Replication-independent instability of Friedreich’s ataxia GAA repeats during chronological aging
Alexander J. Neil, Julia A. Hisey, Ishtiaque Quasem, Ryan J. McGinty, Marcin Hitczenko, Alexandra N. Khristich, Sergei M. Mirkin
Abstract
Significance The inheritance of long (GAA) n repeats in the frataxin gene causes the debilitating neurodegenerative disease Friedreich’s ataxia. Subsequent expansions of these repeats throughout a patient’s lifetime in the affected tissues, like the nervous system, may contribute to disease onset. We developed an experimental model to characterize the mechanisms of repeat instability in nondividing cells to better understand how mutations can occur as cells age chronologically. We show that repeats can expand in nondividing cells. Notably, however, large deletions are the major type of repeat-mediated genome instability in nondividing cells, implicating the loss of important genetic material with aging in the progression of Friedreich’s ataxia.