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: 10705110
• 负责人: Bo Xia
• 金额: $ 36.42万
• 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 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705110
• 关键词: Affect; Algorithms; Alternative Splicing; Alu Elements; Anatomy; Animal Model; Back Pain; Base Pairing; Biological; Biology; Brachyury protein; Chemistry; Code; Communities; Comparative Genomic Analysis; Congenital Abnormality; Creativeness; Custom; DNA Transposable Elements; Data; Dedications; Developmental Biology; Disease; Doctor of Philosophy; Elements; Embryonic Development; Ensure; Equipment; Etiology; Evolution; Exons; Faculty; Fellowship; Funding; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genome; Genomics; Grant; Health; Hindlimb; Human; Human Development; Human Genetics; Human Genome; Human Genome Project; Incidence; Individual; Institution; Introns; Junk DNA; Knee Osteoarthritis; Laboratories; Leadership; Limb Development; Locomotion; Mentors; Modeling; Modernization; Neural Tube Defects; Neural Tube Development; Neurons; Pongidae; Price; Primates; Principal Investigator; Protein Isoforms; Proteins; Publishing; RNA Splicing; Recording of previous events; Research; Retrotransposon; Science; Spinal Dysraphism; Systems Biology; Tail; Testing; Therapeutic; Training; Work; Writing; experience; gene function; human disease; human genomics; innovation; mRNA Precursor; meetings; multidisciplinary; neonate; novel; prevent; success; technology development

PROJECT SUMMARY 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 promises to provide a new paradigm to studying the interaction between TEs and its implication to human health and diseases.

项目摘要 人类基因组计划最令人惊讶的发现之一是， 编码蛋白质，而大约46%的编码蛋白质包含转座因子（TE）。功能评估 这些无处不在的TEs如何影响人类发展和健康已经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诱导的基因调控是强烈的， 由于历史上倾向于通过研究单个TE来探索TE功能， 彼此独立。我建议提供一个新的框架来研究如何之间的相互作用 迄今为止，“垃圾”TE序列可以调节前mRNA剪接以影响基因功能，并研究是否 这种机制可能会对人类的发展和进化产生重大影响，并有助于解释 人类疾病的遗传病因学。这个提议的灵感来自于我最近的发现， 一对Alu反转录转座子之间的联系可能解释了长期以来寻找的尾缺失进化的遗传基础， 人类和猿类。基于这项工作和我的初步数据，我将首先使用TBXT中的Alu对相互作用 基因作为一个模型，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）。目标2：测试 假设由Alu对的相互作用诱导的TBXT亚型多效性有助于 加强后肢，从而直接测试长期存在的假设，即尾巴损失的演变， 类人猿与双足运动进化有关（目标2）。除了Alu对的特定相互作用之外 在TBXT基因中，Aim 3将开发一种称为TEILO（转座因子相互作用和局部）的算法， 组织）系统地识别影响基因功能和人类健康的功能性TE相互作用 通过调节可变剪接。这一工作有望为研究这种相互作用提供一个新的范式 与其对人类健康和疾病的影响之间的关系。