Robust analysis of allele-specific copy number alterations from scRNA-seq data with XClone
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PROVIDER: PRJEB60922 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Somatic copy number alterations (CNAs) are major mutations that contribute to the development and progression of various cancers. Despite a few computational methods proposed to detect CNAs from single-cell transcriptomic data, the technical sparsity of such data makes it challenging to identify allele-specific CNAs, particularly in complex clonal structures. In this study, we present a statistical method, XClone, that strengthens the signals of read depth and allelic imbalance by effective smoothing on cell neighborhood and gene coordinate graphs to detect haplotype-aware CNAs from scRNA-seq data. By applying XClone to multiple datasets with challenging compositions, we demonstrated its ability to robustly detect different types of allele-specific CNAs and potentially indicate whole genome duplication, therefore enabling the discovery of corresponding subclones and the dissection of their phenotypic impacts.
| S-EPMC11303794 | biostudies-literature
Project description:Somatic copy number alterations (CNAs) are major mutations that contribute to the development and progression of various cancers. Despite a few computational methods proposed to detect CNAs from single-cell transcriptomic data, the technical sparsity of such data makes it challenging to identify allele-specific CNAs, particularly in complex clonal structures. In this study, we present a statistical method, XClone, that strengthens the signals of read depth and allelic imbalance by effective smoothing on cell neighborhood and gene coordinate graphs to detect haplotype-aware CNAs from scRNA-seq data. By applying XClone to multiple datasets with challenging compositions, we demonstrated its ability to robustly detect different types of allele-specific CNAs and potentially indicate whole genome duplication, therefore enabling the discovery of corresponding subclones and the dissection of their phenotypic impacts.
| EGAS00001007854 | EGA
Project description:In order to screen potential novel 'driver genes' in lung cancer in Xuanwei (LCXW), genome-wide DNA copy number alterations (CNAs) were detected on 8 paired LCXW and non-cancerous lung (NCL) tissues by array-based comparative genomic hybridization microarrays. The log2 copy-number ratio calculation and CNA calls were determined using segMNT algorithm in NimbleScan. Log2 ratio test/control thresholds of 0.25 and -0.25 were defined as copy number gains and losses, respectively. Deviant signal intensity ratios involving 5 or more neighboring probes were considered as genomic aberrations. A large number of CNAs and DEGs were detected, respectively. Many recurrent CNAs were screened out, including gains at 5p15.33-p15.32, 5p15.1-p14.3 and 5p14.3-p14.2, and losses at 11q24.3, 21q21.1, 21q22.12-q22.13 and 21q22.2.
2016-10-22 | GSE89046 | GEO
Project description:Atrazine is an agricultural herbicide used throughout the Midwestern United States that frequently contaminates potable water supplies resulting in human exposure. Using the zebrafish model system, an embryonic atrazine exposure was previously reported to decrease spawning rates with an increase in progesterone and ovarian follicular atresia in adult females. In addition, alterations in genes associated with distinct molecular pathways of the endocrine system were observed in brain and gonad tissue of the adult females and males. Current hypotheses for mechanistic changes in the developmental origins of health and disease include genetic (e.g., copy number alterations) or epigenetic (e.g., DNA methylation) mechanisms. As such, in the current study we investigated whether an atrazine exposure would generate copy number alterations (CNAs) in the zebrafish genome. A zebrafish fibroblast cell line was used to limit detection to CNAs caused by the chemical exposure. First, cells were exposed to a range of atrazine concentrations and a crystal violet assay was completed, showing confluency decreased by ~60% at 46.3 µM. Cells were then exposed to 0, 0.463, 4.63, or 46.3 µM atrazine and array comparative genomic hybridization completed. Results showed 34, 21, and 44 CNAs in the 0.463, 4.63, and 46.3µM treatments, respectively. Furthermore, CNAs were associated with previously reported gene expression alterations in adult male and female zebrafish. This study demonstrates that atrazine exposure can generate CNAs that are linked to gene expression alterations observed in adult zebrafish exposed to atrazine during embryogenesis providing a mechanism of the developmental origins of atrazine endocrine disruption.
2017-02-20 | GSE93635 | GEO
Project description:BACKGROUND Autofluorescence bronchoscopy (AFB) is a valid strategy for detecting premalignant endobronchial lesions. However, no biomarker can reliably predict lung cancer risk of subjects with AFB-visualized premalignant lesions. Our present study was set out to identify AFB-visualized squamous metaplastic lesions with malignant potential by DNA copy number profiling. METHODS Regular AFB-examinations in 474 subjects at risk of lung cancer identified 6 subjects with SqM lesions at baseline and carcinoma (in situ) at the initial SqM site at follow-up bronchoscopy. These progressive SqM lesions were compared for immunostaining pattern and arrayCGH-based chromosomal profiles to 23 SqM of subjects who remained cancer-free. Specific copy number alterations (CNAs) linked to cancer risk were identified and accuracy of CNAs to predict endobronchial cancer in this series was determined. RESULTS At baseline, p53, p63 and Ki-67 immunostaining were not predictive for a differential clinical outcome of SqM lesions. The mean number of CNAs in baseline SqM of cases was significantly higher compared to controls (p<0.01). Chromosomal regions significantly more frequently altered in SqM of cases were 3p26.3-p11.1, 3q26.2-q29, 9p13.3-p13.2, and 17p13.3-p11.2 (FWER<0.10). CNAs were specifically detected at the site of future cancer. In cases, baseline-detected CNAs persisted in subsequent biopsies taken from the initial site, and levels increased towards cancer progression. CNAs at 3p26.3-p11.1, 3q26.2-29, and 6p25.3-24.3, predicted cancer risk for AFB-visualized SqM with 97% accuracy. CONCLUSION Our data strongly suggest that the presence of specific DNA copy number alterations in endobronchial SqM lesions predict endobronchial cancer.
2011-08-02 | GSE23644 | GEO
Project description:DNA copy number variants (CNVs) are associated with the development of complex neurological diseases and disorders including autism spectrum disorder, schizophrenia, Alzheimer’s disease, and Parkinson’s disease. Exposure to multiple environmental chemicals including various heavy metals is suggested as a risk factor in these neurological diseases and disorders, but few studies have addressed if heavy metal exposure can result in spontaneous DNA copy number changes as a genetic mechanism contributing to these disease outcomes. In this study to further investigate the relationship between heavy metal exposure and spontaneous copy number alterations (CNAs), zebrafish fibroblast cells were exposed to the neurotoxicant lead (Pb). A crystal violet assay was first used to determine exposure concentrations with greater than 80% cell confluency. Then a zebrafish-specific array comparative genomic hybridization (CGH) platform was used to detect CNAs following a 72 hour Pb exposure (0.24, 2.4, or 24 μM). The Pb exposure resulted in 72 CNA amplifications ranging in size from 5 to 329 kb. No deletions were detected. CNAs resulted in 15 copy number alteration regions (CNARs), leaving 7 singlet CNAs. Two of the singlets were within high repeat genomic locations. The number of CNAs tended to increase in a concentration dependent manner. Several CNARs encompassed genes previously reported to have altered expression with Pb exposure, suggesting a mechanistic link. In addition, almost all genes are associated within a molecular network with the amyloid precursor protein (APP). Overall, these findings show that Pb exposure results in spontaneous CNAs that could serve as a mechanism driving adverse health outcomes associated with Pb toxicity including neurological disease pathogenesis for further study.
2020-12-01 | GSE149382 | GEO
Project description:Large but not small copy-number alterations correlate to high-risk genomic aberrations and survival in chronic lymphocytic leukemia: a high-resolution genomic screening of newly diagnosed patients. Single nucleotide polymorphism (SNP)-arrays allow simultaneous detection of copy-number aberrations (CNAs) and copy-number neutral loss-of-heterozygosity (CNN-LOH). In this study we investigated the presence of CNAs and CNN-LOH in newly diagnosed CLL samples from a Swedish chronic lymphocytic leukemia (CLL) cohort. In this study we could detect the known recurrent aberrations in CLL (i.e. deletions of 13q, 11q, 17p and trisomy 12). We also detected other both large and small CNAs which were mostly non-recurrent. CNN-LOH was detected on chromosome 13q in patients that carried homozygous deletion of 13q.
2009-11-23 | GSE16406 | GEO
Project description:Lung cancer, of which more than 80% is non-small cell, is the leading cause of cancer-related death in the United States. Copy number alterations (CNAs) in lung cancer have been shown to be positionally clustered in certain genomic regions. However, it remains unclear whether genes with copy number changes are functionally clustered. Using a dense single nucleotide polymorphism array, we performed genome-wide copy number analyses of a large collection of non-small cell lung tumors (n = 301). We proposed a formal statistical test for CNAs between different groups (e.g., noninvolved lung vs. tumors, early vs. late stage tumors). We also customized the gene set enrichment analysis (GSEA) algorithm to investigate the overrepresentation of genes with CNAs in predefined biological pathways and gene sets (i.e., functional clustering). We found that CNAs events increase substantially from germline, early stage to late stage tumor. In addition to genomic position, CNAs tend to occur away from the gene locations, especially in germline, noninvolved tissue and early stage tumors. Such tendency decreases from germline to early stage and then to late stage tumors, suggesting a relaxation of selection during tumor progression. Furthermore, genes with CNAs in non-small cell lung tumors were enriched in certain gene sets and biological pathways that play crucial roles in oncogenesis and cancer progression, demonstrating the functional aspect of CNAs in the context of biological pathways that were overlooked previously. We conclude that CNAs increase with disease progression and CNAs are both positionally and functionally clustered. The potential functional capabilities acquired via CNAs may be sufficient for normal cells to transform into malignant cells.
2011-12-06 | GSE34140 | GEO
Project description:We present an allele-specific copy number analysis of the in vivo breast cancer genome. We describe a unique bioinformatics approach, ASCAT (allele-specific copy number analysis of tumors), to accurately dissect the allele-specific copy number of solid tumors, simultaneously estimating and adjusting for both tumor ploidy and nonaberrant cell admixture. This allows calculation of "ASCAT profiles" (genome-wide allele-specific copy-number profiles) from which gains, losses, copy number-neutral events, and loss of heterozygosity (LOH) can accurately be determined. In an early-stage breast carcinoma series, we observe aneuploidy (>2.7n) in 45% of the cases and an average nonaberrant cell admixture of 49%. By aggregation of ASCAT profiles across our series, we obtain genomic frequency distributions of gains and losses, as well as genome-wide views of LOH and copy number-neutral events in breast cancer. In addition, the ASCAT profiles reveal differences in aberrant tumor cell fraction, ploidy, gains, losses, LOH, and copy number-neutral events between the five previously identified molecular breast cancer subtypes. Basal-like breast carcinomas have a significantly higher frequency of LOH compared with other subtypes, and their ASCAT profiles show large-scale loss of genomic material during tumor development, followed by a whole-genome duplication, resulting in near-triploid genomes. Finally, from the ASCAT profiles, we construct a genome-wide map of allelic skewness in breast cancer, indicating loci where one allele is preferentially lost, whereas the other allele is preferentially gained. We hypothesize that these alternative alleles have a different influence on breast carcinoma development.
| S-EPMC2947907 | biostudies-other
Project description:Screening for gene copy-number alterations (CNAs) has improved by applying genome-wide microarrays, where SNP arrays also allow analysis of loss of heterozygozity (LOH). We here analyzed 10 chronic lymphocytic leukemia (CLL) samples using four different high-resolution platforms: BAC arrays (32K), oligonucleotide arrays (185K, Agilent), and two SNP arrays (250K, Affymetrix and 317K, Illumina). Cross-platform comparison revealed 29 concordantly detected CNAs, including known recurrent alterations, which confirmed that all platforms are powerful tools when screening for large aberrations. However, detection of 32 additional regions present in 2-3 platforms illustrated a discrepancy in detection of small CNAs, which often involved reported copy-number variations. LOH analysis revealed concordance of mainly large regions, but showed numerous, small nonoverlapping regions and LOH escaping detection. Evaluation of baseline variation and copy-number ratio response showed the best performance for the Agilent platform and confirmed the robustness of BAC arrays. Accordingly, these platforms demonstrated a higher degree of platform-specific CNAs. The SNP arrays displayed higher technical variation, although this was compensated by high density of elements. Affymetrix detected a higher degree of CNAs compared to Illumina, while the latter showed a lower noise level and higher detection rate in the LOH analysis. Large-scale studies of genomic aberrations are now feasible, but new tools for LOH analysis are requested.
2008-12-10 | GSE13557 | GEO