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

项目总结/摘要 我们的长期目标是帮助开发一种有意义的治疗和症状前诊断 因为，虽然改变疾病的治疗方法是必不可少的，但它不会 在症状出现之前没有诊断就足够了。我们寻求 通过帮助识别特定的分子修饰来促进这些长期目标， 因此，特定的机制，驱动疾病使用远程光学DNA图谱， 测序技术。不幸的是，大多数阿尔茨海默病基因只涉及 通过常见的非功能性变异，目前还不清楚大多数阿尔茨海默病是如何 基因与疾病有关。同样，患病大脑中的个体RNA亚型， 阿尔茨海默病基因及其与疾病的关系知之甚少。功能 在患病脑组织中同种型水平的变体和RNA测序将提供特异性 用于治疗和诊断的靶向机制。大型短读测序工作是 已经在进行中，以确定涉及阿尔茨海默病的小功能变异，但结构 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SV和异常RNA亚型 在老年痴呆症中起着直接的作用。一项利用长距离脑成像技术对病变大脑的深入研究 DNA和RNA技术将补充目前的短读工作， 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.