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.

家长奖概要 这是对夏波博士的 NIH 主任早期独立奖的拟议补充 （DP5OD033430）标题：“转座元件相互作用及其对人类发展的影响 以下是该家长奖的摘要： 人类基因组计划最令人惊讶的发现之一是，只有大约 1.5% 的基因组编码蛋白质，而大约 46% 包含转座元件 （TE）对这些无处不在的 TE 如何影响人类发展和健康进行了功能评估。 虽然大多数 TE 被认为是无功能的或“垃圾”DNA，但我在这里认为这是一个重大挑战。 由于探索的历史趋势，TE 诱导的基因调控被严重低估 我建议通过研究彼此独立的各个 TE 来提供一种新颖的功能。 框架来研究迄今为止的“垃圾”TE序列之间的相互作用如何调节预 mRNA 剪接影响基因功能，以及研究这种机制是否可以实质上 影响人类的发育和进化，并有助于解释人类的遗传病因学 这个提议的灵感来自于我最近发现一对 Alu 之间的相互作用。 逆转录转座子可以解释人类和人类尾巴缺失进化的长期寻找的遗传基础。 根据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。 作为模型来证明内含子 TE 之间的相互作用可以深刻影响人类 发育和健康，并解释常见遗传病的病因（目标 1）。 提议检验以下假设：TBXT 亚型是由 Alu 对相互作用诱导的 多效性有助于增强后肢，从而直接测试长期存在的 假设人科动物的尾部丢失进化与双足运动进化有关 （目标 2）。除了 TBXT 基因中 Alu 对的特定相互作用之外，目标 3 将开发一种 称为 TEILO（转置元素交互和本地组织）的算法可以系统地 通过调节来识别影响基因功能和人类健康的功能性 TE 相互作用 这项工作为研究 TE 和 之间的相互作用提供了一个新的范式。 它对人类健康和疾病的影响。