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.

家长奖摘要 这是对夏博博士NIH主任早期独立奖的建议补充 （DP5OD033430）标题：“转座因子相互作用及其对人类发育的影响 健康”。下面是这个奖项的摘要： 人类基因组计划最令人惊讶的发现之一是， 1.5%的基因组编码蛋白质，而约46%的基因组包含转座因子 （TE）。对这些无处不在的TE如何影响人类发育和健康的功能评估 提出了一个重大挑战。虽然大多数TE被认为是无功能的，或“垃圾”DNA，在这里我认为， TE诱导的基因调控被严重低估，这是因为历史上倾向于探索 TE功能通过研究独立的TE彼此。我打算写一本小说 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前 mRNA剪接影响基因功能，并研究这种机制是否可以在很大程度上 影响人类的发展和进化，并有助于解释人类的遗传病因学 疾病这个建议的灵感来自于我最近的发现，一对Alu 反转录转座子可以解释人类尾部缺失进化的长期寻找的遗传基础， 猿类在此基础上，利用TBXT基因中Alu对的互作效应 作为一个模型，以证明内含子TE之间的相互作用可以深刻地影响人类 发展和健康，并解释一种常见遗传疾病的病因（目标1）。目的2 建议测试的假设，TBXT的亚型诱导的相互作用的Alu对 多效性有助于加强后肢，从而直接测试长期存在的 一种假设，即类人猿的尾巴缺失进化与双足运动进化有关 (Aim 2）。除了TBXT基因中Alu对的特异性相互作用外，Aim 3还将开发一种新的基因。 算法称为TEILO（转座元素相互作用和本地组织）， 确定功能性TE相互作用，通过调节基因功能和人类健康， 选择性剪接这一工作为研究TEs与 它对人类健康和疾病影响。