Systematic analysis of functional 3’ UTR genetic variants and their relevance to Alzheimer’s Disease

项目摘要 该项目的目标是鉴定和表征功能性3' UTR遗传变异， mRNA丰度的转录后调控，重点是与 阿尔茨海默病（AD）。最近，越来越多的遗传变异已经被发现。 包括AD在内的人类疾病的风险。然而，它仍然是一个伟大的 鉴定致病变异并阐明其与疾病相关的潜在功能的挑战 发病机制和进展。与精确定位基因变异的进展相比， 改变转录调控或蛋白质编码序列，遗传变异如何影响 对转录后过程了解甚少。许多新发现的AD相关 变体存在于非编码区，如内含子和3'UTR，其可以赋予调节性的功能。 对相关基因的功能，特别是在转录后调控水平。特别是， 人类基因的3 ′ UTR富含许多由 反式因子，如RNA结合蛋白（RBP）。总之，这些顺式元件和 反式因子决定了影响基因最终表达的mRNA的许多方面。mRNA 许多已知的AD相关基因的丰度受RBP或microRNA的调控 与它们的3'UTR结合。影响这些调节机制的遗传变异将导致 mRNA表达异常，从而显著改变相关功能通路。在这 项目，我们将利用大量的RBP-RNA相互作用分析的公共数据集， 从AD和对照受试者中收集的RNA-seq和基因分型数据，以及我们的内部数据 一代我们将开发和应用新的方法来充分利用这些数据集， 辅以进一步的生物信息学预测和高通量实验测试， 精确定位3' UTR遗传变异改变AD中mRNA丰度。这项工作将允许一个 以前未达到的水平的理解遗传变异的转录后调控 并提供新的手段来解决基因功能解释的迫切任务， AD的变体。

Project Summary The goal of this project is to identify and characterize functional 3’ UTR genetic variants that alter post-transcriptional regulation of mRNA abundance, with a focus on variants relevant to Alzheimer’s disease (AD). Recently, an increasing number of genetic variants have been cataloged that confer risks to human diseases, including AD. However, it remains a great challenge to identify causal variants and elucidate their potential function relevant to disease pathogenesis and progression. Compared to the progress in pinpointing genetic variants that alter transcriptional regulation or protein-coding sequences, how genetic variants may affect post-transcriptional processes is poorly understood. Many of the newly identified AD-associated variants reside in non-coding regions, such as introns and 3’ UTRs, that may confer regulatory function to the related gene, especially at the level of post-transcriptional regulation. In particular, the 3’ UTRs of human genes are enriched with many cis-regulatory elements recognized by trans-factors, such as RNA-binding proteins (RBPs). Together, these cis-elements and trans-factors dictate many aspects of the mRNA that affect the final expression of a gene. mRNA abundance of a number of well-known AD-relevant genes are regulated by RBPs or microRNAs bound to their 3’ UTRs. Genetic variants that affect these regulatory mechanisms will lead to abnormal mRNA expression, thus significantly altering related functional pathways. In this project, we will leverage the large collection of public data sets on RBP-RNA interaction profiling, RNA-seq and genotyping data collected from AD and control subjects, and our in-house data generation. We will develop and apply novel methodologies to make full use of these data sets, complemented by further bioinformatic prediction and high-throughput experimental testing, to pinpoint 3’ UTR genetic variants that alter mRNA abundance in AD. This work will allow a previously unattained level of understanding of genetic variants in post-transcriptional regulation and provide new means to tackle the imperative task of functional interpretation of genetic variants in AD.