Mapping Somatic TE-derived Transcriptional Diversity

项目摘要/摘要 近一半的人类基因组来自转座元件(TES)--可移动的遗传元件 在整个基因组中复制并插入自身的副本。每个人都有一个唯一的TE签名 插入由遗传的种系插入和获得性体细胞插入组成。这个签名是一个少校 个体之间和个体内部的遗传变异的来源。TES有可能改变 转录组有多种方式，但个体内TE衍生的转录多样性的程度是 未知。检测体细胞转位的转录效应历来具有挑战性。 考虑到每个细胞上每个插入事件的稀有性。新的方法终于实现了同时审问 从单个细胞中提取基因组和转录组，从而有可能同时检测种系的多态和 体细胞转位事件，并直接探讨其后果。这项提议将利用单细胞多 利用组学技术绘制大脑中体细胞TE衍生的转录和功能多样性图。理解 躯体TE活动的功能影响最终将有助于我们对个体差异的理解 潜在的复杂疾病过程。该项目的培训方面将支持申请者的职业目标 领导一个翻译研究小组，研究体细胞变异对人类的功能影响 疾病过程。单细胞基因组学培训对于探索罕见体细胞突变的影响至关重要 在大脑里。该提案将建立在申请人以前的实验生物学经验和 分子神经科学，同时支持生物信息学和计算基因组学的关键培训。

Project Summary/Abstract Nearly half of the human genome is derived from transposable elements (TEs) -- mobile genetic elements that replicate and insert copies of themselves throughout the genome. Each individual has a unique signature of TE insertions comprised of inherited germline insertions and acquired somatic insertions. This signature is a major source of genetic variation both between individuals and within an individual. TEs have the potential to alter the transcriptome in a variety of ways, but the extent of intra-individual TE-derived transcriptional diversity is unknown. Detecting the transcriptional effects of somatic transposition has historically been challenging given the rarity of each insertion event on a per cell basis. New methods are finally enabling simultaneous interrogation of genome and transcriptome from a single cell, making it possible to detect both germline polymorphic and somatic transposition events and directly probe their consequences. This proposal will leverage single cell multi- omics technology to map somatic TE-derived transcriptional and functional diversity in the brain. Understanding the functional impact of somatic TE activity will ultimately contribute to our understanding of individual variation underlying complex disease processes. The training aspect of this project will support the applicant’s career goal to lead a translational research group that investigates the functional effects of somatic variation on human disease processes. Training in single-cell genomics is essential to probe the influence of rare somatic mutations in the brain. The proposal will build upon the applicant’s previous experience with experimental biology and molecular neuroscience while supporting critical training in bioinformatics and computational genomics.