Reply to: APP gene copy number changes reflect exogenous contamination.
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ABSTRACT:
SUBMITTER: Lee MH
PROVIDER: S-EPMC7507937 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Dermatofibrosarcoma protuberans (DFSP) is an aggressive spindle cell neoplasm. It is associated with the chromosomal translocation, t(17:22), which fuses the COL1A1 and PDGFbeta genes. We determined the characteristic gene expression profile of DFSP and characterized DNA copy number changes in DFSP by array-based comparative genomic hybridization (array CGH). Fresh frozen and formalin-fixed, paraffin-embedded samples of DFSP were analyzed by array CGH (four cases) and DNA microarray analysis of global gene expression (nine cases). The nine DFSPs were readily distinguished from 27 other diverse soft tissue tumors based on their gene expression patterns. Genes characteristically expressed in the DFSPs included PDGF beta and its receptor, PDGFRB, APOD, MEOX1, PLA2R, and PRKCA. Array CGH of DNA extracted either from frozen tumor samples or from paraffin blocks yielded equivalent results. Large areas of chromosomes 17q and 22q, bounded by COL1A1 and PDGF beta, respectively, were amplified in DFSP. Expression of genes in the amplified regions was significantly elevated. Our data shows that: 1) DFSP has a distinctive gene expression profile; 2) array CGH can be applied successfully to frozen or formalin-fixed, paraffin-embedded tumor samples; 3) a characteristic amplification of sequences from chromosomes 17q and 22q, demarcated by the COL1A1 and PDGF beta genes, respectively, was associated with elevated expression of the amplified genes.
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Project description:Along the transformation process, cells accumulate DNA aberrations, including mutations, translocations, amplifications, and deletions. Despite numerous studies, the overall effects of amplifications and deletions on the end point of gene expression--the level of proteins--is generally unknown. Here we use large-scale and high-resolution proteomics combined with gene copy number analysis to investigate in a global manner to what extent these genomic changes have a proteomic output and therefore the ability to affect cellular transformation. We accurately measure expression levels of 6,735 proteins and directly compare them to the gene copy number. We find that the average effect of these alterations on the protein expression is only a few percent. Nevertheless, by using a novel algorithm, we find the combined impact that many of these regional chromosomal aberrations have at the protein level. We show that proteins encoded by amplified oncogenes are often overexpressed, while adjacent amplified genes, which presumably do not promote growth and survival, are attenuated. Furthermore, regulation of biological processes and molecular complexes is independent of general copy number changes. By connecting the primary genome alteration to their proteomic consequences, this approach helps to interpret the data from large-scale cancer genomics efforts.
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Project description:The Y-chromosomal TSPY gene is one of the highest copy number mammalian protein coding gene and represents a unique biological model to study various aspects of genomic copy number variations. This study investigated the age-related copy number variability of the bovine TSPY gene, a new and unstudied aspect of the biology of TSPY that has been shown to vary among cattle breeds, individual bulls and somatic tissues. The subjects of this prospective 30-month long study were 25 Holstein bulls, sampled every six months. Real-time quantitative PCR was used to determine the relative TSPY copy number (rTSPY CN) and telomere length in the DNA samples extracted from blood. Twenty bulls showed an altered rTSPY CN after 30 months, although only 9 bulls showed a significant change (4 significant increase while 5 significant decrease, P<0.01). The sequential sampling provided the flow of rTSPY CN over six observations in 30 months and wide-spread variation of rTSPY CN was detected. Although a clear trend of the direction of change was not identifiable, the highly dynamic changes of individual rTSPY CN in aging bulls were observed here for the first time. In summary we have observed a highly variable rTSPY CN in bulls over a short period of time. Our results suggest the importance of further long term studies of the dynamics of rTSPY CN variablility.
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Project description:The expression dynamics of interacting genes depends, in part, on the structure of regulatory networks. Genetic regulatory networks include an overrepresentation of subgraphs commonly known as network motifs. In this article, we demonstrate that gene copy number is an omnipresent parameter that can dramatically modify the dynamical function of network motifs. We consider positive feedback, bistable feedback, and toggle switch motifs and show that variation in gene copy number, on the order of a single or few copies, can lead to multiple orders of magnitude change in gene expression and, in some cases, switches in deterministic control. Further, small changes in gene copy number for a 3-gene motif with successive inhibition (the "repressilator") can lead to a qualitative switch in system behavior among oscillatory and equilibrium dynamics. In all cases, the qualitative change in expression is due to the nonlinear nature of transcriptional feedback in which duplicated motifs interact via common pools of transcription factors. We are able to implicitly determine the critical values of copy number which lead to qualitative shifts in system behavior. In some cases, we are able to solve for the sufficient condition for the existence of a bifurcation in terms of kinetic rates of transcription, translation, binding, and degradation. We discuss the relevance of our findings to ongoing efforts to link copy number variation with cell fate determination by viruses, dynamics of synthetic gene circuits, and constraints on evolutionary adaptation.
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| S-BSST7 | biostudies-other
Project description:Carbapenemase production is one of the leading mechanisms of carbapenem resistance in Gram-negative bacteria. An increase in carbapenemase gene (blaCarb) copies is an important mechanism of carbapenem resistance. No currently available bioinformatics tools allow for reliable detection and reporting of carbapenemase gene copy numbers. Here, we describe the carbapenemase-encoding gene copy number estimator (CCNE), a ready-to-use bioinformatics tool that was developed to estimate blaCarb copy numbers from whole-genome sequencing data. Its performance on Klebsiella pneumoniae carbapenemase gene (blaKPC) copy number estimation was evaluated by simulation and quantitative PCR (qPCR), and the results were compared with available algorithms. CCNE has two components, CCNE-acc and CCNE-fast. CCNE-acc detects blaCarb copy number in a comprehensive and high-accuracy way, while CCNE-fast rapidly screens blaCarb copy numbers. CCNE-acc achieved the best accuracy (100%) and the lowest root mean squared error (RMSE; 0.07) in simulated noise data sets, compared to the assembly-based method (23.4% accuracy, 1.697 RMSE) and the OrthologsBased method (78.9% accuracy, 0.395 RMSE). In the qPCR validation, a high consistency was observed between the blaKPC copy number determined by qPCR and that determined with CCNE. Reverse transcription-qPCR transcriptional analysis of 40 isolates showed that blaKPC expression was positively correlated with the blaKPC copy numbers detected by CCNE (P < 0.001). An association study of 357 KPC-producing K. pneumoniae isolates and their antimicrobial susceptibility identified a significant association between the estimated blaKPC copy number and MICs of imipenem (P < 0.001) and ceftazidime-avibactam (P < 0.001). Overall, CCNE is a useful genomic tool for the analysis of antimicrobial resistance genes copy number; it is available at https://github.com/biojiang/ccne. IMPORTANCE Globally disseminated carbapenem-resistant Enterobacterales is an urgent threat to public health. The most common carbapenem resistance mechanism is the production of carbapenemases. Carbapenemase-producing isolates often exhibit a wide range of carbapenem MICs. Higher carbapenem MICs have been associated with treatment failure. The increase of carbapenemase gene (blaCarb) copy numbers contributes to increased carbapenem MICs. However, blaCarb gene copy number detection is not routinely conducted during a genomic analysis, in part due to the lack of optimal bioinformatics tools. In this study, we describe a ready-to-use tool we developed and designated the carbapenemase-encoding gene copy number estimator (CCNE) that can be used to estimate the blaCarb copy number directly from whole-genome sequencing data, and we extended the data to support the analysis of all known blaCarb genes and some other antimicrobial resistance genes. Furthermore, CCNE can be used to interrogate the correlations between genotypes and susceptibility phenotypes and to improve our understanding of antimicrobial resistance mechanisms.
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Project description:Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including 18F-fluorodeoxy-glucose (FDG) avidity of patient tumors, and increased proliferation. The primary CNA signature is enriched for p53 mutations and is associated with glycolysis through coordinate amplification of glycolytic genes and other cancer-linked metabolic enzymes. A pan-cancer and cross-species comparison of CNAs highlighted 26 consistently altered DNA regions, containing 11 enzymes in the glycolysis pathway in addition to known cancer-driving genes. Furthermore, exogenous expression of hexokinase and enolase enzymes in an experimental immortalization system altered the subsequent copy number status of the corresponding endogenous loci, supporting the hypothesis that these metabolic genes act as drivers within the conserved CNA amplification regions. Taken together, these results demonstrate that metabolic stress acts as a selective pressure underlying the recurrent CNAs observed in human tumors, and further cast genomic instability as an enabling event in tumorigenesis and metabolic evolution.
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Project description:A characteristic of sporadic and familial breast tumours is genomic instability, resulting from either inherited mutations in genes that control genome integrity or mutations that are acquired in somatic cells during development. It is well established that abnormal chromosome number and structural changes to chromosomes play an important role in the cause and progression of breast cancer. Familial BRCA1 breast tumours are characterised by basal-like phenotype and high-histological grade which are typically associated with increased genomic instability. Consistent with previous studies, the genomes with the greatest number of base pairs covered by copy number change were typically found in basal-like and/or high-histological grade breast tumours within our cohort. Moreover, we show that luminal A tumours that are high grade had significantly less copy number variant (CNV) coverage than the more clinically aggressive high-grade luminal B tumours, suggesting that chromosomal instability rather than cellular differentiation contributes to the aggressive nature of luminal B tumours. It has previously been proposed that germline CNVs may contribute to somatically acquired chromosome changes in the tumour, but this is the first study to address this idea in breast cancer. By comparing germline CNVs and tumour-specific CNVs in matched breast tumour and normal tissue using data from the Illumina Human CNV370 duo beadarray, we provide evidence that germline CNVs do not tend to act as a foundation on which larger chromosome copy number aberrations develop in tumour cells. Further studies are required with increased sequence resolution that will detect smaller CNVs and define CNV breakpoints to comprehensively assess the relationship between inherited genomic variation and genome evolution in breast cancer.
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