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Analysis of functional genetic variants in RNA processing and expression

RNA加工和表达中的功能性遗传变异分析

基本信息

批准号：
10240961
负责人：
Xinshu Grace Xiao
金额：
$ 53.13万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2023-01-31
项目状态：
已结题

项目摘要

Project Summary The goal of this project is to functionally annotate genetic variants in post-transcriptional regulation of RNA expression, 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 expression. In human, a myriad of processes mediate RNA expression at the post-transcriptional stage, such as splicing, editing, polyadenylation and mRNA decay. Post-transcriptional regulation is extremely versatile, yet closely regulated, affecting most human genes. 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 methodologies 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 understanding of genetic variants in post-transcriptional regulation of RNA expression and provide new means to tackle the imperative task of functional annotations of genetic variants.

项目概要该项目的目标是对转录后基因变异进行功能注释 RNA表达的调控，扩展和补充了ENCODE当前的重点数据分析。最近，在构建目录方面取得了巨大成功。疾病基因组或人群中的遗传变异。下一个巨大的挑战是识别因果变异并阐明它们在生物和疾病中的潜在功能流程。为此，研究工作致力于研究位于蛋白质编码、启动子和剪接位点区域，因为它们对基因有明显的影响表达。然而，许多新发现的与疾病相关的变异存在于其他非编码区，例如内含子，可能赋予相关基因调节功能。这些变异的机制一直难以破译。预计他们中的许多人可能在转录后水平发挥作用，从而影响 mRNA 的表达。在人类中，一个转录后阶段有多种过程介导 RNA 表达，例如剪接、编辑、聚腺苷酸化和 mRNA 衰减。转录后调控的用途极其广泛，但受到严格调控，影响大多数人类基因。尽管很重要，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。到为了解决这个问题，大量的 ENCODE 表达和蛋白质结合数据代表着一种无价的资源。我们将开发新颖的方法来充分利用 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。这项工作将使以前未达到的水平了解 RNA 表达转录后调控中的遗传变异提供新的方法来解决遗传变异功能注释的迫切任务。