Analysis of causal genetic variants in pre-mRNA processing using ENCODE data

描述（由申请人提供）：项目概述本项目的目标是在mRNA加工调节中功能性地注释遗传变异，这扩展并补充了ENCODE数据分析的当前重点。最近，在构建疾病基因组或跨人群的遗传变异目录方面取得了巨大成功。下一个巨大的挑战是识别致病变异并阐明它们在生物学和疾病过程中的潜在功能。为此，研究工作已经针对研究位于蛋白质编码区、启动子区和剪接位点区的变体，因为它们对基因表达有明显的影响。然而，许多新发现的疾病相关变异存在于其他非编码区，如内含子，这可能赋予相关基因调控功能。这些变异的机制一直难以破译。预期它们中的许多可能在转录后水平起作用，从而影响mRNA加工。在人类中，mRNA加工是非常通用的，但受到密切调控，大多数基因参与至少一种替代加工途径。尽管重要，但如何准确地识别这些过程中的功能性遗传变异仍然是该领域的关键问题。为了解决这个问题，大量收集的ENCODE表达和蛋白质结合数据是一个宝贵的资源。我们将开发新的分析策略，以充分利用ENCODE和其他公开可用的数据集，并辅以进一步的生物信息学预测和实验验证。这项工作将允许检测基因调控的mRNA加工事件的先前未达到的水平，并提供新的手段来解决遗传变异的功能注释的迫切任务。 公共卫生相关性：替代mRNA加工可以显著改变基因表达并导致人类疾病。拟议的研究旨在使用ENCODE数据功能性地注释mRNA加工调节中的遗传变异。这项工作将为遗传变异如何导致疾病提供机制基础，以便未来的干预措施可以在治疗上靶向特定基因。

DESCRIPTION (provided by applicant): Project Summary The goal of this project is to functionally annotate genetic variants in the regulation of mRNA processing, which extends and complements the current focus of ENCODE data analysis. Recently, tremendous success has been achieved in constructing a catalog of genetic variants in disease genomes or across population. The next great challenge is to identify causal variants and elucidate their potential function in biological and disease processes. To this end, research efforts have been directed to studying variants located in protein-coding, promoter, and splice site regions due to their apparent impacts on gene expression. However, many of the newly identified disease-associated variants reside in other non-coding regions, such as introns, that may confer regulatory function to the related gene. The mechanisms of these variants have been hard to decipher. It is expected that many of them may function at the post-transcriptional level, thus affecting mRNA processing. In human, mRNA processing is extremely versatile, yet closely regulated, with most genes involved in at least one of the alternative processing pathways. Despite the importance, how to accurately identify functional genetic variants in these processes remains a key question in the field. To address this question, the large collection of ENCODE expression and protein-binding data represent an invaluable resource. We will develop novel analysis strategies to make full use of the ENCODE and other publicly available data sets, complemented by further bioinformatic prediction and experimental validations. This work will allow a previously unattained level of detection of genetically regulated mRNA processing events and provide new means to tackle the imperative task of functional annotations of genetic variants. PUBLIC HEALTH RELEVANCE: Alternative mRNA processing can significantly alter gene expression and contribute to human diseases. The proposed research aims to functionally annotate genetic variants in the regulation of mRNA processing using ENCODE data. This work will provide mechanistic basis for how genetic variations may contribute to diseases, such that future interventions can target specific genes therapeutically.