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.

项目总结 复杂结构变异体(Complex Structure Variants，SVS)是一类由聚集的DNA拷贝数变化组成的突变 和重新编排。这些改变可以导致癌症的驱动程序突变，但还没有得到充分的研究 由于批量短读测序的分析限制。迫切需要新的计算方法 可将远程和单细胞基因组图谱应用于结构变异分析的工具。基因组图 是一种计算框架，可以扩展到这些新的数据模式来研究等位基因结构 和复杂SVS的演变。我们实验室对泛癌全基因组的最新基因组图谱分析 一种新的复杂结构变异模式，称为Pirgo。PYRGO由群集式串联的“塔”组成 在前列腺癌和卵巢腺癌中含量较高。在目标1中，我们将构建单倍型 用曲线图来描述Pirgo的等位基因结构。单倍型图代表特定等位基因的基因组 片段和连接的拷贝数，并将从长距离剖面数据中推断。使用这些图表，我们 将表征泛癌基因组中Pirgo复制的亲本和体细胞等位基因结构。我们会 确定等位基因结构与起源细胞、既往系统治疗和基因组特征之间的关系 例如染色质环和复制计时。在目标2中，我们将构建单细胞基因组图 简单回顾一下Pyrgo的演变。单细胞基因组图是一组与系统发育相关的基因组 代表存在于单个细胞中的结构变体的曲线图，以及其中的祖先亚克隆 每个异常的基因组连接最先出现。这些曲线图将从单细胞全基因组图谱中推断出来。 我们将使用单细胞基因组图对包含PYRGO的串联复制的获取进行建模 卵巢腺癌组织标本中肿瘤的演变。