Genomic and physiological impact of transposable elements

项目总结 转座元件(TES)占人类基因组的一半以上，它们的转座和 基因重排直接导致了100多种遗传病。因为. 这些突变特性是物种间和物种内遗传变异的重要驱动因素。 TE活动占每个哺乳动物物种独有的DNA的大部分，并负责 人类群体中多达30%的结构基因组变异。然而，这是如何 遗传变异的巨大来源影响了物种的进化，但生理学仍然很差 明白了。该项目旨在对TES的生物学意义产生变革性的见解。 在进化和疾病方面。这项提案检验的中心假设是，预制的监管 在脊椎动物中，由TES编码的祖先编码的编码活动被反复选择 进化促进新的细胞功能的出现。在监管层面，我们将部署 创新的计算和实验方法来检验多态和多态的假设 谱系特定的TES对转录和顺式调节变异有很大贡献 人类和各种哺乳动物物种，包括灵长类动物、啮齿动物和蝙蝠，都有 重点介绍了长的非编码RNA曲目的来源和周转。此外，我们将调查 TES在先天免疫系统的一个主要组成部分的调节进化中的作用 干扰素反应。细胞系的实验操作，包括基因组编辑和功能 分析，将用于验证TE衍生的调控序列的功能意义。在 蛋白质编码水平，我们将结合进化序列分析和功能分析来 描述人类基因组中为细胞功能而增选的几个TE衍生基因。值得注意的是，我们 将检验来自内源性逆转录病毒的包膜蛋白能够 保护细胞免受逆转录病毒感染。我们还将研究几种驯化的转座酶。 参与大脑的功能和发育。这项提案的结果预计将综合起来 将对TES的感知从惰性分子化石转变为对进化可塑性的积极贡献者 脊椎动物的基因组。此外，我们的研究一定会揭示出关键的新见解， 促进疾病状态的移动遗传因素，包括癌症、自身免疫和 神经发育障碍。

PROJECT SUMMARY Transposable elements (TEs) make up more than half of the human genome, and their transposition and rearrangement have been directly implicated in causing more than 100 genetic diseases. Because of these mutagenic properties, TEs are important drivers of genetic variation between and within species. TE activity accounts for most of the DNA that is unique to each mammal species, and is responsible for as much as 30% of structural genomic variation within the human population. However how this enormous source of genetic variation impacts the evolution and physiology of species remains poorly understood. This project is designed to yield transformative insights into the biological significance of TEs in evolution and disease. The central hypothesis tested in this proposal is that prefabricated regulatory and coding activities ancestrally encoded by TEs have been co-opted repeatedly during vertebrate evolution to promote the emergence of new cellular functions. At the regulatory level, we will deploy innovative computational and experimental approaches to test the hypothesis that polymorphic and lineage-specific TEs make a substantial contribution to transcriptomic and cis-regulatory variation within humans and across a diverse set of mammal species, including primates, rodents and bats, with an emphasis on the origin and turnover of long noncoding RNA repertoires. Furthermore, we will investigate the role of TEs in the regulatory evolution of a major component of the innate immune system, the interferon response. Experimental manipulations in cell lines, including genome editing and functional assays, will be used to validate the functional significance of TE-derived regulatory sequences. At the protein-coding level, we will combine evolutionary sequence analysis and functional assays to characterize several TE-derived genes co-opted for cellular function in the human genome. Notably we will test the hypothesis that envelope proteins derived from endogenous retroviruses are capable of protecting cells from retroviral infection. We will also investigate several domesticated transposases involved in brain function and development. Together the outcomes of this proposal are anticipated to shift the perception of TEs from inert molecular fossils to active contributors to the evolutionary plasticity of vertebrate genomes. In addition, our studies are bound to reveal crucial new insights into the role of mobile genetic elements in promoting disease states, including cancer, autoimmunity, and neurodevelopmental disorders.