Transposable Element Interaction and Its Impact on Human Development and Health

转座元件相互作用及其对人类发育和健康的影响

• 批准号: 10894990
• 负责人: Bo Xia
• 金额: $ 4.8万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10894990
• 关键词: Affect; Algorithms; Alternative Splicing; Award; Code; DNA Transposable Elements; Data; Disease; Etiology; Evolution; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genome; Health; Hindlimb; Human; Human Development; Human Genome Project; Individual; Junk DNA; Locomotion; Modeling; Parents; Pongidae; Protein Isoforms; Proteins; RNA Splicing; Retrotransposon; Tail; Testing; United States National Institutes of Health; Work; gene function; human disease; mRNA Precursor; novel

Summary of Parent Award This is a proposed supplement to Dr. Bo Xia’s NIH Director’s Early Independence Award (DP5OD033430) titled: “Transposable Element Interaction and Its Impact on Human Development and Health”. Below is the abstract of this parent award: One of the most surprising discoveries from the Human Genome Project is that only about 1.5% of the genome codes for proteins, whereas around 46% comprises transposable elements (TEs). Functional assessment of how these ubiquitous TEs affect human development and health has posed a major challenge. While most TEs are considered non-functional, or “junk” DNA, here I argue that TE-induced gene regulation is strongly underestimated due to the historical tendency to explore TE functionality by studying individual TEs independently of each other. I propose to provide a novel framework to study how interactions between the hitherto “junk” TE sequences can regulate pre- mRNA splicing to affect gene function, and investigate whether such a mechanism could substantially affect both human development and evolution, and help explain the genetic etiology of human diseases. This proposal is inspired from my recent discovery that the interaction between a pair of Alu retrotransposons may explain the long-sought genetic basis for the evolution of tail loss in human and apes. Based on this work and my preliminary data, I will first use the Alu pair interaction in TBXT gene as a model to demonstrate that the interaction between intronic TEs can profoundly impact human development and health, and explain the etiology of a common genetic disease (Aim 1). Aim 2 proposes to test the hypothesis that the isoform of TBXT induced by interaction of the Alu pair pleiotropically contributes to strengthening of hindlimbs, thus directly testing the long-standing hypothesis that the tail-loss evolution in hominoids is associated with bipedal locomotion evolution (Aim 2). Beyond the specific interaction of the Alu pair in the TBXT gene, Aim 3 will develop an algorithm called TEILO (Transposable Element Interaction & Local Organization) to systematically identify the functional TE interactions that affect gene function and human health by modulating alternative splicing. This work premises a new paradigm to studying the interaction between TEs and its implication to human health and diseases.

父母奖摘要 这是Bo Xia博士的NIH董事早期独立奖提议的补充 （DP5OD033430）标题：“转座元素相互作用及其对人类发展的影响 和健康”。下面是该父母奖的摘要： 人类基因组项目中最令人惊讶的发现之一就是关于 蛋白质的1.5％的基因组代码，而大约46％的蛋白质构成了转座元素 （TES）。这些无处不在的TE如何影响人类发展和健康的功能评估 提出了一个重大挑战。虽然大多数TE被认为是非功能或“垃圾” DNA，但我在这里认为 由于历史探索趋势，该TE诱导的基因调节被强烈低估 通过独立研究个人TE来进行功能。我建议提供小说 研究击球手“垃圾”序列之间的相互作用的框架如何调节前 mRNA剪接以影响基因功能，并研究这种机制是否可以基本上可以 影响人类的发展和进化，并有助于解释人类的遗传病因 疾病。这项提案的灵感来自我最近发现的一对Alu之间的相互作用 逆转座子可能解释了人类尾部损失进化的长期遗传基础和 猿。基于这项工作和我的初步数据，我将首先使用TBXT基因中的Alu对相互作用 作为证明内含子TE之间的相互作用可以深远影响人类的模型 发展和健康，并解释常见遗传疾病的病因（AIM 1）。目标2 提议测试以Alu对相互作用引起的TBXT的同工型的假设 多效性有助于加强后肢，因此直接测试了长期的 假设人型中的尾部损伤演变与两体运动的演化有关 （目标2）。除了tbxt基因中ALU对的特定相互作用之外，AIM 3还将发展 算法称为Teilo（可转座元素互动和本地组织）至系统地 通过调节来确定影响基因功能和人类健康的功能性相互作用 替代剪接。这项工作将一个新的范式研究TES与TE之间的相互作用 它对人类健康和疾病的影响。