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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结