Inferring the structure and evolution of tandem duplication towers

项目摘要 复杂结构变异体（SV）是一类由成簇的DNA拷贝数变化组成的突变 和重新安排。这些改变可以在癌症中产生驱动突变，但尚未得到充分研究 这是由于批量短读测序的分析限制。迫切需要新的计算 可以将长距离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 是一个计算框架，可以扩展到这些新的数据模式，以研究等位基因结构 和复杂SV的进化。我们实验室最近对泛癌全基因组的基因组图谱分析确定了 一种称为pyrgo的新的复杂结构变体模式。Pyrgo由“塔”组成的集群串联 在前列腺和卵巢腺癌中富集。在目标1中，我们将构建单体型 图来表征pyrgo的等位基因结构。单倍型图表示等位基因特异性基因组 片段和连接拷贝数，并将从长范围剖析数据推断。利用这些图表，我们 将表征泛癌基因组中pyrgo重复的亲本和体细胞等位基因结构。我们将 确定等位基因结构与细胞来源、既往系统治疗和基因组特征之间的关联 例如染色质环和复制定时。在目标2中，我们将构建单细胞基因组图， 概括了双鱼座的进化过程单细胞基因组图谱是一组遗传连锁的基因组 代表单个细胞中存在的结构变体的图，沿着祖先亚克隆，其中 每个异常的基因组连接首先出现。这些图将从单细胞全基因组谱推断。 我们将使用单细胞基因组图来模拟在细胞周期中获得包含pyrgo的串联重复。 卵巢腺癌组织样品中的肿瘤演变。

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.