Mapping Somatic TE-derived Transcriptional Diversity

项目总结/摘要 近一半的人类基因组来自转座因子（TE）--移动的遗传因子， 在整个基因组中复制并插入自己的拷贝。每个人都有一个独特的TE签名 插入包括遗传的生殖系插入和获得的体细胞插入。这个签名是一个主要的 个体之间和个体内部的遗传变异来源。TE有可能改变 转录组以各种方式，但在个体内TE衍生的转录多样性的程度， 未知检测体细胞转座的转录效应历来具有挑战性 假定每个插入事件在每个单元的基础上是罕见的。新的方法终于使同时审讯成为可能 基因组和转录组从一个单一的细胞，使得有可能检测两个种系多态性和 体细胞转座事件，并直接探讨其后果。该提案将利用单细胞多- 组学技术来绘制脑中体细胞TE衍生的转录和功能多样性。理解 体细胞TE活动的功能影响将最终有助于我们理解个体差异 潜在的复杂疾病过程。这个项目的培训方面将支持申请人的职业目标 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 在大脑中。该提案将建立在申请人以前的经验与实验生物学， 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.