Diversity Supplement for Prioritization of Splicing-Altering Genetic Variants in Alzheimer's disease

项目摘要 这个项目的目标是开发计算管道，允许在硅片预测 破坏阿尔茨海默病中前mRNA剪接和相关通路的功能性遗传变异 疾病（AD）。近年来，在建立一个目录， 不同患者群体的AD基因组中的遗传变异。下一个巨大的挑战是 鉴定致病变异并阐明它们与疾病过程相关的潜在功能。到 为此，研究工作已致力于研究位于蛋白质编码中的变体， 启动子和剪接位点区域，因为它们对基因表达有明显的影响。然而，在这方面， 许多新鉴定的疾病相关变体存在于其它非编码区， 例如内含子，其可赋予相关基因调节功能。的机制 这些变体很难破译。预计其中许多机构将在 转录后水平，从而影响mRNA表达。在人类中，无数的过程 在转录后阶段介导RNA表达，其中之一是剪接。剪接 选择性剪接是哺乳动物基因表达的重要步骤， 基因.最近的文献报道，RNA剪接是GV和疾病之间的主要联系。 一般来说，据估计，15-60%的点突变，导致人类遗传 疾病破坏了剪接，突出了这一调节步骤的重要性。在AD中，异常 剪接已在许多功能关键基因中检测到，其中一些基因受 GVs。尽管重要，如何准确识别剪接中的功能性遗传变异 监管仍然是该领域的一个关键问题。为了解决这个问题， 从AD和对照受试者收集的RNA-Seq和基因分型数据集代表了 无价的资源我们将开发和应用新的方法，充分利用这些 数据集，辅以进一步的生物信息学预测和实验验证。这 这项工作将使人们对剪接过程中的遗传变异有一个前所未有的了解 规则，并提供新的手段来解决功能注释的迫切任务， AD的遗传变异

Project Summary The goal of this project is to develop computational pipelines that allow in silico prediction of functional genetic variants that disrupt pre-mRNA splicing and related pathways in Alzheimer's disease (AD). Recently, tremendous success has been achieved in constructing a catalog of genetic variants in AD genomes of various patient cohorts. The next great challenge is to identify causal variants and elucidate their potential function relevant to 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, one of which being splicing. Splicing is an essential step of mammalian gene expression and alternative splicing affects most human genes. Recent literature reported that RNA splicing is a primary link between GVs and disease. In general, it was estimated that 15-60% of point mutations that result in human genetic diseases disrupt splicing, highlighting the importance of this regulatory step. In AD, aberrant splicing has been detected in many functionally critical genes, some of which are modulated by GVs. Despite the importance, how to accurately identify functional genetic variants in splicing regulation remains a key question in the field. To address this question, the large collection of RNA-Seq and genotyping data sets collected from AD and control subjects represent an invaluable resource. We will develop and apply novel methodologies to make full use of these data sets, complemented by further bioinformatic prediction and experimental validations. This work will allow a previously unattained level of understanding of genetic variants in splicing regulation and provide new means to tackle the imperative task of functional annotations of genetic variants in AD.