Mosaicism in focal cortical dysplasias spectrum seen in neuropsychiatric disease

摘要/概要 我们的母基金U 01-MH 108898，题为“在大脑皮质发育不良中发现的局灶性皮质发育不良频谱中的镶嵌现象”， 神经精神疾病”的重点是了解大脑皮层发育不良的机制， 大脑躯体嵌合体对这一过程的贡献。镶嵌现象是两个（或更多） 来自单个受精卵的个体的基因组。NIMH支持的Brain Somatic 镶嵌网络（BSMN）正在描述其他神经精神疾病的镶嵌变异， 共同目标是评估体细胞嵌合变异在包括BPD，精神分裂症， 自闭症谱系障碍、图雷特综合征和发育不良。我们提出了三个顶点项目，以绘制 在人类大脑的体细胞变异的全谱，并表征马赛克变体的贡献， 神经精神疾病风险。这些顶点可以推进BSMN的使命， 通过组合和协调深度覆盖全基因组发现体细胞突变的能力 对跨节点生成的数据进行测序，以及将通过 在神经发育和疾病的背景下研究脑体细胞镶嵌现象（BSM）。为了整合这一多- 从BSMN以及其他联合体获得的尺寸数据，要求行政补充， 在该奖项的最后两年，继续三个顶点项目，并为数据做出贡献 协调中心（DCC）和数据分析核心（DAC）。我们预计这些顶点项目将增加 通过创建一个前所未有的体细胞镶嵌变异的数据资源， 发展和疾病的科学界广泛提供。所提供的增强功率 BSMN的综合分析将提供指导未来工作的基础知识，并导致新的 对大脑躯体镶嵌现象的深入了解。具体目的是（1）对于Capstone 2，评估体细胞突变， 在人类大脑的景观，由一个前所未有的，全面的大脑马赛克映射在一个单一的 对于Capstone 3，利用深度测序的批量短读WGS检测体细胞结构 通过改进和采用一种名为CHONK的新型机器学习分类器方法， 在我们的实验室里开发的。

Abstract/Summary Our parent grant U01-MH108898 entitled “Mosaicism in focal cortical dysplasias spectrum seen in neuropsychiatric disease” has a focus on understanding the mechanisms of dysplasia of the cerebral cortex, and the contribution of brain somatic mosaicism to this process. Mosaicism is the occurrence of two (or more) genomes in an individual who is derived from a single zygote. Members of the NIMH-supported Brain Somatic Mosaicism Network (BSMN) are characterizing mosaic variation in other neuropsychiatric disorders with a common goal of assessing the role of somatic mosaic variation across diseases including BPD, schizophrenia, autism spectrum disorder, Tourette syndrome, and dysplasias. We propose three capstone projects to map the full spectrum of somatic variation in human brain and characterize the contributions of mosaic variants to neuropsychiatric disease risk. These capstones can advance the mission of the BSMN, to both achieve greater power of discovery of somatic mutations by combining and harmonizing deep coverage whole genome sequencing data that have been generated across nodes, as well as placing the variants identified through the study of brain somatic mosaicism (BSM) in the context of neurodevelopment and disease. To integrate this multi- dimensional data from the BSMN, as well as other consortia, administrative supplements are requested to continue, in the final two years of the award, three capstone projects, as well as to contribute to the Data Coordinating Center (DCC) and data analytic core (DAC). We expect these Capstone Projects to increase the profile of the BSMN by creating an unprecedented data resource of somatic mosaicism variants across development and diseases widely available to the scientific community. The enhanced power provided by the combined analyses of the BSMN will provide foundational knowledge that will guide future work, and lead to new insight into brain somatic mosaicism. The specific aims are (1) for Capstone 2, to assess the somatic mutational landscape in the human brain, by an unprecedented, comprehensive mapping of brain mosaicism in a single person; (2) for Capstone 3, to exploit deeply sequenced bulk short-read WGS to detect somatic structural variation by refining and employing a novel machine-learning classifier approach named CHONK that was developed in our lab.