Dataset Information

Integrative detection and analysis of structural variation in cancer genomes.

ABSTRACT: Structural variants (SVs) can contribute to oncogenesis through a variety of mechanisms. Despite their importance, the identification of SVs in cancer genomes remains challenging. Here, we present a framework that integrates optical mapping, high-throughput chromosome conformation capture (Hi-C), and whole-genome sequencing to systematically detect SVs in a variety of normal or cancer samples and cell lines. We identify the unique strengths of each method and demonstrate that only integrative approaches can comprehensively identify SVs in the genome. By combining Hi-C and optical mapping, we resolve complex SVs and phase multiple SV events to a single haplotype. Furthermore, we observe widespread structural variation events affecting the functions of noncoding sequences, including the deletion of distal regulatory sequences, alteration of DNA replication timing, and the creation of novel three-dimensional chromatin structural domains. Our results indicate that noncoding SVs may be underappreciated mutational drivers in cancer genomes.

SUBMITTER: Dixon JR

PROVIDER: S-EPMC6301019 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

Integrative detection and analysis of structural variation in cancer genomes.

Dixon Jesse R JR Xu Jie J Dileep Vishnu V Zhan Ye Y Song Fan F Le Victoria T VT Yardımcı Galip Gürkan GG Chakraborty Abhijit A Bann Darrin V DV Wang Yanli Y Clark Royden R Zhang Lijun L Yang Hongbo H Liu Tingting T Iyyanki Sriranga S An Lin L Pool Christopher C Sasaki Takayo T Rivera-Mulia Juan Carlos JC Ozadam Hakan H Lajoie Bryan R BR Kaul Rajinder R Buckley Michael M Lee Kristen K Diegel Morgan M Pezic Dubravka D Ernst Christina C Hadjur Suzana S Odom Duncan T DT Stamatoyannopoulos John A JA Broach James R JR Hardison Ross C RC Ay Ferhat F Noble William Stafford WS Dekker Job J Gilbert David M DM Yue Feng F

Nature genetics 20180910 10

Structural variants (SVs) can contribute to oncogenesis through a variety of mechanisms. Despite their importance, the identification of SVs in cancer genomes remains challenging. Here, we present a framework that integrates optical mapping, high-throughput chromosome conformation capture (Hi-C), and whole-genome sequencing to systematically detect SVs in a variety of normal or cancer samples and cell lines. We identify the unique strengths of each method and demonstrate that only integrative ap ...[more]

PMID: 30202056

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Project description:Genetic variation amongst individual humans occurs on many different scales, ranging from gross alterations in the human karyotype to single-nucleotide changes. In this manuscript we explore variation on an intermediate scale-particularly insertions, deletions, and inversions affecting from a few thousand to a few million base pairs. We employed a clone-based method to interrogate this intermediate structural variation in eight individuals of diverse geographic ancestry. Our analysis provides a comprehensive overview of the normal pattern of structural variation present in these genomes, refining the location of 1695 structural variants. We find that 50% were seen in more than one individual and that nearly half lay outside regions of the genome previously described as structurally variant. We discover 525 new insertion sequences that are not present in the human reference genome and show that many of these are variable in copy number among individuals. Sequencing of a subset of structural variants reveals considerable locus complexity and provides insights into the different mutational processes that have shaped the human genome. These data provide the first high-resolution sequence-map of human structural variation-an important standard for genotyping platforms and a prelude to future individual genome sequencing projects. Keywords: comparative genomic hybridization The DNA samples are a panel of 8 Hapmap samples, described by E. Eichler et al. (2007, Nature 447, 161-165). This set of 7 female, and one male samples are from from the Coriell Cell Repository, and is comprised of samples from four populations: four Yoruban, two CEPH, one Chinese, and one Japanese. The reference sample, NA15510, is female and also from the Corriel Cell Repository. This sample has been extensively characterized, (for example in Tuzan et al. 2005, Nature Genetics 10, p1038) and has been recommended for use in CNV detection programs to allow meaningful comparison of data between studies (discussed in Scherer, et al. 2007, Nature Genetics Supplement 39: S7-S15). Each of these samples was hybridized in pairs with the reversed labeling polarities. Additionally, 3 self-self control hybridizations were carried out for the reference sample, NA15510, one on each hybridization date.

Dataset Information

Integrative detection and analysis of structural variation in cancer genomes.

Publications

Integrative detection and analysis of structural variation in cancer genomes.

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