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Results for “genomic integrity”

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At least 19 recordsLinked to original sources
PubMed2007

Molecular characterization of human multiple myeloma cell lines by integrative genomics: insights into the biology of the disease.

To investigate the patterns of genetic lesions in a panel of 23 human multiple myeloma cell lines (HMCLs), we made a genomic integrative analysis involving FISH, and both gene expression and genome-wide profiling approaches. The expression profiles of the genes targeted by the main IGH translocations showed that the WHSC1/MMSET gene involved in t(4;14)(p16;q32) was expressed at different levels in all of the HMCLs, and that the expression of the MAF gene was not restricted to the HMCLs carrying t(14;16)(q32;q23). Supervised analyses identified a limited number of genes specifically associated with t(4;14) and involved in different biological processes. The signature related to MAF/MAFB expression included the known MAF target genes CCND2 and ITGB7, as well as genes controlling cell shape and cell adhesion. Genome-wide DNA profiling allowed the identification of a gain on chromosome arm 1q in 88% of the analyzed cell lines, together with recurrent gains on 8q, 18q, 7q, and 20q; the most frequent deletions affected 1p, 13q, 17p, and 14q; and almost all of the cell lines presented LOH on chromosome 13. Two hundred and twenty-two genes were found to be simultaneously overexpressed and amplified in our panel, including the BCL2 locus at 18q21.33. Our data further support the evidence of the genomic complexity of multiple myeloma and reinforce the role of an integrated genomic approach in improving our understanding of the molecular pathogenesis of the disease. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

Cell Line, Tumor↗
PubMed2026

AEGIS: an annotation extraction and genomic integration resource.

MOTIVATION: Genome annotation files (GFF3/GTF) are the standard for storing genomic feature data, yet their flexibility often results in formatting inconsistencies that create bottlenecks for downstream bioinformatics analyses. A robust, unified framework is required to parse, standardise, and validate these files to ensure interoperability and facilitate complex comparative genomic tasks. RESULTS: We present AEGIS (Annotation Extraction and Genomic Integration Suite), a comprehensive toolkit designed to parse, correct, and standardise genome annotations. Beyond quality control, AEGIS provides advanced modules for flexible feature extraction (e.g., coding sequences, promoters) and comparative genomic analysis. Uniquely, it integrates multiple lines of evidence, including sequence homology, synteny, and coordinate-based lift-overs, to assess gene model correspondence and infer orthology. We demonstrate the utility of AEGIS by quantifying complex structural changes between Arabidopsis annotation versions and identifying high-confidence orthologues across diverse plant genomes. AVAILABILITY: AEGIS is implemented in Python. Source code and documentation are freely available under the GPL-3 license at https://github.com/Tomsbiolab/aegis and as a Docker container at https://hub.docker.com/r/tomsbiolab/aegis. The package is also available on PyPI (pip install aegis-bio).

Software↗
PubMed2003

Elg1 forms an alternative RFC complex important for DNA replication and genome integrity.

Genome-wide synthetic genetic interaction screens with mutants in the mus81 and mms4 replication fork-processing genes identified a novel replication factor C (RFC) homolog, Elg1, which forms an alternative RFC complex with Rfc2-5. This complex is distinct from the DNA replication RFC, the DNA damage checkpoint RFC and the sister chromatid cohesion RFC. As expected from its genetic interactions, elg1 mutants are sensitive to DNA damage. Elg1 is redundant with Rad24 in the DNA damage response and contributes to activation of the checkpoint kinase Rad53. We find that elg1 mutants display DNA replication defects and genome instability, including increased recombination and mutation frequencies, and minichromosome maintenance defects. Mutants in elg1 show genetic interactions with pathways required for processing of stalled replication forks, and are defective in recovery from DNA damage during S phase. We propose that Elg1-RFC functions both in normal DNA replication and in the DNA damage response.

Carrier Proteins↗
PubMed2004

Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower genital tract.

Cancers of the anogenital tract as well as some head and neck cancers are caused by persistent infections with high-risk type human papillomaviruses (HPVs). Two viral oncogenes, E6 and E7, induce severe chromosomal instability associated with centrosome aberrations, anaphase bridges, chromosome lagging, and breaking. This occurs early in preneoplastic lesions, when the viral genome still persists in an episomal state. In most invasive cancers and also in a few high-grade dysplastic lesions, however, integration of high-risk HPV genomes into the host genome is observed. Integration seems to be a direct consequence of chromosomal instability and an important molecular event in the progression of preneoplastic lesions. Disruption or deregulation of defined critical cellular gene functions by insertional mutagenesis by integrated HPV genome fragments has been hypothesized as one major promoting factor in the pathogenesis of HPV-associated cancers. This hypothesis was based on the detection of HPV integration events in the area of tumor-relevant genes in few cases. Here, we reviewed >190 reported integration loci with respect to changes in the viral structure and the targeted genomic locus. This analysis confirms that HPV integration sites are randomly distributed over the whole genome with a clear predilection for genomic fragile sites. No evidence for targeted disruption or functional alteration of critical cellular genes by the integrated viral sequences could be found.

Cell Transformation, Viral↗
PubMed2000

Integrated genomic map from uropathogenic Escherichia coli J96.

Escherichia coli J96 is a uropathogen having both broad similarities to and striking differences from nonpathogenic, laboratory E. coli K-12. Strain J96 contains three large (>100-kb) unique genomic segments integrated on the chromosome; two are recognized as pathogenicity islands containing urovirulence genes. Additionally, the strain possesses a fourth smaller accessory segment of 28 kb and two deletions relative to strain K-12. We report an integrated physical and genetic map of the 5,120-kb J96 genome. The chromosome contains 26 NotI, 13 BlnI, and 7 I-CeuI macrorestriction sites. Macrorestriction mapping was rapidly accomplished by a novel transposon-based procedure: analysis of modified minitransposon insertions served to align the overlapping macrorestriction fragments generated by three different enzymes (each sharing a common cleavage site within the insert), thus integrating the three different digestion patterns and ordering the fragments. The resulting map, generated from a total of 54 mini-Tn10 insertions, was supplemented with auxanography and Southern analysis to indicate the positions of insertionally disrupted aminosynthetic genes and cloned virulence genes, respectively. Thus, it contains not only physical, macrorestriction landmarks but also the loci for eight housekeeping genes shared with strain K-12 and eight acknowledged urovirulence genes; the latter confirmed clustering of virulence genes at the large unique accessory chromosomal segments. The 115-kb J96 plasmid was resolved by pulsed-field gel electrophoresis in NotI digests. However, because the plasmid lacks restriction sites for the enzymes BlnI and I-CeuI, it was visualized in BlnI and I-CeuI digests only of derivatives carrying plasmid inserts artificially introducing these sites. Owing to an I-SceI site on the transposon, the plasmid could also be visualized and sized from plasmid insertion mutants after digestion with this enzyme. The insertional strains generated in construction of the integrated genomic map provide useful physical and genetic markers for further characterization of the J96 genome.

Blotting, Southern↗
PubMed2007

Targets of genome copy number reduction in primary breast cancers identified by integrative genomics.

The identification of specific oncogenes and tumor suppressor genes in regions of recurrent aneuploidy is a major challenge of molecular cancer research. Using both oligonucleotide single-nucleotide polymorphism and mRNA expression arrays, we integrated genomic and transcriptional information to identify and prioritize candidate cancer genes in regions of increased and decreased chromosomal copy number in a cohort of primary breast cancers. Confirming the validity of this approach, several regions of previously-known copy number (CN) alterations in breast cancer could be successfully reidentified. Focusing on regions of decreased CN, we defined a prioritized list of eighteen candidate genes, which included ARPIN, FBN1, and LZTS1, previously shown to be associated with cancers in breast or other tissue types, and novel genes such as P29, MORF4L1, and TBC1D5. One such gene, the RUNX3 transcription factor, was selected for further study. We show that RUNX3 is present at reduced CNs in proportion to the rest of the tumor genome and that RUNX3 CN reductions can also be observed in a breast cancer series from a different center. Using tissue microarrays, we demonstrate in an independent cohort of over 120 breast tissues that RUNX3 protein is expressed in normal breast epithelium but not fat and stromal tissue, and widely down-regulated in the majority of breast cancers (>85%). In vitro, RUNX3 overexpression suppressed the invasive potential of MDA-MB-231 breast cancer cells in a matrigel assay. Our results demonstrate the utility of integrative genomic approaches to identify novel potential cancer-related genes in primary tumors. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

Breast Neoplasms↗
PubMed1994

Prototype implementation of the integrated genomic database.

We aim to develop an open software system to handle human genome data. The system, called Integrated Genomic Database (IGD), will integrate information from many genomic databases and experimental resources into a comprehensive target-end database (IGD TED). Users will access front-end client systems (IGD FRED) to download data of interest to their computers and merge them with their own local data. FREDs will provide persistent storage of, and instant access to, retrieved data; a friendly graphical interface; tools for querying, browsing, analyzing, and editing local data; interface to external analysis; and tools for communicating with the outside world. The TED will be accessible over the network (online and offline) as a read-only resource for multiple clients. It collects data from major databases for nucleotide and protein sequences and structures, genome maps, experimental reagents, phenotypes, and bibliographic data, and sets of raw data produced at genome centers and laboratories. Beside character-based access via Gopher, WAIS, FTP, and several query language interfaces to the TED, we will develop a specialized front-end client, IGD FRED, with its own database manager, based on the ACEDB program. The FRED will support graphical display methods for sequence feature maps, chromosomal genetic and physical maps, and experimental objects like clone grids, etc. FRED will also provide an interface to important analysis software packages and tools for submitting data to external databases in their own format.

Computer Communication Networks↗
PubMed2026

Quantile Tensor Regression for Integrative Genomic Analysis of Oesophageal Carcinoma.

Recent integrative genomic studies have increasingly exploited the tensor structure of multi-omics data to develop statistical methods that jointly model the relationship between clinical outcomes and multiple genomes. However, genomic measurements and clinical outcomes are frequently contaminated by outliers or heavy-tailed noise, necessitating robust tensor-based inference approaches. In this paper, we investigate the quantile tensor regression with an emphasis on the region selection problem. We introduce a novel estimator that integrates quantile regression for robustness with a nonconvex penalty to encourage sparsity in the tensor coefficient, thereby enabling the identification of localized genomic regions that significantly influence the clinical response. To solve the resulting optimization problem, we devise an effective algorithm tailored to the nonconvex objective and tensor architecture. We establish the asymptotic properties of the proposed nonconvex penalized estimator. Extensive simulations demonstrate the excellent finite-sample performance of the proposed estimator. We further illustrate the practical utility of the proposed estimator through an application to esophageal carcinoma data, providing empirical validation.

Humans↗
PubMed2002

Site-specific genomic integration produces therapeutic Factor IX levels in mice.

We used the integrase from phage phiC31 to integrate the human Factor IX (hFIX) gene permanently into specific sites in the mouse genome. A plasmid containing attB and an expression cassette for hFIX was delivered to the livers of mice by using high-pressure tail vein injection. When an integrase expression plasmid was co-injected, hFIX serum levels increased more than tenfold to approximately 4 microg/ml, similar to normal FIX levels, and remained stable throughout the more than eight months of the experiment. hFIX levels persisted after partial hepatectomy, suggesting genomic integration of the vector. Site-specific integration was proven by characterizing and quantifying genomic integration in the liver at the DNA level. Integration was documented at two pseudo-attP sites, native sequences with partial identity to attP, with one site highly predominant. This study demonstrates in vivo gene transfer in an animal by site-specific genomic integration.

Animals↗
PubMed1991

Semiquantitative analysis of integrated genomes of human T-lymphotropic virus type I in asymptomatic virus carriers.

A semiquantitative estimation of human T-lymphotropic virus type I (HTLV-I) integration by peripheral blood mononuclear cells (PBMC) was performed. Genomic DNA samples derived from 134 HTLV-I carriers were subjected to 40 or 60 cycles of the polymerase chain reaction to amplify the pol region of HTLV-I. The HTLV-I genome was detected by dot hybridization using a 32P-labeled oligonucleotide probe for the pol region. The radioactivity of hybridized dot membranes was then counted with an RI Imaging System (Ambis Inc, San Diego, CA) and the HTLV-I genome dose was determined by comparison with standard curve for serially diluted HTLV-I genome-positive DNA. A wide range of variation of HTLV-I genome integration was observed. When the integrated genome dose was calculated as the number of HTLV-I copies per 100 PBMC, 7 carriers (5%) had more than 10 copies, 56 (42%) had 1 to 10 copies, 46 (34%) had 0.1 to 1 copy, and 24 (18%) had less than 0.1 copy. In one sample, the HTLV-I genome was undetectable, which may indicate that the integrated genome was present at less than 0.01 copies per 100 PBMC. Age- or sex-related variations in the distribution of individuals with different HTLV-I genome were rather limited. However, carriers with a high level of the HTLV-I genome were always more than 30 years old and were predominantly male (six of seven).

Aging↗
PubMed2005

Replication checkpoint kinase Cds1 regulates Mus81 to preserve genome integrity during replication stress.

The replication checkpoint kinase Cds1 preserves genome integrity by stabilizing stalled replication forks. Cds1 targets substrates through its FHA domain. The Cds1 FHA domain interacts with Mus81, a subunit of the Mus81-Eme1 structure-specific endonuclease. We report here that Mus81 and Rhp51 are required for generating deletion mutations in fission yeast replication mutants that experience replication stress. A mutation in the Mus81 FHA-binding motif eliminates its Cds1-binding and Cds1-dependent phosphorylation. Furthermore, this mutation exacerbates the deletion mutator phenotype of a replication mutant, and induces a hyper-recombination phenotype in hydroxyurea-treated cells. In unperturbed cells, Mus81 associates with chromatin throughout S phase. In replication mutants grown at semipermissive temperature, Mus81 undergoes minor Cds1-dependent phosphorylation, remains chromatin-associated, generates deletion mutations, and maintains cell growth. Upon S-phase arrest by acute hydroxyurea treatment, Mus81 is not required for cell viability but is essential for recovery from replication fork collapse. Moreover, Mus81 undergoes extensive Cds1-dependent phosphorylation and dissociates from chromatin in hydroxyurea-arrested cells, thereby preventing it from cleaving stalled replication forks that could lead to fork breakage and chromosomal rearrangement. These results provide novel insights into how Cds1 regulates Mus81 accordingly when cells experience different replication stress to preserve genome integrity.

Checkpoint Kinase 2↗
PubMed2001

Suppression of mismatched mutation by p53: a mechanism for guarding genomic integrity.

The tumor suppressor p53 plays an important role in guarding the genomic integrity of the cells. The 3'-->5' exonuclease activity of p53 has recently been recognized as a novel biochemical function of this molecule, and has been shown to preferentially excise mismatched nucleotides from DNA and enhance the DNA replication fidelity of polymerase alpha in vitro. The present study further investigated the role of this biochemical function in whole cells by testing the possibility that p53 may reduce mismatched mutations in cells under a stress of DNA replication errors. Cells with different states of p53 expression, either endogenously or ectopically, were exposed to hydroxyurea to induce an imbalance of cellular dNTP pools and cause replication errors. The rates of mutation at the hypoxanthine guanine phosphoribosyltransferase ( HPRT) gene were determined by selecting colonies of HPRT- mutants. Incubation of cells with hydroxyurea induced a similar degree of dNTP pool imbalance in each cell line, but caused significantly more mutations in cells lacking p53 protein expression. The mutation frequency was significantly reduced by introduction of a wild-type p53 expression vector into the p53-null cells. Analysis of the mutants demonstrated that the clones were devoid of HPRT enzyme activity, but appeared to transcribe full-length HPRT mRNA. These data suggest that p53 is able to reduce mutations caused by misincorporation of deoxynucleotides. Thus, the preferential removal of mismatched nucleotides from DNA by p53 may be a mechanism to maintain genomic integrity. Defect in this biochemical function of p53 may contribute to genetic instability associated with cancer development and progression.

Base Pair Mismatch↗
PubMed2003

ATM and related protein kinases: safeguarding genome integrity.

Maintenance of genome stability is essential for avoiding the passage to neoplasia. The DNA-damage response--a cornerstone of genome stability--occurs by a swift transduction of the DNA-damage signal to many cellular pathways. A prime example is the cellular response to DNA double-strand breaks, which activate the ATM protein kinase that, in turn, modulates numerous signalling pathways. ATM mutations lead to the cancer-predisposing genetic disorder ataxia-telangiectasia (A-T). Understanding ATM's mode of action provides new insights into the association between defective responses to DNA damage and cancer, and brings us closer to resolving the issue of cancer predisposition in some A-T carriers.

Animals↗
PubMed2005

Integrative genomics based identification of potential human hepatocarcinogenesis-associated cell cycle regulators: RHAMM as an example.

DNA microarray has been widely used to examine gene expression profile of different human tumors. The information generated from microarray analysis usually represents the overall range of cancer-associated abnormality associated with gene regulation. In order to identify key regulatory genes involved in carcinogenesis of human cancer, hypothesis driven data mining of the microarray data plus experimental validation becomes a critical approach in the post-genome era. Here, we present an integrative genomic analysis of published microarray data and homolog gene database. Over 20,000 genes were examined to reveal 16 genes specific to vertebrates, cell cycle G2/M regulated, and overexpressed in human HCC. Using Affymetrix microarray analysis, we found that all 16 genes were up-regulated in human HCC. Among these 16 genes, we experimentally validated the up-regulation of receptor for hyaluronan-mediated motility (RHAMM) in different cell model systems. We first confirmed elevation of RHAMM in the G2/M phase of synchronized HeLa cells. We also found that RHAMM had an elevated level of expression in all the HCC samples we examined and it was induced during the G2/M phase of regenerating mouse hepatocytes after partial hepatectomy. Thus, the expression of RHAMM appears to be tightly regulated during mammalian cell cycle G2/M progression. The ectopic overexpression of RHAMM in 293T cells resulted in the accumulation of cells at G2/M phase. RHAMM-induced mitotic arrest of cells was predominantly in the prophase. Taken together, using an integrated functional genomic approach, we have uncovered a set of genes that may play specific roles in cell cycle progression and in HCC development. To elucidate the function of these genes in cell cycle regulation may shed light on the control mechanism of human HCC in the future.

Amino Acid Sequence↗
PubMed2002

Defending genome integrity during S-phase: putative roles for RecQ helicases and topoisomerase III.

The maintenance of genome stability is important not only for cell viability, but also for the suppression of neoplastic transformation in higher eukaryotes. It has long been recognised that a common feature of cancer cells is genomic instability. Although the so-called three 'Rs' of genome maintenance, DNA replication, recombination and repair, have historically been studied in isolation, a wealth of recent evidence indicates that these processes are intimately interrelated and interdependent. In this article, we will focus on challenges to the maintenance of genome integrity that arise during the S-phase of the cell cycle, and the possible roles that RecQ helicases and topoisomerase III play in the maintenance of genome integrity during the process of DNA replication.

Adenosine Triphosphatases↗
PubMed1978

The integrated genome of murine leukemia virus.

The Southern gel filter transfer technique has been used to characterize the integrated genome of Moloney murine leukemia virus (M-MuLV) and the genomes of the endogenous viruses of the mouse. Study of 10 clones of rat cell independently infected by M-MuLV indicates a minimum of 15 integration sites into which the M-MuLV provirus can be inserted. No common integration site is observed among these clones. Clones productively infected by M-MuLV acquire multiple proviruses, whereas infected cells unable to produce virus contain only one M-MuLV provirus. Once established, the integrated genomes are stable for at least two years after initial infection. The use of M-MuLV probe allows detection of a spectrum of Eco RI-cleaved mouse DNA fragments containing endogenous MuLV genomes. DNAs of different inbred laboratory mouse strains yield similar patterns of provirus with each strain showing minor characteristic differences. In some instances, mouse cells infected by M-MuLV reveal additional proviruses beyond those seen in the uninfected cell. DNAs from three different M-MuLV-induced thymomas indicate, as in rat cells, multiple possible integration sites.

Animals↗