Computational approaches for identifying epigenomic contexts of somatic mutations

摘要 在正常发育、衰老和癌症等疾病期间，由于内源性和 外部因素和修复缺陷导致不同类型的体细胞突变的积累，包括 单核苷酸替换、小内切、拷贝数改变、易位和倍性改变。 虽然基因组中的绝大多数体细胞突变不是疾病的驱动因素，但它们的遗传模式 变化和相关的背景可以提供对过去接触诱变剂的洞察，DNA的机制 损伤和修复缺陷，以及基因组不稳定的程度，这对了解疾病很重要 病因学，将危险环境暴露降至最低，并预测新出现的治疗方法的疗效 免疫治疗等策略。一些突变签名已经根据本地 对上下文进行排序以满足这一需求。但是，DNA损伤和修复偏好的机制取决于 既有局部序列又有表观基因组背景，表观基因组背景是否存在还有待理解 可以在全基因组范围内提供关键的、互补的病因学见解 规模，这在仅从序列上下文中并不明显。这具有根本性的重要性，因为(I) 许多新出现的突变特征的病因目前尚不清楚，(Ii)DNA损伤反应和 修复依赖于组织环境，核心DNA修复基因的缺陷通常会导致癌症的发展 组织特异性方式，以及(Iii)茎和茎之间DNA损伤和修复程度的差异 同一组织内分化的细胞会导致衰老和疾病发病率。已建成 在我们以前工作的基础上，我们建议开发计算方法来确定 关于组织类型内和跨组织类型的体细胞突变模式的表观基因组学背景，并验证 使用定向实验的计算预测。在AIM-1中，我们将开发表观基因组学背景 新出现的突变签名的偏好图。在AIM-2中，我们将确定组织依赖的基础 由于DNA修复缺陷导致的突变图谱的差异。在AIM-3中，我们将预测细胞的范围 来自末端细胞突变格局的依赖于世系的突变累积模式。我是 目前是一名早期研究员，该提案与我确定根本原因的长期目标一致 体细胞基因组的可变性和可进化性原理。我们的项目将提供新的资源和 关于解决发育和衰老过程中的基因组完整性问题以及疾病的知识 比如癌症。 好了！

ABSTRACT During normal development, aging, and diseases such as cancer, DNA damage due to endogenous and external factors, and repair defects result in accumulation of different types of somatic mutations including single nucleotide substitutions, small InDels, copy number alterations, translocations, and ploidy changes. While a vast majority of somatic mutations in the genome are not disease drivers, their patterns of genetic changes and associated context can provide insights into past exposure to mutagens, mechanisms of DNA damage and repair defects, and extent of genomic instability, which are important for understanding disease etiology, minimizing hazardous environmental exposure, and also predicting efficacy of emerging treatment strategies such as immunotherapy. A number of mutation signatures have been identified based on local sequence contexts to address this need. But, mechanisms of DNA damage and repair preferences depend on both local sequence and epigenomic contexts, and it remains to be understood whether epigenomic contexts of emerging mutation signatures can provide critical, complementary etiological insights at a genome-wide scale, which are not apparent from sequence contexts alone. This is of fundamental importance, because (i) etiology of many of the emerging mutation signatures is currently unknown, (ii) DNA damage response and repair depends on tissue contexts, and defects in core DNA repair genes often result in cancer development in tissue-specific manner, and (iii) differences in the extent of DNA damage and repair between stem and differentiated cells within the same tissues have consequences for aging and disease incidence rates. Built logically on our previous works, we propose to develop computational approaches to determine the impact of epigenomic contexts on the patterns of somatic mutations within and across tissue types, and validate computational predictions using targeted experiments. In Aim-1, we will develop an epigenomic context preference map for emerging mutation signatures. In Aim-2, we will determine the basis of tissue-dependent differences in mutation profiles attributed to DNA repair defects. In Aim-3, we will predict the extent of cell lineage-dependent patterns of mutation accumulation from the mutational landscape of terminal cells. I am currently an early stage investigator, and the proposal is aligned with my long-term goal to identify fundamental principles of mutability and evolvability of somatic genomes. Our project will deliver novel resources and knowledge for addressing questions regarding genomic integrity during development and aging, and diseases such as cancer. !