generate this sequence: 
CAG-CAG-CAG-CAG-CAG-CAG-CAG(n)-CAA-CAG-CAA-CAG
These subtle changes in CAG tract composition are now known factors that radically change the age of disease onset. However, how these subtle changes translate into a different clinical outcome is unknown. The hypothesis is that they could affect the ability of the CAGs to expand further into brain tissue, leading to the accumulation of CAGs tracts longer than the inherited length. With our project, we want to study if and how this happens. We hypothesize that the pathological CAG tract forms unusual secondary DNA structures and releases small extrachromosomal circular DNA molecules, which could drive the genomic instability underlying the disease. If so, these upstream mechanisms and molecules may become a target for intervention and/or a biomarker for HD.