Comprehensive analysis of structural variants in breast cancer genomes using single molecule sequencing
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PROVIDER: PRJNA671422 | ENA |
REPOSITORIES: ENA
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Project description:Structural characterization of ribosome variants
| PRJNA414663 | ENA
Project description:Improved identification of structural variants (SVs) in cancer can lead to more targeted and effective treatment options as well as advance our basic understanding of the disease and its progression. We performed whole-genome sequencing of the SKBR3 breast cancer cell line and patient-derived tumor and normal organoids from two breast cancer patients using Illumina/10x Genomics, Pacific Biosciences (PacBio), and Oxford Nanopore Technologies (ONT) sequencing. We then inferred SVs and large-scale allele-specific copy number variants (CNVs) using an ensemble of methods. Our findings show that long-read sequencing allows for substantially more accurate and sensitive SV detection, with between 90% and 95% of variants supported by each long-read technology also supported by the other. We also report high accuracy for long reads even at relatively low coverage (25×-30×). Furthermore, we integrated SV and CNV data into a unifying karyotype-graph structure to present a more accurate representation of the mutated cancer genomes. We find hundreds of variants within known cancer-related genes detectable only through long-read sequencing. These findings highlight the need for long-read sequencing of cancer genomes for the precise analysis of their genetic instability.
| S-EPMC7545150 | biostudies-literature
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: comparitive genomic hybridization, copy number variation, structural variation, fosmid end sequencing CGH analysis targeted against sites identified by fosmid end sequencing. 8 HapMap samples (sources of libraries ABC7-ABC14) are hybed against NA15510 (source of fosmid library G248).
2008-05-01 | E-GEOD-10037 | biostudies-arrayexpress
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: comparitive genomic hybridization, copy number variation, structural variation, fosmid end sequencing
2008-05-01 | GSE10037 | GEO
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
2008-05-01 | GSE10008 | GEO
Project description:Higher order chromatin structure is important for regulation of genes by distal regulatory sequences. Structural variants that alter 3D genome organization can lead to enhancer-promoter rewiring and human disease, particularly in the context of cancer. However, only a small minority of structural variants are associated with altered gene expression and it remains unclear why certain structural variants lead to changes in distal gene expression and others do not. To address these questions, we used a combination of genomic profiling and genome engineering to identify sites of recurrent changes in 3D genome structure in cancer and determine the effects of specific rearrangements on oncogene activation. By analyzing Hi-C data from 92 cancer cell lines and patient samples, we identified loci affected by recurrent alterations to 3D genome structure, including oncogenes such as MYC, TERT, and CCND1. Using CRISPR/Cas9 genome engineering to generate de novo structural variants, we show that oncogene activity can be predicted using “Activity-by-Contact” models that consider partner region chromatin contacts and enhancer activity. However, Activity-by-Contact models are only predictive of specific subsets of genes in the genome, suggesting that different classes of genes engage in distinct modes of regulation by distal regulatory elements. These results indicate that structural variants that alter 3D genome organization are widespread in cancer genomes and begin to illustrate predictive rules for the consequences of structural variants on oncogene activation.
2022-10-04 | GSE147123 | GEO
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.
2008-05-01 | E-GEOD-10008 | biostudies-arrayexpress
Project description:Linked-Read Sequencing to Resolve Complex Structural Variants
| PRJNA516493 | ENA
Project description:Linked-Read Sequencing to Resolve Complex Structural Variants
| PRJNA516494 | ENA
Project description:Clarifying structural variants (SV) profiles in nonhuman primates could provide insights into the genetic background underlying human-specific traits, but such resources are largely lacking. Here, we report the largest SV atlas generated to date from a population of 1,026 macaques, verified by genome assembly for one of them. This accurate, quantitative map indicates stronger purifying selection on inversions located in regulatory regions, suggesting a strategy for prioritizing those with the most important functions. We then identified 75 human-specific inversions and prioritized them. Notably, the top-ranked inversions have substantially shaped the transcriptome through their dual-effects of reconfiguring the ancestral genomic architecture and introducing regional mutation hotspots. As a proof-of-concept, the overexpression of APCDD1, located on one of these inversions and downregulated during human evolution, significantly accelerated neuronal maturation, while its depletion in mice delays the neuronal maturation and subsequently improved their cognitive ability. This study thus provides a valuable resource to explore human evolution and diseases,and broaden the understanding of the contribution of SVs in shaping the distinct features in human brain development.
2024-04-23 | GSE221928 | GEO