2/3 Schizophrenia Genetics and Brain Somatic Mosaicism

摘要 我们在密歇根大学(UM)合作的U01家长助学金(5U01 MH106892)的目标是， 题为《2/3精神分裂症遗传学与脑体细胞嵌合体》，旨在发现和表征躯体细胞 嵌合体(即单核苷酸变异(SNV)、可移动遗传元件插入和拷贝数 神经典型个体和精神分裂症患者死后脑组织中的变异(CNV)。体细胞 嵌合体是指来自单个受精卵的个体体内出现两个(或更多)基因组。 NIMH支持的脑体细胞嵌合体网络(BSMN)的成员具有镶嵌的特征 其他神经精神障碍的变异，其共同目标是评估躯体嵌合体的作用 各种疾病，包括双相情感障碍、精神分裂症、自闭症谱系障碍、癫痫和抽动症 综合症。我们提出了三个Capstone计划来绘制人脑中体细胞变异的全谱。 并表征了马赛克变体对神经精神疾病风险的贡献。这些顶石可以 推进BSMN的使命，通过以下方式实现更大的体细胞突变发现能力 合并和协调已生成的深度覆盖全基因组测序数据 BSMN节点，并将已识别的体细胞变异置于神经发育和疾病的背景下。至 整合多维BSMN数据，以及来自其他联合体的数据、行政补充 要求开展三个Capstone项目，这些项目也将补充正在进行的数据工作 协调中心(DCC)和数据分析核心(DAC)。我们预计这些Capstone项目将增加 通过创建史无前例的体细胞花叶变异体数据资源来描述BSMN 将向科学界广泛提供的发展和疾病。增强的力量 由BSMN的综合分析提供的基础知识将指导未来 工作，并导致对大脑体细胞嵌合体的新见解。密歇根/弗吉尼亚州网站的具体目标是： 目标1(Capstone 1，目标2b)，利用10倍基因组连锁读取(即扩展单倍型)的能力 数据和增强的计算策略，以识别和验证体细胞SNV和移动遗传元件 在神经典型和精神分裂症大脑样本中插入；以及目标2(Capstone 3，Goal 4)，以开发10倍 基因组学连锁读取(即扩展的DNA单倍型)和单细胞测序数据以识别和验证 神经典型和神经精神疾病脑样本中的拷贝数变异(CNV)。我们假设 10倍基因组学技术的使用代表了一项变革性的技术，它将允许一个强大的平台 识别和验证SNV、移动遗传元件和CNV体细胞嵌合体 神经精神疾病大脑样本。

Abstract The goal of our collaborative U01 parent grant (5U01MH106892) at the University of Michigan (UM), entitled “2/3 Schizophrenia Genetics and Brain Somatic Mosaicism,” is to discover and characterize somatic mosaicism (i.e., single nucleotide variants (SNVs), mobile genetic element insertions, and copy number variants (CNVs)) in post-mortem brain tissue from neurotypical and schizophrenic individuals. Somatic 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 mosaicism across diseases including bipolar disorder, schizophrenia, autism spectrum disorder, epilepsy, and Tourette syndrome. 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 has been generated across BSMN nodes and placing the identified somatic variants in the context of neurodevelopment and disease. To integrate the multi-dimensional BSMN data, as well as data from other consortia, administrative supplements are requested to conduct three Capstone projects, which will also complement ongoing efforts of 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 mosaic variants across development and diseases that will be 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 of the Michigan/Virginia site are: Aim 1 (Capstone 1, Goal 2b), to leverage the power of 10X Genomics linked read (i.e., extended haplotype) data and enhance computational strategies to identify and validate somatic SNVs and mobile genetic element insertions in neurotypical and schizophrenia brain samples; and Aim 2 (Capstone 3, Goal 4), to exploit 10X Genomics linked-read (i.e., extended DNA haplotype) and single cell sequencing data to identify and validate copy number variants (CNVs) in neurotypical and neuropsychiatric disease brain samples. We posit that the use of 10X Genomics technology represents a transformative technology that will allow a robust platform to identify and validate SNV, mobile genetic element, and CNV somatic mosaicism in both healthy and neuropsychiatric disease brain samples.