Biomedical subjects

Hans-Werner Mewes

Publications and source records attributed to Hans-Werner Mewes.

At least 19 recordsLinked to original sources

PubMed2007

Separation of sequences from host-pathogen interface using triplet nucleotide frequencies.

The identification of genes involved in host-pathogen interactions is important for the elucidation of mechanisms of disease resistance and host susceptibility. A traditional way to classify the origin of genes sampled from a pool of mixed cDNA is through sequence similarity to known genes from either the pathogen or host organism or other closely related species. This approach does not work when the identified sequence has no close homologues in the sequence databases. In our previous studies, we classified genes using their codon frequencies. This method, however, explicitly required the prediction of CDS regions and thus could not be applied to sequences composed from the non-coding regions of genes. In this study, we show that the use of sliding-window triplet frequencies extends the application of the algorithm to both coding and non-coding sequences and also increases the prediction accuracy of a Support Vector Machine classifier from 95.6+/-0.3 to 96.5+/-0.2. Thus the use of the triplet frequencies increased the prediction accuracy of the new method by more than 20% compared to our previous approach. A functional analysis of sequences detected gene families having significantly higher or lower probability to be correctly classified compared to the average accuracy of the method is described. The server to perform classification of EST sequences using triplet frequencies is available at (URL: http://mips.gsf.de/proj/est3).

Algorithms↗

PubMed2006

PEDANT genome database: 10 years online.

The PEDANT genome database provides exhaustive annotation of 468 genomes by a broad set of bioinformatics algorithms. We describe recent developments of the PEDANT Web server. The all-new Graphical User Interface (GUI) implemented in Javatrade mark allows for more efficient navigation of the genome data, extended search capabilities, user customization and export facilities. The DNA and Protein viewers have been made highly dynamic and customizable. We also provide Web Services to access the entire body of PEDANT data programmatically. Finally, we report on the application of association rule mining for automatic detection of potential annotation errors. PEDANT is freely accessible to academic users at http://pedant.gsf.de.

Computer Graphics↗

PubMed2006

Insights from the genome of the biotrophic fungal plant pathogen Ustilago maydis.

Ustilago maydis is a ubiquitous pathogen of maize and a well-established model organism for the study of plant-microbe interactions. This basidiomycete fungus does not use aggressive virulence strategies to kill its host. U. maydis belongs to the group of biotrophic parasites (the smuts) that depend on living tissue for proliferation and development. Here we report the genome sequence for a member of this economically important group of biotrophic fungi. The 20.5-million-base U. maydis genome assembly contains 6,902 predicted protein-encoding genes and lacks pathogenicity signatures found in the genomes of aggressive pathogenic fungi, for example a battery of cell-wall-degrading enzymes. However, we detected unexpected genomic features responsible for the pathogenicity of this organism. Specifically, we found 12 clusters of genes encoding small secreted proteins with unknown function. A significant fraction of these genes exists in small gene families. Expression analysis showed that most of the genes contained in these clusters are regulated together and induced in infected tissue. Deletion of individual clusters altered the virulence of U. maydis in five cases, ranging from a complete lack of symptoms to hypervirulence. Despite years of research into the mechanism of pathogenicity in U. maydis, no 'true' virulence factors had been previously identified. Thus, the discovery of the secreted protein gene clusters and the functional demonstration of their decisive role in the infection process illuminate previously unknown mechanisms of pathogenicity operating in biotrophic fungi. Genomic analysis is, similarly, likely to open up new avenues for the discovery of virulence determinants in other pathogens.

Fungal Proteins↗

PubMed2006

Deciphering the evolution and metabolism of an anammox bacterium from a community genome.

Anaerobic ammonium oxidation (anammox) has become a main focus in oceanography and wastewater treatment. It is also the nitrogen cycle's major remaining biochemical enigma. Among its features, the occurrence of hydrazine as a free intermediate of catabolism, the biosynthesis of ladderane lipids and the role of cytoplasm differentiation are unique in biology. Here we use environmental genomics--the reconstruction of genomic data directly from the environment--to assemble the genome of the uncultured anammox bacterium Kuenenia stuttgartiensis from a complex bioreactor community. The genome data illuminate the evolutionary history of the Planctomycetes and allow us to expose the genetic blueprint of the organism's special properties. Most significantly, we identified candidate genes responsible for ladderane biosynthesis and biological hydrazine metabolism, and discovered unexpected metabolic versatility.

Anaerobiosis↗

PubMed2006

Spatiotemporal expression control correlates with intragenic scaffold matrix attachment regions (S/MARs) in Arabidopsis thaliana.

Scaffold/matrix attachment regions (S/MARs) are essential for structural organization of the chromatin within the nucleus and serve as anchors of chromatin loop domains. A significant fraction of genes in Arabidopsis thaliana contains intragenic S/MAR elements and a significant correlation of S/MAR presence and overall expression strength has been demonstrated. In this study, we undertook a genome scale analysis of expression level and spatiotemporal expression differences in correlation with the presence or absence of genic S/MAR elements. We demonstrate that genes containing intragenic S/MARs are prone to pronounced spatiotemporal expression regulation. This characteristic is found to be even more pronounced for transcription factor genes. Our observations illustrate the importance of S/MARs in transcriptional regulation and the role of chromatin structural characteristics for gene regulation. Our findings open new perspectives for the understanding of tissue- and organ-specific regulation of gene expression.

Arabidopsis↗

PubMed2006

Development of a Fusarium graminearum Affymetrix GeneChip for profiling fungal gene expression in vitro and in planta.

Recently the genome sequences of several filamentous fungi have become available, providing the opportunity for large-scale functional analysis including genome-wide expression analysis. We report the design and validation of the first Affymetrix GeneChip microarray based on the entire genome of a filamentous fungus, the ascomycetous plant pathogen Fusarium graminearum. To maximize the likelihood of representing all putative genes (approximately 14,000) on the array, two distinct sets of automatically predicted gene calls were used and integrated into the online F. graminearum Genome DataBase. From these gene sets, a subset of calls was manually annotated and a non-redundant extract of all calls together with additional EST sequences and controls were submitted for GeneChip design. Experiments were conducted to test the performance of the F. graminearum GeneChip. Hybridization experiments using genomic DNA demonstrated the usefulness of the array for experimentation with F. graminearum and at least four additional pathogenic Fusarium species. Differential transcript accumulation was detected using the F. graminearum GeneChip with treatments derived from the fungus grown in culture under three nutritional regimes and in comparison with fungal growth in infected barley. The ability to detect fungal genes in planta is surprisingly sensitive even without efforts to enrich for fungal transcripts. The Plant Expression Database (PLEXdb, http://www.plexdb.org) will be used as a public repository for raw and normalized expression data from the F. graminearum GeneChip. The F. graminearum GeneChip will help to accelerate exploration of the pathogen-host pathways that may involve interactions between pathogenicity genes in the fungus and disease response in the plant.

Computational Biology↗

PubMed2006

DNA damage-induced expression of p53 suppresses mitotic checkpoint kinase hMps1: the lack of this suppression in p53MUT cells contributes to apoptosis.

DNA damage induced by the topoisomerase I inhibitor irinotecan (CPT-11) triggers in p53(WT) colorectal carcinoma cells a long term cell cycle arrest and in p53MUT cells a transient arrest followed by apoptosis (Magrini, R., Bhonde, M. R., Hanski, M. L., Notter, M., Scherübl, H., Boland, C. R., Zeitz, M., and Hanski, C. (2002) Int. J. Cancer 101, 23-31; Bhonde, M. R., Hanski, M. L., Notter, M., Gillissen, B. F., Daniel, P. T., Zeitz, M., and Hanski, C. (2006) Oncogene 25, 165-175). The mechanism of the p53-independent apoptosis still remains largely unclear. Here we used five p53WT and five p53MUT established colon carcinoma cell lines to identify gene expression alterations associated with apoptosis in p53MUT cells after treatment with SN-38, the irinotecan metabolite. After treatment, 16 mitosis-related genes were found to be expressed at least 2-fold stronger in the apoptosis-executing p53MUT cells than in the cell cycle-arrested p53WT cells by oligonucleotide microarray analysis. One of the genes whose strong post-treatment expression was associated with apoptosis was the mitotic checkpoint kinase hMps1 (human ortholog of the yeast monopolar spindle 1 kinase). hMps1 mRNA and protein expression were suppressed by the treatment-induced and by the exogenous adenovirus-coded p53 protein. The direct suppression of hMps1 on RNA level or inhibition of its activity by a dominant-negative hMps1 partly suppressed apoptosis. Together, these data indicate that the high expression of mitotic genes in p53MUT cells after SN-38 treatment contributes to DNA damage-induced apoptosis, whereas their suppression in p53WT cells acts as a safeguard mechanism preventing mitosis initiation and the subsequent apoptosis. hMps1 kinase is one of the mitotic checkpoint proteins whose expression after DNA damage in p53MUT cells activates the checkpoint and contributes to apoptosis.

Antineoplastic Agents, Phytogenic↗

PubMed2006

MPact: the MIPS protein interaction resource on yeast.

In recent years, the Munich Information Center for Protein Sequences (MIPS) yeast protein-protein interaction (PPI) dataset has been used in numerous analyses of protein networks and has been called a gold standard because of its quality and comprehensiveness [H. Yu, N. M. Luscombe, H. X. Lu, X. Zhu, Y. Xia, J. D. Han, N. Bertin, S. Chung, M. Vidal and M. Gerstein (2004) Genome Res., 14, 1107-1118]. MPact and the yeast protein localization catalog provide information related to the proximity of proteins in yeast. Beside the integration of high-throughput data, information about experimental evidence for PPIs in the literature was compiled by experts adding up to 4300 distinct PPIs connecting 1500 proteins in yeast. As the interaction data is a complementary part of CYGD, interactive mapping of data on other integrated data types such as the functional classification catalog [A. Ruepp, A. Zollner, D. Maier, K. Albermann, J. Hani, M. Mokrejs, I. Tetko, U. Güldener, G. Mannhaupt, M. Münsterkötter and H. W. Mewes (2004) Nucleic Acids Res., 32, 5539-5545] is possible. A survey of signaling proteins and comparison with pathway data from KEGG demonstrates that based on these manually annotated data only an extensive overview of the complexity of this functional network can be obtained in yeast. The implementation of a web-based PPI-analysis tool allows analysis and visualization of protein interaction networks and facilitates integration of our curated data with high-throughput datasets. The complete dataset as well as user-defined sub-networks can be retrieved easily in the standardized PSI-MI format. The resource can be accessed through http://mips.gsf.de/genre/proj/mpact.

Databases, Protein↗

PubMed2006

FGDB: a comprehensive fungal genome resource on the plant pathogen Fusarium graminearum.

The MIPS Fusarium graminearum Genome Database (FGDB) is a comprehensive genome database on one of the most devastating fungal plant pathogens of wheat and barley. FGDB provides information on two gene sets independently derived by automated annotation of the F.graminearum genome sequence. A complete manually revised gene set will be completed within the near future. The initial results of systematic manual correction of gene calls are already part of the current gene set. The database can be accessed to retrieve information from bioinformatics analyses and functional classifications of the proteins. The data are also organized in the well established MIPS catalogs and novel query techniques are available to search the data. The comprehensive set of gene calls was also used for the design of an Affymetrix GeneChip. The resource is accessible on http://mips.gsf.de/genre/proj/fusarium/.

Databases, Genetic↗

PubMed2006

Can we estimate the accuracy of ADME-Tox predictions?

There have recently been developments in the methods used to access the accuracy of the prediction and applicability domain of absorption, distribution, metabolism, excretion and toxicity models, and also in the methods used to predict the physicochemical properties of compounds in the early stages of drug development. The methods are classified into two main groups: those based on the analysis of similarity of molecules, and those based on the analysis of calculated properties. An analysis of octanol-water distribution coefficients is used to exemplify the consistency of estimated and calculated accuracy of the ALOGPS program (http://www.vcclab.org) to predict in-house and publicly available datasets.

Algorithms↗

PubMed2006

Resources and tools for investigating biomolecular networks in mammals.

Molecular databases serve as primary information resources for the analysis of biological networks providing an essential and invaluable treasure for information exploration. Tools for projecting experimental data sets onto known functional information are a major need to support the analysis of samples produced in clinical research. A new concept is the notation of functional modules, i.e. the characterisation of sets of proteins that perform a defined biological function in cooperation. The determination and analysis of functional modules overcome the limitations of the analysis of individual genes and their properties. Although functional modules are not suitable to fully capture systems properties, they have the potential to unify the information generated by different types of experiments. We describe advances related to the problem of integrating heterogeneous data sets into functional modules for mouse and/or human cellular networks based on publicly available data resources, including advances in the design of ontologies for functional classification, problems of automatic protein functional annotation and integration of microarray data.

Algorithms↗

PubMed2005

Super paramagnetic clustering of protein sequences.

BACKGROUND: Detection of sequence homologues represents a challenging task that is important for the discovery of protein families and the reliable application of automatic annotation methods. The presence of domains in protein families of diverse function, inhomogeneity and different sizes of protein families create considerable difficulties for the application of published clustering methods. RESULTS: Our work analyses the Super Paramagnetic Clustering (SPC) and its extension, global SPC (gSPC) algorithm. These algorithms cluster input data based on a method that is analogous to the treatment of an inhomogeneous ferromagnet in physics. For the SwissProt and SCOP databases we show that the gSPC improves the specificity and sensitivity of clustering over the original SPC and Markov Cluster algorithm (TRIBE-MCL) up to 30%. The three algorithms provided similar results for the MIPS FunCat 1.3 annotation of four bacterial genomes, Bacillus subtilis, Helicobacter pylori, Listeria innocua and Listeria monocytogenes. However, the gSPC covered about 12% more sequences compared to the other methods. The SPC algorithm was programmed in house using C++ and it is available at http://mips.gsf.de/proj/spc. The FunCat annotation is available at http://mips.gsf.de. CONCLUSION: The gSPC calculated to a higher accuracy or covered a larger number of sequences than the TRIBE-MCL algorithm. Thus it is a useful approach for automatic detection of protein families and unsupervised annotation of full genomes.

Algorithms↗

PubMed2005

The PEDANT genome database in 2005.

The PEDANT genome database (http://pedant.gsf.de) contains pre-computed bioinformatics analyses of publicly available genomes. Its main mission is to provide robust automatic annotation of the vast majority of amino acid sequences, which have not been subjected to in-depth manual curation by human experts in high-quality protein sequence databases. By design PEDANT annotation is genome-oriented, making it possible to explore genomic context of gene products, and evaluate functional and structural content of genomes using a category-based query mechanism. At present, the PEDANT database contains exhaustive annotation of over 1,240,000 proteins from 270 eubacterial, 23 archeal and 41 eukaryotic genomes.

Computational Biology↗

PubMed2005

Exploiting scale-free information from expression data for cancer classification.

Most studies concerning expression data analyses usually exploit information on the variability of gene intensity across samples. This information is sensitive to initial data processing, which affects the final conclusions. However expression data contains scale-free information, which is directly comparable between different samples. We propose to use the pairwise ratio of gene expression values rather than their absolute intensities for a classification of expression data. This information is stable to data processing and thus more attractive for classification analyses. In proposed schema of data analyses only information on relative gene expression levels in each sample is exploited. Testing on publicly available datasets leads to superior classification results.

Breast Neoplasms↗

PubMed2004

The MIPS mammalian protein-protein interaction database.

SUMMARY: The MIPS mammalian protein-protein interaction database (MPPI) is a new resource of high-quality experimental protein interaction data in mammals. The content is based on published experimental evidence that has been processed by human expert curators. We provide the full dataset for download and a flexible and powerful web interface for users with various requirements.

Animals↗

PubMed2004

Integrative annotation of 21,037 human genes validated by full-length cDNA clones.

The human genome sequence defines our inherent biological potential; the realization of the biology encoded therein requires knowledge of the function of each gene. Currently, our knowledge in this area is still limited. Several lines of investigation have been used to elucidate the structure and function of the genes in the human genome. Even so, gene prediction remains a difficult task, as the varieties of transcripts of a gene may vary to a great extent. We thus performed an exhaustive integrative characterization of 41,118 full-length cDNAs that capture the gene transcripts as complete functional cassettes, providing an unequivocal report of structural and functional diversity at the gene level. Our international collaboration has validated 21,037 human gene candidates by analysis of high-quality full-length cDNA clones through curation using unified criteria. This led to the identification of 5,155 new gene candidates. It also manifested the most reliable way to control the quality of the cDNA clones. We have developed a human gene database, called the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/). It provides the following: integrative annotation of human genes, description of gene structures, details of novel alternative splicing isoforms, non-protein-coding RNAs, functional domains, subcellular localizations, metabolic pathways, predictions of protein three-dimensional structure, mapping of known single nucleotide polymorphisms (SNPs), identification of polymorphic microsatellite repeats within human genes, and comparative results with mouse full-length cDNAs. The H-InvDB analysis has shown that up to 4% of the human genome sequence (National Center for Biotechnology Information build 34 assembly) may contain misassembled or missing regions. We found that 6.5% of the human gene candidates (1,377 loci) did not have a good protein-coding open reading frame, of which 296 loci are strong candidates for non-protein-coding RNA genes. In addition, among 72,027 uniquely mapped SNPs and insertions/deletions localized within human genes, 13,215 nonsynonymous SNPs, 315 nonsense SNPs, and 452 indels occurred in coding regions. Together with 25 polymorphic microsatellite repeats present in coding regions, they may alter protein structure, causing phenotypic effects or resulting in disease. The H-InvDB platform represents a substantial contribution to resources needed for the exploration of human biology and pathology.

Alternative Splicing↗

PubMed2004

Illuminating the evolutionary history of chlamydiae.

Chlamydiae are the major cause of preventable blindness and sexually transmitted disease. Genome analysis of a chlamydia-related symbiont of free-living amoebae revealed that it is twice as large as any of the pathogenic chlamydiae and had few signs of recent lateral gene acquisition. We showed that about 700 million years ago the last common ancestor of pathogenic and symbiotic chlamydiae was already adapted to intracellular survival in early eukaryotes and contained many virulence factors found in modern pathogenic chlamydiae, including a type III secretion system. Ancient chlamydiae appear to be the originators of mechanisms for the exploitation of eukaryotic cells.

Acanthamoeba↗

PubMed2004

MIPS Arabidopsis thaliana Database (MAtDB): an integrated biological knowledge resource for plant genomics.

Arabidopsis thaliana is the most widely studied model plant. Functional genomics is intensively underway in many laboratories worldwide. Beyond the basic annotation of the primary sequence data, the annotated genetic elements of Arabidopsis must be linked to diverse biological data and higher order information such as metabolic or regulatory pathways. The MIPS Arabidopsis thaliana database MAtDB aims to provide a comprehensive resource for Arabidopsis as a genome model that serves as a primary reference for research in plants and is suitable for transfer of knowledge to other plants, especially crops. The genome sequence as a common backbone serves as a scaffold for the integration of data, while, in a complementary effort, these data are enhanced through the application of state-of-the-art bioinformatics tools. This information is visualized on a genome-wide and a gene-by-gene basis with access both for web users and applications. This report updates the information given in a previous report and provides an outlook on further developments. The MAtDB web interface can be accessed at http://mips.gsf.de/proj/thal/db.

Arabidopsis↗