Genomic and physiological impact of transposable elements

转座元件的基因组和生理影响

• 批准号: 10238949
• 负责人: Cedric Feschotte
• 金额: $ 50.77万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-08 至 2023-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238949
• 关键词: Autoimmunity; Biological; Biological Assay; Brain; Cell Line; Cell physiology; Cells; Chiroptera; Code; DNA; DNA Transposable Elements; Development; Disease; Elements; Endogenous Retroviruses; Evolution; Fossils; Fostering; Genes; Genetic Diseases; Genetic Variation; Genome; Genomics; Health; Human; Human Genome; Infection; Innate Immune System; Interferons; Malignant Neoplasms; Mammals; Mobile Genetic Elements; Molecular; Neurodevelopmental Disorder; Outcome; Perception; Physiological; Physiology; Population; Primates; Property; Proteins; Rodent; Role; Sequence Analysis; Source; Testing; Time; Transposase; Untranslated RNA; Variant; design; env Gene Products; genome editing; genomic variation; innovation; insight; mammalian genome; response; structural genomics; transcriptomics; vertebrate genome

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.

项目摘要 转座因子（TE）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多种遗传疾病。因为 除了这些致突变特性之外，TE是物种之间和物种内遗传变异的重要驱动因素。 TE活性占每个哺乳动物物种所特有的大部分DNA，并负责 人类群体中多达30%的结构基因组变异。然而这怎么 巨大的遗传变异源影响物种的进化和生理仍然很差 明白该项目旨在对TE的生物学意义产生变革性的见解 在进化和疾病中。在这个提议中测试的中心假设是，预制监管 和编码活动的祖先编码的TE已增选反复在脊椎动物 进化，以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测试假设，多态性和 谱系特异性TE对转录组和顺式调节变异有重要贡献， 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， 强调长非编码RNA库的起源和周转。此外，我们将调查 TE在先天免疫系统的主要组成部分的调节进化中的作用， 干扰素应答细胞系中的实验操作，包括基因组编辑和功能 测定，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，我们将结合联合收割机进化序列分析和功能测定， 表征了人类基因组中用于细胞功能的几个TE衍生基因。值得注意的是， 将测试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 参与大脑功能和发育。预计这一提案的结果将 将对TE的看法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，我们的研究势必会揭示关键的新见解， 移动的遗传元件促进疾病状态，包括癌症、自身免疫和 神经发育障碍