Using long-range technologies as a multi-omic approach to understand Alzheimer’s disease in brain tissue

项目摘要/摘要 我们的长期目标是帮助开发有意义的治疗和症状前诊断 对于阿尔茨海默氏症，因为虽然改变疾病的治疗是必不可少的，但它不会 在没有在症状出现之前识别疾病的诊断的情况下就足够了。我们寻求 通过帮助确定特定的分子修饰来为这些长期目标做出贡献，以及 因此，使用远程光学DNA测绘和驱动疾病的特定机制 测序技术。不幸的是，大多数阿尔茨海默病基因只与 通过常见的非功能性变异，目前仍不清楚大多数阿尔茨海默病 基因与疾病有关。同样，在患病的大脑中，单个RNA亚型 人们对阿尔茨海默病的基因及其与疾病的关系知之甚少。功能性 病变脑组织中异构体水平的变异和RNA测序将提供特异的 以治疗和诊断为目标的机制。大量短读测序工作包括 已经在进行识别与阿尔茨海默氏病有关的小功能变异，但具有结构性 DNA变异--其中许多直接影响下游RNA和蛋白质--也会导致 神经退行性疾病。我们假设未发现的SVS和异常的RNA异构体 在阿尔茨海默氏症中起直接作用。远程脑成像在脑病变中的应用研究 DNA和RNA技术将补充目前的短读努力，提供重要的 疾病洞察。

PROJECT SUMMARY/ABSTRACT Our long-term goal is to help develop a meaningful therapeutic and pre-symptomatic diagnostic for Alzheimer’s disease because, while a disease-altering therapeutic is essential, it will not be sufficient without a diagnostic that identifies disease before symptoms onset. We seek to contribute to these long-term goals by helping identify specific molecular modifications, and therefore specific mechanisms, driving disease using long-range optical DNA mapping and sequencing technologies. Unfortunately, most Alzheimer’s disease genes are only implicated through common non-functional variants, and it is still unclear how most Alzheimer’s disease genes are involved in disease. Likewise, individual RNA isoforms in diseased brains for top Alzheimer’s disease genes and their involvement in disease are poorly understood. Functional variants and RNA sequencing at the isoform level in diseased brain tissue will provide specific mechanisms to target for therapeutics and diagnostics. Large short-read sequencing efforts are already ongoing to identify small functional variants involved in Alzheimer’s disease, but structural DNA variants—many of which directly affect downstream RNA and proteins—also cause neurodegenerative diseases. We hypothesize that undiscovered SVs and aberrant RNA isoforms play a direct role in Alzheimer’s disease. A thorough study in diseased brain using long-range DNA and RNA technologies will complement current short-read efforts, providing important disease insights.