Understanding the NMD regulatory path from genetic variation to phenotypes

项目总结 我们对胡说八道的监管机制的理解存在根本性的差距- 介导的信使核糖核酸衰减(NMD)。最初被设想为一个质量控制检查点，以识别 和降解异常转录本，NMD已被认为是转录后基因 微调多种非异常内源性mRNAs表达的调控机制。 然而，尽管NMD途径上有过多的生化特征，但 对NMD的调控机制和NMD目标选择的标准知之甚少。 我们的长期目标是开发计算机方法来发现基因的原理 表达调控，并探索基因调控中的变异或缺陷是如何导致 表型变异或疾病。本应用程序的总体目标是阐明 通过遗传基因组学对单个基因进行上下文相关的NMD调控。遗传 与基因表达变化相关的变异(表达数量性状基因座，eQTL) 在越来越大的人类研究中被编目，例如基因组织 表达式(GTEx)项目。我们将利用这一前所未有的资源来剖析 控制国家导弹防御系统，以系统和公正的方式发现国家导弹防御系统监管规则。 传统的生化和分子方法是破译NMD的关键 机制，但由于固有的局限性，进展缓慢。基因基因组学将提供一种 新的观点，并有很大希望发现新的NMD监管规则。我们将发展 为分析NMD规则量身定做的新统计和计算方法。这些 该方法也可广泛应用于其他调节变种的研究。我们的悠久历史 在转录分析、eQTL分析和NMD监管方面的专业知识使我们处于一个独特的 完成提议的项目的职位。 所提出的方法满足了转录组学eqtl带来的分析挑战。 测绘和RNA生物学。该项目的竣工将纵向推进和扩大 我们对NMD如何调控基因表达的理解。归根结底，这种知识具有 开发基于NMD的预防和治疗干预措施的潜力。

PROJECT SUMMARY There are fundamental gaps in our understanding of the regulatory mechanisms of nonsense- mediated mRNA decay (NMD). Originally conceived as a quality-control checkpoint to recognize and degrade aberrant transcripts, NMD has become appreciated as a post-transcriptional gene regulation mechanism to fine-tune expression of many non-aberrant endogenous mRNAs. However, despite a plethora of biochemical characterization on the NMD pathway, the mechanism of NMD regulation and the criteria for NMD target selection are poorly understood. Our long-term goal is to develop computational methods to discover the principles of gene expression regulation and explore how variations or defects in gene regulation cause phenotypic variation or disease. The overall objective of this application is to elucidate the context-dependent NMD regulation of individual genes through genetical genomics. Genetic variants associated with changes in gene expression (expression quantitative trait loci, eQTLs) are being catalogued in increasingly large-scale human studies, such as the Genotype-Tissue Expression (GTEx) project. We will take advantage of this unprecedented resource to dissect NMD control and to discover NMD regulatory rules in a systematic and unbiased manner. Traditional biochemical and molecular approaches are essential to deciphering NMD mechanism but are slow in progress with intrinsic limitations. Genetical genomics will provide a fresh view and has great promise to uncover new regulatory rules of NMD. We will develop novel statistical and computational methods tailored to the analysis of NMD regulation. These methods can also be broadly applied to studies of other regulatory variants. Our long-standing expertise in transcriptomics analysis, eQTL analysis, and NMD regulation places us in a unique position to accomplish the proposed project. The proposed methods meet the analysis challenges arising from transcriptomics, eQTL mapping, and RNA biology. The completion of this project will vertically advance and expand our understanding of how NMD regulates gene expression. Ultimately, such knowledge has the potential to develop NMD-based preventive and therapeutic interventions.