DNA MICROSATELLITE REPEAT INSTABILITY AT THE FRIEDREICH AXTAXIA LOCUS

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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. The grant supports 25% release time for spring semester 2006 for the PI to carry out research development in support of the collaborative project: A Model based investigation of DNA microsatellite repeat instability at the Friedreich ataxia locus. Friedreich ataxia, the most common inherited ataxia, is characterized clinically by progressive ataxia, cardiomyopathy and diabetes. It is caused by an unusual DNA mutation, the expansion of a GAA triplet-repeat (GAA-TR) sequence in the FXN. 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 and/or repair. Here we propose to examine the likelihood that the instability results from replication or from repair by mathematically modeling the GAA-TR length variation data for various tissues isolated from several human subject autopsies. In addition, examination of the sensitivity of maximum likelihood parameter estimates for best-fitting models will more specifically indicate the features of replication and/or repair mechanisms that direct the repeat-length variation, e.g. large versus small mutations (expansions / contractions) of the various GAA-TR alleles.