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At least 1,351 records · Page 75Linked to original sources
PubMed2002

Combined transcriptome and genome analysis of single micrometastatic cells.

In human cancer, early systemic spread of tumor cells is recognized as a leading cause of death. Adjuvant therapies are administered to patients after complete resectioning of their primary tumors to eradicate the few residual and latent metastatic cells. These therapeutic regimens, however, are currently designed without direct information about the presence or nature of the latent cells. To address this problem, we developed a PCR-based technique to analyze the transcriptome of individual tumor cells isolated from the bone marrow of cancer patients. From the same cells, genomic aberrations were identified by comparative genomic hybridization. The utility of this approach for understanding the biology of occult disseminated cells and for the identification of new therapeutic targets is demonstrated here by the detection of frequent extracellular matrix metalloproteinase inducer (EMMPRIN; CD147) expression which was verified by immunostaining.

Cell Cycle↗
PubMed2006

An integrative approach for the identification of quantitative trait loci.

The genetic dissection of complex traits is one of the most difficult and most important challenges facing science today. We discuss here an integrative approach to quantitative trait loci (QTL) mapping in mice. This approach makes use of the wealth of genetic tools available in mice, as well as the recent advances in genome sequence data already available for a number of inbred mouse strains. We have developed mapping strategies that allow a stepwise narrowing of a QTL mapping interval, prioritizing candidate genes for further analysis with the potential of identifying the most probable candidate gene for the given trait. This approach integrates traditional mapping tools, fine mapping tools, sequence-based analysis, bioinformatics and gene expression.

Animals↗
PubMed2005

Tools and strategies for physiological genomics: the Rat Genome Database.

The broad goal of physiological genomics research is to link genes to their functions using appropriate experimental and computational techniques. Modern genomics experiments enable the generation of vast quantities of data, and interpretation of this data requires the integration of information derived from many diverse sources. Computational biology and bioinformatics offer the ability to manage and channel this information torrent. The Rat Genome Database (RGD; http://rgd.mcw.edu) has developed computational tools and strategies specifically supporting the goal of linking genes to their functional roles in rat and, using comparative genomics, to human and mouse. We present an overview of the database with a focus on these unique computational tools and describe strategies for the use of these resources in the area of physiological genomics.

Animals↗
PubMed2001

Individual metabolism should guide agriculture toward foods for improved health and nutrition.

Genomics and bioinformatics have the vast potential to identify genes that cause disease by investigating whole-genome databases. Comparison of an individual's geno-type with a genomic database will allow the prescription of drugs to be tailored to an individual's genotype. This same bioinformatic approach, applied to the study of human metabolites, has the potential to identify and validate targets to improve personalized nutritional health and thus serve to define the added value for the next generation of foods and crops. Advances in high-throughput analytic chemistry and computing technologies make the creation of a vast database of metabolites possible for several subsets of metabolites, including lipids and organic acids. In creating integrative databases of metabolites for bioinformatic investigation, the current concept of measuring single biomarkers must be expanded to 3 dimensions to 1) include a highly comprehensive set of metabolite measurements (a profile) by multiparallel analyses, 2) measure the metabolic profile of individuals over time rather than simply in the fasted state, and 3) integrate these metabolic profiles with genomic, expression, and proteomic databases. Application of the knowledge of individual metabolism will revolutionize the ability of nutrition to deliver health benefits through food in the same way that knowledge of genomics will revolutionize individual treatment of dis-ease with pharmaceuticals.

Biomarkers↗
PubMed2005

Genomic technologies and the interrogation of the transcriptome.

Functional genomics refers to the study of whole genomes and the function of its constituent parts to explain biological processes. Though these investigations may involve whole proteome analysis, the primary focus is on the transcriptome and how it is regulated. Recent advances in technologies that can interrogate cellular transcripts on a genome-wide scale seek the complete disclosure of the transcriptome over time-intervals and across many different cellular states. This massively complex data when viewed as a whole can provide surprisingly precise assessment of cellular conditions. Moreover, these data can define hierarchies of importance and have shown us new transcriptional elements. Herein, we describe the technologies and the experimental strategies to study the transcriptome that would be pertinent to cancer and ageing research.

Animals↗
PubMed2006

Burkholderia xenovorans LB400 harbors a multi-replicon, 9.73-Mbp genome shaped for versatility.

Burkholderia xenovorans LB400 (LB400), a well studied, effective polychlorinated biphenyl-degrader, has one of the two largest known bacterial genomes and is the first nonpathogenic Burkholderia isolate sequenced. From an evolutionary perspective, we find significant differences in functional specialization between the three replicons of LB400, as well as a more relaxed selective pressure for genes located on the two smaller vs. the largest replicon. High genomic plasticity, diversity, and specialization within the Burkholderia genus are exemplified by the conservation of only 44% of the genes between LB400 and Burkholderia cepacia complex strain 383. Even among four B. xenovorans strains, genome size varies from 7.4 to 9.73 Mbp. The latter is largely explained by our findings that >20% of the LB400 sequence was recently acquired by means of lateral gene transfer. Although a range of genetic factors associated with in vivo survival and intercellular interactions are present, these genetic factors are likely related to niche breadth rather than determinants of pathogenicity. The presence of at least eleven "central aromatic" and twenty "peripheral aromatic" pathways in LB400, among the highest in any sequenced bacterial genome, supports this hypothesis. Finally, in addition to the experimentally observed redundancy in benzoate degradation and formaldehyde oxidation pathways, the fact that 17.6% of proteins have a better LB400 paralog than an ortholog in a different genome highlights the importance of gene duplication and repeated acquirement, which, coupled with their divergence, raises questions regarding the role of paralogs and potential functional redundancies in large-genome microbes.

Burkholderia↗
PubMed2002

Unlocking the mysteries of virus-host interactions: does functional genomics hold the key?

The interactions between viruses and the cells they infect are complex and multifaceted. While viruses strive to usurp cellular functions to their advantage, the cell strives to thwart these efforts by mounting a variety of defensive responses. These responses may include the induction of interferon, stress response, or apoptotic pathways, all of which are accompanied by changes in gene expression. Some viruses consistently win this tug of war, whereas others succumb to cellular defense mechanisms. The viral and cellular factors that determine the outcome are for the most part still unknown. With the advent of functional genomics, potent new technologies are now available to probe the complexities of virus-host interactions in ever increasing depth and detail. We describe here our efforts to use microarrays, proteomics, and bioinformatics to focus in on the changes in gene expression and protein production that occur in a virus-infected cell and to use these technologies to unlock the mysteries of virus-host interactions.

Animals↗
PubMed2025

Chromosome-specific centromeric patterns define the centeny map of the human genome.

Centromeres are epigenetically specified by distinct chromatin, whereas their DNA varies between species and individuals. This extensive sequence divergence makes comparative analyses between centromeres challenging. In this study, we identified a chromosome-specific architectural pattern across the human genome, defined by the conserved spacing of a functionally relevant centromeric DNA motif. The distribution of these sites along chromosome arms constitutes the human "centeny map." By using a custom Genomic Centromere Profiling (GCP) pipeline, we leveraged the motif's position, orientation, and organization to construct structural models that enable reclassification of human chromosomal clusters, detection of centromere expansion, and identification of structural variants and misassembled regions. The high-resolution maps derived from this pattern not only provide a framework for comparative analysis of centromeres across evolution and disease but also offer a new dimension for chromosome annotation, assembly, and characterization.

Humans↗
PubMed2002

The use and analysis of microarray data.

Functional genomics is the study of gene function through the parallel expression measurements of genomes, most commonly using the technologies of microarrays and serial analysis of gene expression. Microarray usage in drug discovery is expanding, and its applications include basic research and target discovery, biomarker determination, pharmacology, toxicogenomics, target selectivity, development of prognostic tests and disease-subclass determination. This article reviews the different ways to analyse large sets of microarray data, including the questions that can be asked and the challenges in interpreting the measurements.

Animals↗
PubMed2001

Gene transcription analysis of Saccharomyces cerevisiae exposed to neocarzinostatin protein-chromophore complex reveals evidence of DNA damage, a potential mechanism of resistance, and consequences of prolonged exposure.

The natural product neocarzinostatin (NCS), a protein-small molecule complex, exhibits potent antiproliferative activity in mammalian cells but has little apparent effect on the growth of the unicellular eukaryotic organism, Saccharomyces cerevisiae. Here, we show by whole-genome transcription profiling experiments that incubation of S. cerevisiae with NCS leads to dramatic and wide-ranging modifications in the expression profile of yeast genes. Approximately 18% of yeast transcripts are altered by 2-fold or more within 4 h of treatment with NCS. Analysis of the observed transcription profile provides evidence that yeast rapidly and continuously overexpress multiple DNA-damage repair genes during NCS exposure. Perhaps to meet the energetic requirements of continuous DNA-damage repair, yeast cells enter respiration upon prolonged exposure to NCS, although grown in nutrient-rich medium. The NCS protein component is readily transported into S. cerevisiae, as demonstrated by fluorescence microscopy of yeast treated with fluorescently labeled NCS. Transcription profiling experiments with neocarzinostatin protein alone implicate a specific resistance mechanism in yeast that targets the NCS protein component, one involving the nonclassical export pathway. These experiments provide a detailed picture of the effects of exposure to NCS upon yeast and the mechanisms they engage as a response to this protein-small molecule DNA-damaging agent.

Antibiotics, Antineoplastic↗
PubMed2001

New (and used) approaches to the study of fungal pathogenicity.

The fungi are the most economically important plant pathogens and continue to be the focus of extensive research with a wide variety of methodologies. Enhancements in microscopy techniques have increased our ability to visualize the intimate interaction of fungi and their host plants. Improving methods allow pharmacological inhibition and genetic dissection of the determinants of fungal pathogenicity in a gene-by-gene approach. Identification and analysis of genes differentially transcribed in ways pertinent to pathogenicity continues to be a frequent research approach. Genome-wide analysis is gaining favor in biological research and fungal plant pathogens are no exception. Several industrial research groups are exploring fungal plant pathogenesis based on genomic sequence data and genome-wide mutagenesis. In March 2001 the first publicly available complete genome of a filamentous fungus (Neurospora crassa) was released. N. crassa is of course a saprophyte and there is no complete sequence available for a plant pathogenic fungus in public databases. However, freely accessible entire genome sequences for both plant pathogenic fungi and their hosts are on the horizon. Sequence availability promises to revolutionize the rate at which data relevant to disease processes will be accrued. In this review we describe approaches currently applied to the study of plant pathogenic fungi and explore developments of potential future benefit with existing technologies not yet applied to this group of important organisms.

Fungi↗
PubMed2005

Genome-wide identification of genes upregulated at the onset of gametocytogenesis in Plasmodium falciparum.

A genome-wide expression analysis was undertaken to identify novel genes specifically activated from early stages of gametocytogenesis in Plasmodium falciparum. A comparative analysis was conducted on sexually induced cultures of reference parasite clone 3D7 and its gametocyteless derivative clone F12. Competitive hybridisations on long-oligomer microarrays representing 4488 P. falciparum genes identified a remarkably small number of transcripts differentially produced in the two clones. Upregulation of the mRNAs for the early gametocyte markers Pfs16 and Pfg27 was however readily detected in 3D7, and such genes were used as reference transcripts in a comparative time course analysis of 3D7 and F12 parasites between 30 and 40 h post-invasion in cultures induced to enter gametocytogenesis. One hundred and seventeen genes had expression profiles which correlated to those of pfs16 and pfg27, and Northern blot analysis and published proteomic data identified those whose expression was gametocyte-specific. Immunofluorescence analysis with antibodies against two of these gene products identified two novel parasite membrane associated, sexual stage-specific proteins. One was produced from stage I gametocytes and the second showed peak production in stage II gametocytes. The two proteins were named Pfpeg-3 and Pfpeg-4, for P. falciparum proteins of early gametocytes.

Animals↗
PubMed2001

Functional associations of proteins in entire genomes by means of exhaustive detection of gene fusions.

BACKGROUND: It has recently been shown that the detection of gene fusion events across genomes can be used for predicting functional associations of proteins, including physical interaction or complex formation. To obtain such predictions we have made an exhaustive search for gene fusion events within 24 available completely sequenced genomes. RESULTS: Each genome was used as a query against the remaining 23 complete genomes to detect gene fusion events. Using an improved, fully automatic protocol, a total of 7,224 single-domain proteins that are components of gene fusions in other genomes were detected, many of which were identified for the first time. The total number of predicted pairwise functional associations is 39,730 for all genomes. Component pairs were identified by virtue of their similarity to 2,365 multidomain composite proteins. We also show for the first time that gene fusion is a complex evolutionary process with a number of contributory factors, including paralogy, genome size and phylogenetic distance. On average, 9% of genes in a given genome appear to code for single-domain, component proteins predicted to be functionally associated. These proteins are detected by an additional 4% of genes that code for fused, composite proteins. CONCLUSIONS: These results provide an exhaustive set of functionally associated genes and also delineate the power of fusion analysis for the prediction of protein interactions.

Algorithms↗
PubMed2002

Staking out novelty on the genomic frontier.

Recent advances in genomics include global assessment and classification of genome content, high-throughput biological pathway construction, systematic identification of previously unpredicted genes and the in vitro creation of novel motifs with biological function not found in nature (extra-genomic gene discovery). The ability to make global surveys of transcriptomes has given rise to fields such as pharmacogenomics and toxicogenomics. These applications of genomics technologies, with conventional drug assessment methodologies, will lead to more tolerable drugs and a better understanding of clinical populations. Integration of pathway mapping, using proteomics married to expression, will also significantly affect how new therapeutics are discovered as cross-biological cross-pathway interactions lead to novel drug targets and better predictions of drug tolerance.

Alternative Splicing↗
PubMed2025

Genomic context-dependent roles of 5-hydroxymethylcytosine in regulating gene expression during rice drought response.

DNA methylation (5-methylcytosine, 5mC) is a key epigenetic regulator of genome stability and stress adaptation in plants. However, the functional role of its oxidative derivative, 5-hydroxymethylcytosine (5hmC), remains poorly understood in plant systems, largely due to its low abundance and unresolved enzymatic origins. Here, we integrated ACE-seq (APOBEC-coupled epigenetic sequencing) with an optimized Tn5mC-seq (transposase-based library preparation in the context of whole-genome bisulfite sequencing, WGBS) approach to generate the first single-base resolution map of 5hmC in rice (Oryza sativa), unveiling its stress-responsive dynamics and regulatory interplay with 5mC during drought adaptation. Genome-wide profiling revealed a basal 5hmC level of ~0.03 (defined as the ratio of C/(C + T) at each site), with drought triggering a pronounced reduction in 5hmC abundance and locus number, followed by incomplete recovery post-rehydration. Unlike 5mC, which accumulates in heterochromatin, 5hmC preferentially localized to euchromatic regions, including promoters, exons, and intergenic elements, and exhibited enrichment at ABA-responsive transcription factors (e.g., OsATAF1, bZIP50). Strikingly, drought induced an antagonistic relationship between 5hmC and 5mC, with the latter increasing globally to reinforce transposon silencing. Multi-omics analyses demonstrated that 5hmC depletion in promoters correlated with transcriptional downregulation, while its accumulation in gene bodies (notably 5'-UTRs) suppressed stress-responsive genes. These findings highlight 5hmC's bifunctional regulatory capacity, contingent on genomic context, and its role in balancing transcriptional plasticity with genome stability during stress. Our work establishes 5hmC as a dynamic epigenetic mark in plant environmental adaptation and provides a foundation for leveraging DNA hydroxymethylation in crop resilience engineering.

Oryza↗
PubMed2004

In silico analysis of complete bacterial genomes: PCR, AFLP-PCR and endonuclease restriction.

UNLABELLED: We have developed a website, www.in-silico.com, which runs a software program that performs three basic tasks in completely sequenced bacterial genomes by in silico analysis: PCR amplification, amplified fragment length polymorphism (AFLP-PCR) and endonuclease restriction. For PCR, after selection of the genome and introduction of primers, fragment size, DNA sequence and corresponding open reading frame (ORF) identity of the resulting PCR product is computed. Plasmids of sequenced species may be included in the analysis. Theoretical AFLP-PCR analyzes similar parameters, and includes a suggestion tool providing a list of commercial restriction enzyme pairs yielding up to 50 amplicons in the selected genome. Endonuclease restriction analysis of complete genomes and plasmids calculates the number of restriction sites for endonucleases in a given genome. If the number of fragments is 50 or fewer, pulsed field gel electrophoresis image and restriction maps are illustrated. Other tools that have been included in this site are ORF search by name and DNA to protein translation as well as restriction digestion of user-defined DNA sequences. AVAILABILITY: This is a new molecular biology resource freely available over the Internet at http://www.in-silico.com

Algorithms↗
PubMed2003

Genome-scale design of PCR primers and long oligomers for DNA microarrays.

During the last years, the demand for custom-made cDNA chips/arrays as well as whole genome chips is increasing rapidly. The efficient selection of gene-specific primers/oligomers is of the utmost importance for the successful production of such chips. We developed GenomePRIDE, a highly flexible and scalable software for designing primers/oligomers for large-scale projects. The program is able to generate either long oligomers (40-70 bases), or PCR primers for the amplification of gene-specific DNA fragments of user-defined length. Additionally, primers can be designed in-frame in order to facilitate large-scale cloning into expression vectors. Furthermore, GenomePRIDE can be adapted to specific applications such as the generation of genomic amplicon arrays or the design of fragments specific for alternative splice isoforms. We tested the performance of GenomePRIDE on the entire genomes of Listeria monocytogenes (1584 gene-specific PCRs, 48 long oligomers) as well as of eukaryotes such as Schizosaccharomyces pombe (5006 gene-specific PCRs), and Drosophila melanogaster (21 306 gene-specific PCRs). With its computing speed of 1000 primer pairs per hour and a PCR amplification success of 99%, GenomePRIDE represents an extremely cost- and time-effective program.

Animals↗
PubMed2005

Local coexpression domains of two to four genes in the genome of Arabidopsis.

Expression of genes in eukaryotic genomes is known to cluster, but cluster size is generally loosely defined and highly variable. We have here taken a very strict definition of cluster as sets of physically adjacent genes that are highly coexpressed and form so-called local coexpression domains. The Arabidopsis (Arabidopsis thaliana) genome was analyzed for the presence of such local coexpression domains to elucidate its functional characteristics. We used expression data sets that cover different experimental conditions, organs, tissues, and cells from the Massively Parallel Signature Sequencing repository and microarray data (Affymetrix) from a detailed root analysis. With these expression data, we identified 689 and 1,481 local coexpression domains, respectively, consisting of two to four genes with a pairwise Pearson's correlation coefficient larger than 0.7. This number is approximately 1- to 5-fold higher than the numbers expected by chance. A small (5%-10%) yet significant fraction of genes in the Arabidopsis genome is therefore organized into local coexpression domains. These local coexpression domains were distributed over the genome. Genes in such local domains were for the major part not categorized in the same functional category (GOslim). Neither tandemly duplicated genes nor shared promoter sequence nor gene distance explained the occurrence of coexpression of genes in such chromosomal domains. This indicates that other parameters in genes or gene positions are important to establish coexpression in local domains of Arabidopsis chromosomes.

Arabidopsis↗