This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Friedreich ataxia is the most common inherited ataxia. It is characterized clinically by progressive ataxia (incoordination), cardiomyopathy and diabetes. It is caused by an unusual DNA mutation, which involves the expansion of a GAA triplet-repeat (GAA-TR) sequence in the FRDA gene from a normal size of 30 to 100-1700 triplets. The length of the expanded allele determines the severity of the clinical presentation. Our goal is to understand what makes the GAA-TR unstable and to reverse it in somatic cells from patients as a potential therapeutic strategy. Using a novel technique that allows the detection of repeat lengths in individual cells, we recently discovered that the GAA-TR sequence displays somatic instability with a remarkable degree of cell-to-cell and tissue-specific variability, and we hypothesized that this instability is induced via erroneous DNA replication. Here we propose to test this hypothesis in simulation by mathematically modeling the complex data set generated in our experiments using various tissues isolated from several human subjects. We will apply a broad family of Markov chain models to analyze the pattern of instability observed in vivo and to construct realistic models based on the biology of DNA replication and test them in comparison to standard models of microsatellite DNA instability. We believe that this will lead us to experimentally testable hypotheses to investigate the molecular etiology of GAA-TR instability.
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