Inferring the structure and evolution of tandem duplication towers

推断串联复制塔的结构和演化

• 批准号: 10536029
• 负责人: Zi-Ning Choo
• 金额: $ 5.18万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536029
• 关键词: Algorithms; Alleles; Automobile Driving; Cells; Chromatin Loop; Chromatin Structure; Complex; DNA; DNA Repair; DNA copy number; Data; Defect; Development; Evolution; Genome; Genomic Segment; Genomics; Graph; Haplotypes; Individual; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Modality; Modeling; Mutation; Ovarian Adenocarcinoma; Pattern; Phase; Phylogenetic Analysis; Positioning Attribute; Prognostic Marker; Prostate Adenocarcinoma; Recurrence; Single-Stranded DNA; Structure; Systemic Therapy; Taxonomy; Technology; Tissue Sample; Variant; Work; base; cancer genome; computer framework; computerized tools; data structure; dosage; driver mutation; genome sequencing; genomic profiles; new technology; novel; repaired; tool; tumor; whole genome

PROJECT SUMMARY Complex structural variants (SVs) are a class of mutations consisting of clustered DNA copy number changes and rearrangements. These alterations can produce driver mutations in cancer but have been underexplored due to the analytical limitations of bulk short read sequencing. There is an urgent need for new computational tools that can apply long-range and single cell genomic profiles to structural variant analysis. Genome graphs are a computational framework that can be extended to these new data modalities to study the allelic structure and evolution of complex SVs. Recent genome graph analysis of pan-cancer whole genomes by our lab identified a novel complex structural variant pattern termed pyrgo. Pyrgo consist of “towers” of clustered tandem duplications and are enriched in prostate and ovarian adenocarcinomas. In Aim 1, we will construct haplotype graphs to characterize the allelic structure of pyrgo. Haplotype graphs represent allele-specific genomic segment and junction copy numbers and will be inferred from long range profiling data. Using these graphs, we will characterize the parental and somatic allele structure of pyrgo duplications in pan-cancer genomes. We will identify associations between allelic structure and cell-of-origin, prior systemic therapy, and genomic features such as chromatin loops and replication timing. In Aim 2, we will construct single cell genome graphs that recapitulate the evolution of pyrgo. Single cell genome graphs are a set of phylogenetically linked genome graphs representing the structural variants present in individual cells, along with the ancestral subclone in which each aberrant genomic junction first arose. These graphs will be inferred from single cell whole genome profiles. We will use single cell genome graphs to model the acquisition of tandem duplications comprising pyrgo during tumor evolution in ovarian adenocarcinoma tissue samples.

项目摘要 复杂的结构变体（SVS）是一类突变，由聚类的DNA拷贝数变化组成 和重排。这些改变会在癌症中产生驱动器突变 由于批量简短读取测序的分析限制。迫切需要新的计算 可以将远距离和单细胞基因组概况应用于结构变异分析的工具。基因组图 是一个计算框架，可以扩展到这些新数据模式以研究等位基因结构 和复杂SV的演变。我们的实验室确定的泛 - 癌全基因组的最新基因组图分析 一种新颖的复杂结构变体模式称为pyrgo。 Pyrgo由聚集串联的“塔”组成 重复，并富含前列腺和卵巢腺癌。在AIM 1中，我们将构建单倍型 图表以表征Pyrgo的等位基因结构。单倍型图代表等位基因特异性基因组 段和连接拷贝数，将从远程分析数据中推断出来。使用这些图，我们 将表征Pan-Cancer基因组中Pyrgo重复的父母和体细胞等位基因结构。我们将 识别Allic结构与原始细胞之间的关联，先验的全身疗法和基因组特征 例如染色质环和复制时间。在AIM 2中，我们将构造单细胞基因组图 概括了皮尔戈的演变。单细胞基因组图是一组系统发育连接的基因组 代表单个细胞中存在的结构变体的图以及祖先亚克隆 每个异常基因组结首先出现。这些图将从单细胞整体基因组谱推断。 我们将使用单细胞基因组图来对串联复制的获取进行建模，以涵盖Pyrgo 卵巢腺癌组织样品中的肿瘤进化。