SEMIColon: Somatic Exploration of Mosaicism in Colon

项目摘要/摘要 如果我们了解健康组织的体细胞嵌合体，以及这种嵌合体是如何通过 在疾病的发病机制方面，我们将更好地装备起来筛查、监测和治疗疾病。体细胞突变 在疾病发病机制中发挥核心作用，从发育综合征到癌症，而且有越来越多的 人们一致认为，健康组织中的体细胞嵌合体会影响健康状况和疾病易感性。新的 方法上的突破使得能够准确地检测体细胞突变、突变率和 突变特征。在健康和患病组织中建立镶嵌轮廓的生物基线可以 促进基因驱动的疾病状态的预测和疾病管理的优化。 通过研究健康和患病结肠的体细胞嵌合体，我将对结直肠有更深入的了解 并建立了适用于其他组织的研究框架。结肠是马赛克的理想选择 研究，考虑到它的克隆地穴，提高的突变率，以及经过充分研究的架构。也有 体细胞嵌合体与结直肠疾病之间的重要关联：体细胞突变是致病因素 在结直肠癌(CRC)中，并被认为是导致炎症性肠病(IBD)的因素。这些 疾病有很好的区域性表现，沿着结肠长度有不同的病理， 如“右”和“左”结直肠癌以及不同聚集性的IBD亚型。然而，遗传病因 鉴于先前马赛克研究的局限性，这些病理基础尚不清楚。这项提议将 在健康组织和发病机制的背景下，检查结肠嵌合体的时空动力学。 评估整个结肠长度的嵌合体将提供对区域特异性的洞察 突变，无论是内源性的还是外源性的，解释了区域发病机制的差异。 Lee-Six等人的初步研究。报告的突变签名比例在整个 冒号。然而，这种分析受到测序覆盖率低(~15倍)和对小样本的检查的限制 一个小队列中的结肠亚区的数量。通过利用身体组织和结肠镜检查 随着生物学和计算的进步，我将用更大的 假设检验的决心和能力。这项建议将以个人和队列为基础确定 根据结肠解剖亚点的突变率并提取突变特征 突变过程，如细胞增殖或微生物群变异。我假设中肠- 后肠来源的结肠结构将具有独特的突变特征和独特的突变 不同地区的突变率。这些变异的地貌很可能会在区域上与 结直肠癌和炎症性肠病的空间关联发现，提示在发病机制中的作用。完成这项提案将 然后作为一个理想的框架来研究其他组织的区域变异和发病机制。

Project Summary/Abstract If we understand the somatic mosaicism of healthy tissues and how this changes through pathogenesis, we will be better equipped to screen for, monitor, and treat disease. Somatic mutations play a central role in disease pathogenesis, from developmental syndromes to cancer, and there is growing consensus that somatic mosaicism in healthy tissue influences fitness and disease predisposition. New methodological breakthroughs enable the accurate detection of somatic mutations, mutation rates, and mutational signatures. Establishing a biological baseline of mosaic profiles in healthy and diseased tissue can facilitate the prediction of genetically-driven disease states and the optimization of disease management. By studying somatic mosaicism in healthy and diseased colon, I will gain insight into colorectal pathogenesis and establish a research framework to apply to other tissues. The colon is ideal for mosaic research, given its monoclonal crypts, elevated mutation rate, and well-studied architecture. There are also significant associations between somatic mosaicism and colorectal disease: somatic mutations are causative in colorectal cancer (CRC) and are proposed to contribute to inflammatory bowel disease (IBD). These diseases have well-established regional presentations, with distinct pathologies along the length of the colon, such as “right” and “left” CRC and differently-clustered subtypes of IBD. However, the genetic etiologies underlying these pathologies are unknown, given previous limitations in mosaic research. This proposal will examine the spatiotemporal dynamics of colonic mosaicism in the context of healthy tissue and pathogenesis. Evaluating mosaicism across the length of the colon will provide insight into whether region-specific mutagenesis, either endogenous or exogenous, explains variation in regional pathogenesis. A preliminary study by Lee-Six et al. reported variation in mutational signature proportions across the colon. However, this analysis was limited by its low sequencing coverage (~15x) and examination of a small number of colonic subregions in a small cohort. By leveraging access to cadaver tissue and colonoscopy samples in tandem with biological and computational advances, I will quantify mosaicism with greater resolution and capacity for hypothesis testing. This proposal will determine individual and cohort-based mutational rates by anatomic subsite of the colon and extract mutational signatures that indicate mutagenic processes, such as cellular proliferation or microbiome variation. I hypothesize that midgut- and hindgut-derived colonic structures will harbor distinct mutational signatures from unique mutagenesis and regionally distinct mutation rates. These mutational landscapes will likely overlap regionally with the spatially-linked findings of CRC and IBD, suggesting a role in pathogenesis. Completion of this proposal will then serve as an ideal framework to examine regional variation and pathogenesis in other tissues.