2/3 Schizophrenia Genetics and Brain Somatic Mosaicism

摘要 我们在密歇根大学（UM）的合作U 01家长补助金（5 U 01 MH 106892）的目标， 题为“2/3精神分裂症遗传学和脑体细胞嵌合体”，是为了发现和表征体细胞嵌合体， 镶嵌性（即，单核苷酸变异（SNV）、移动的遗传元件插入和拷贝数 CNVs）。体细胞 嵌合现象是指在一个个体中出现两个（或多个）基因组，而该个体是由一个受精卵衍生而来的。 NIMH支持的大脑体细胞镶嵌网络（BSMN）的成员正在描述镶嵌 其他神经精神疾病的变异，共同目标是评估躯体嵌合体的作用 包括双相情感障碍、精神分裂症、自闭症谱系障碍、癫痫和抽动秽语症在内的疾病 综合征我们提出了三个Capstone项目来绘制人类大脑中体细胞变异的全谱 并描述嵌合体变异对神经精神疾病风险的贡献。这些顶点可以 推进BSMN的使命，以实现更大的发现体细胞突变的能力， 结合和协调已产生的深度覆盖全基因组测序数据 BSMN节点和放置在神经发育和疾病的背景下识别的体细胞变异。到 整合多维BSMN数据，以及来自其他联盟的数据，行政补充 被要求进行三个顶点项目，这也将补充正在进行的努力，数据 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嵌合体变异的数据资源， 科学界将广泛获得的发展和疾病。述增强型功率 BSMN的综合分析提供的信息将提供指导未来发展的基础知识 工作，并导致新的洞察大脑体细胞镶嵌。密歇根州/弗吉尼亚州网站的具体目标是： 目标1（顶点1，目标2b），利用10 X基因组学链接读取的力量（即，扩展单体型） 数据和增强计算策略，以识别和验证体细胞SNV和移动的遗传元件 在神经型和精神分裂症大脑样本中的插入;以及Aim 2（Capstone 3，目标4），利用10 X 基因组学链接阅读（即，扩展的DNA单倍型）和单细胞测序数据来鉴定和验证 拷贝数变异（CNVs）在神经典型和神经精神疾病脑样品。我们认为， 10 X Genomics技术的使用代表了一种变革性技术，它将允许一个强大的平台， 在健康人和正常人中鉴定和验证SNV、移动的遗传元件和CNV体细胞嵌合现象， 神经精神疾病的大脑样本

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.