Investigating the Role of Somatic Mutations in Neurofibromatosis Brain

点击翻译按钮获取中文摘要

PROJECT SUMMARY Neurofibromatosis type 1 (NF) is an autosomal dominant cancer predisposition syndrome characterized by tumors that form throughout the central and peripheral nervous systems. In addition to tumors, ~80% of individuals with NF have neurological deficits including impairment of memory, attention, perception, and executive functioning. Previous work has established the importance of somatic mutations-post-zygotic changes to DNA that only exist in a subset of cells-for tumor formation in NF. Despite the critical importance of somatic mutation in NF pathogenesis and the deep study of particular mutations that drive tumor formation, the overall dynamics of somatic mutagenesis is poorly understood. Do individuals with NF have a higher burden of somatic mutations compared to unaffected individuals? Do infrequent somatic mutations in neurons contribute to the neurological deficits in NF? What genetic mechanisms drive the acquisition of new somatic mutations? To address these questions, I will use cutting-edge duplex single-nucleus whole genome sequencing to quantify the burden of somatic mutations in neuronal cell types in NF compared to age-matched controls and use the well-established method of unbiased non-negative matrix factorization to identify specific mechanisms driving mutagenesis.