Computational methods for detecting patterns of complex genomic variation

检测复杂基因组变异模式的计算方法

• 批准号: 10077847
• 负责人: Vineet Bafna
• 金额: $ 28.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077847
• 关键词: Architecture; Bioinformatics; Biological Sciences; Cataloging; Cells; Cervical; Chromosomal Rearrangement; Collaborations; Complex; Computing Methodologies; Cytogenetics; DNA Sequence Rearrangement; Data; Detection; Development; Directed Molecular Evolution; Disease; Elements; Epigenetic Process; Event; Evolution; Funding; Gene Amplification; Genetic Variation; Genome; Genomic Segment; Genomics; Germ Lines; Grant; Histologic; Hot Spot; Human; Human Genome; Human Papilloma Virus-Related Malignant Neoplasm; Image; Lead; Location; Malignant Neoplasms; Maps; Mechanics; Mediating; Metaphase; Nature; Oncogenes; Optics; Partner in relationship; Pattern; Play; Publications; Research; Role; Sampling; Somatic Cell; Source; Structure; Tandem Repeat Sequences; Technology; Transcript; Variant; Viral; Viral Genome; Virus Integration; Work; cancer diagnosis; cancer subtypes; chromothripsis; computerized tools; extrachromosomal DNA; genomic signature; genomic variation; nanopore; novel; tool; whole genome

Project Summary Structural variations (SVs) – involving changes in copy number, inversions, translocations, and other mechanisms– are an important source of genetic variation. They occur in the germ-line and also in so- matic cells, where they sometimes play an outsized role in diseases, cancer being a prominent example. Much work has been done in identifying and cataloging `simple' variants such as deletions, duplications, translocations, and others. In contrast, our continuing proposal is about `complex' structural variation, characterized by extensive structural changes involving multiple breakpoints and simple SV events. In previous research funded by the grant (17 publications), we developed and extended tools for identifying complex SVs including Breakage Fusion Bridge characterized by specific copy number patterns, detec- tion of chains of disparate genomic segments as defined by Chromothripsis and Chromoplexy, and viral mediated rearrangements. Perhaps most relevant to the current proposal, is the problem of determining architecture and origin of focal amplification of smaller (< 10Mb) genomic segments. Working with col- laborators, we observed an abundance of large circular, extrachromosomal DNA (Turner, Nature 2017), detecting them in 40% of all cancer samples across a multitude of histological subtypes. EcDNA are hot- spots for complex, even multi-chromosomal genomic rearrangements, and o↵er a mechanistic explanation of focal amplifications. These discoveries were supported by the devlopment of many computational tools: AmpliconArchitect (AA) for reconstructing the fine structure of ecDNA using Illumina short-reads, ViFi for identifying complex variation due to viral integration in humans, and ecDetect for detection and quantification of ecDNA in cytogenetic images acquired in metaphase. For this grant, we will (i) develop Amplicon Reconstructor (AR) as a tool for disambiguated AA reconstructed amplicons using long reads–Oxford Nanopore, Pacific Biosciences, and Optical Nanopore technology; (ii) use AR to understand the evolution of complex structural variation thorugh directed evolution of ecDNA in the lab; and (iii), integrate data from thousands of whole genome sequences, transcript and other epigenetic data to elucidate the functional aspects of ecDNA elements.

项目概要 结构变异 (SV) – 涉及拷贝数、倒位、易位和其他变化 机制——是遗传变异的重要来源。它们发生在种系中，也存在于如此- 有时它们在疾病中发挥着巨大的作用，癌症就是一个突出的例子。 在识别和编目“简单”变体（例如删除、重复、 易位等。相比之下，我们持续提出的建议是关于“复杂”的结构变化， 其特点是广泛的结构变化，涉及多个断点和简单的 SV 事件。在 之前由该赠款资助的研究（17 篇出版物），我们开发并扩展了用于识别 复杂的SV，包括以特定拷贝数模式为特征的断裂融合桥，检测 由 Chromothripsis 和 Chromoplexy 定义的不同基因组片段的链和病毒 介导的重排。也许与当前提案最相关的是确定问题 较小（< 10Mb）基因组片段的局部扩增的结构和起源。与同事合作 在实验室中，我们观察到了大量的大型环状染色体外 DNA（Turner，Nature 2017）， 在多种组织学亚型的 40% 癌症样本中检测到它们。 EcDNA很热门- 复杂的甚至多染色体基因组重排的斑点，并提供机械解释 的焦点放大。这些发现得到了许多计算工具的开发的支持： AmpliconArchitect (AA)，用于使用 Illumina 短读长重建 ecDNA 的精细结构， ViFi 用于识别由于人类病毒整合而产生的复杂变异，而 ecDetect 用于检测 以及中期获得的细胞遗传学图像中 ecDNA 的定量。对于这笔赠款，我们将 (i) 开发 Amplicon Reconstructor (AR) 作为使用长的消除歧义 AA 重建扩增子的工具 阅读：Oxford Nanopore、Pacific Biosciences 和 Optical Nanopore 技术； (ii) 使用 AR 来理解 通过实验室中 ecDNA 的定向进化实现复杂结构变异的进化；和（三）， 整合来自数千个全基因组序列、转录本和其他表观遗传数据的数据来阐明 ecDNA 元件的功能方面。