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: 10481466
• 负责人: Bo Xia
• 金额: $ 34.91万
• 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/10481466
• 关键词: Affect; Algorithms; Alternative Splicing; Alu Elements; Anatomy; Animals; Back Pain; Base Pairing; Biological; Biology; Brachyury protein; Code; Communities; Comparative Genomic Analysis; Congenital Abnormality; Custom; DNA Transposable Elements; Data; 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; Introns; Junk DNA; Knee joint; Laboratories; Leadership; Light; 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; base; computational chemistry; experience; gene function; human disease; human genomics; innovation; mRNA Precursor; meetings; multidisciplinary; novel; prevent; success

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 人类基因组项目中最令人惊讶的发现之一是，只有约1.5％的基因组 代码蛋白质，而约46％的蛋白质包含转座元素（TES）。功能评估 这些无处不在的TE如何影响人类的发展和健康已引起重大挑战。而大多数 被认为是非功能性或“垃圾” DNA，我在这里认为TE诱导的基因调节强烈 由于历史倾向探索TE功能的历史趋势而低估了通过研究单个TES 彼此独立。我建议提供一个新颖的框架来研究如何之间的相互作用 迄今为止的“垃圾”序列可以调节前mRNA剪接以影响基因功能，并研究是否是否 这种机制可以实质上影响人类发展和进化，并有助于解释 人类疾病的遗传病因。该提议的灵感来自我最近发现的互动 在一对Alu逆转座子之间，可以解释尾巴损失演变的长期遗传基础 人和猿。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 基因作为一种模型，以证明内含子TE之间的相互作用可以深刻影响人类 发展和健康，并解释常见遗传疾病的病因（AIM 1）。 AIR 2提议测试 Alu对Pleiotiotiopopopopational诱导的TBXT的同工型的假设有助于 加强后肢，因此直接检验了长期存在的假设 类型与两足动力的演化有关（AIM 2）。超出ALU对的特定相互作用 在TBXT基因中，AIM 3将开发一种称为Teilo的算法（转座元素相互作用和局部 组织）系统地确定影响基因功能和人类健康的功能性相互作用 通过调节替代剪接。这项工作有望为研究互动提供新的范式 在TES及其对人类健康和疾病的影响之间。