Investigating the Role of Somatic Mutations in Neurofibromatosis Brain

项目摘要 1型神经纤维瘤病（NF）是一种常染色体显性遗传的癌症易感综合征，其特征是在整个中枢和外周神经系统形成的肿瘤。除了肿瘤，约80%的NF患者有神经功能缺损，包括记忆、注意力、感知和执行功能的损害。以前的工作已经确定了体细胞突变的重要性-合子后的变化，DNA只存在于一个子集的细胞-肿瘤形成的NF。尽管体细胞突变在NF发病机制中至关重要，并且对驱动肿瘤形成的特定突变进行了深入研究，但体细胞诱变的整体动力学仍知之甚少。与未受影响的个体相比，NF个体是否具有更高的体细胞突变负担？神经元中罕见的体细胞突变是否会导致NF的神经功能缺损？什么样的遗传机制驱动新的体细胞突变的获得？为了解决这些问题，我将使用先进的双链单核全基因组测序来量化NF中神经元细胞类型与年龄匹配对照相比的体细胞突变负担，并使用无偏非负矩阵因子分解的成熟方法来确定驱动诱变的特定机制。

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.