Hans-Werner Mewes

Technische Universität München | TUM · Chair of Bioinformatics

There is an increasing need to use genome and transcriptome sequencing to genetically diagnose patients suffering from suspected monogenic rare diseases. The proper detection of compound heterozygous variant combinations as disease-causing candidates is a challenge in diagnostic workflows as haplotype information is lost by currently used next-gene...

From 1989 to 1997 the Yeast Genome was sequenced by a worldwide international consortium initiated and conducted by André Goffeau (1935‐2018). The article describes the pioneering collaboration of yeast scientists from a bioinformatics perspective. Indeed, the yeast genome has turned bioinformatics from an exotic hobby of few nerds into a disciplin...

Background Thoroughly annotated data resources are a key requirement in phenotype dependent analysis and diagnosis of diseases in the area of precision medicine. Recent work has shown that curation and systematic annotation of human phenome data can significantly improve the quality and selectivity for the interpretation of inherited diseases. We h...

Analysis of Next Generation Sequencing (NGS) data requires the processing of large datasets by chaining various tools with complex input and output formats. In order to automate data analysis, we propose to standardize NGS tasks into modular workflows. This simplifies reliable handling and processing of NGS data, and corresponding solutions become...

Increasing frequencies of 3-acetyl-deoxynivalenol (3-ADON)-producing strains of Fusarium graminearum (3-ADON chemotype) have been reported in North America and Asia. 3-ADON is nearly nontoxic at the level of the ribosomal target and has to be deacetylated to cause inhibition of protein biosynthesis. Plant cells can efficiently remove the acetyl gro...

Hematopoietic stem cells (HSCs) are preserved in co-cultures with UG26-1B6 stromal cells or their conditioned medium. We performed a genome-wide study of gene expression changes of UG26-1B6 stromal cells in contact with Lineage(-) SCA-1(+) KIT(+) (LSK) cells. This analysis identified connective tissue growth factor (CTGF) to be upregulated in respo...

ToppFun analysis of functional categories significantly associated with genes down-regulated after performing two-way comparison of 24 h co-culture-derived (Day1; d1) vs. separately cultured UG26-1B6 (Day0; d0) cells (Supplementary Table1) and unified in STEM ((Ernst and Bar-Joseph, 2006); http://www.cs.cmu.edu/jernst/stem) cluster #1 (C1; Figure 1...

Document S1. Supplemental Experimental Procedures, Figures S1–S6, and Tables S7 and S8

Table S3. Total List of Differentially Expressed Stromal Genes upon Contact with LSK Cells Genes differentially expressed (DEGs) after performing two-way comparison of 24 h co-culture-derived (Day1; d1 cc) vs. separately cultured UG26-1B6 (Day0; d0) cells. GcRMA-normalized gene expression data were first filtered using an additional control 24 h a...

ToppFun analysis of functional categories significantly associated with genes up-regulated after performing two-way comparison of 24 h coculture- derived (Day1; d1 cc) vs. separately cultured UG26-1B6 (Day0; d0) cells (Supplementary Table1) and unified in STEM ((Ernst and Bar-Joseph, 2006); http://www.cs.cmu.edu/jernst/stem) cluster #2 (C2; Figure...

CTGF interaction partners retrieved by performing extensive biomedical literature search using the textmining tool EXCERBT (Extraction of Classified Entities and Relations from Biomedical Texts) (Barnickel et al., 2009; Mewes et al., 2011). Co-occurrence search was employed in order to retrieve all the molecular species and phenotypes associated wi...

Table S6. CTGF Signaling Network Model of Cell-Cycle Regulation, Related to Figure 5 Construction of the literature-based signaling network model of CTGF-regulated HSC cell-cycle progression. Literature mining using EXCERBT (Extraction of Classified Entities and Relations from Biomedical Texts) (Barnickel et al., 2009; Mewes et al., 2011) and manu...

Table S4. Seed List of Hematopoiesis-Associated Genes for Network Modeling, Related to Figure 5 Hematopoiesis-associated genes retrieved by performing extensive biomedical literature search using the text-mining tool EXCERBT (Extraction of Classified Entities and Relations from Biomedical Texts) (Barnickel et al., 2009; Mewes et al., 2011). Co-occ...

Editorial summary The cause of a complex disease cannot be pinpointed to a single origin; rather, a highly complex network of many factors that interact on different levels over time and space is disturbed. This complexity requires novel approaches to diagnosis, treatment, and prevention. To foster the necessary shift to a pro-active systems medici...

Fungal secondary metabolite biosynthesis genes are of major interest due to the pharmacological properties of their products (like mycotoxins and antibiotics). The genome of the plant pathogenic fungus Fusarium graminearum codes for a large number of candidate enzymes involved in secondary metabolite biosynthesis. However, the chemical nature of mo...

Understanding how regulatory networks globally coordinate the response of a cell to changing conditions, such as perturbations by shifting environments, is an elementary challenge in systems biology which has yet to be met. Genome-wide gene expression measurements are high dimensional as these are reflecting the condition-specific interplay of thou...

Approximately 20 % of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset PD to identify 15 potentially causal variants. Segregation analysis and frequency assessm...

Hematopoietic stem cells (HSC) are regulated by an interplay of intrinsic and extrinsic signals, the latter of which are mostly transmitted by the niche. The processes involved and their interactions are largely unknown. We studied the dynamic interaction of HSC and niche stromal cells, using co-cultures of HSC (lineage-negative Sca-1+ c-Kit+: LSK)...

Although histopathological diagnosis is essential in decision of therapeutic strategy for gliomas, sometimes the tumors diagnosed in one histological entity show thoroughly different clinical courses. This phenomenon is believed to be due primarily to the presence of the genetic subgroup. In fact, relationship between treatment response and certain...

Several cancer types consist of multiple, genetically and phenotypically distinct subpopulations. The underlying mechanism for this intra-tumoral heterogeneity can be explained by the clonal evolution model, whereby growth advantageous mutations cause the expansion of cancer cell subclones. The recurrent phenotype of many cancers may be a consequen...

The Similarity Matrix of Proteins (SIMAP, http://mips.gsf.de/simap/) database has been designed to massively accelerate computationally expensive protein sequence analysis tasks in bioinformatics. It provides pre-calculated sequence similarities interconnecting the entire known protein sequence universe, complemented by pre-calculated protein featu...

Psychiatric diseases provoke human tragedies. Asocial behaviour, mood imbalance, uncontrolled affect, and cognitive malfunction are the price for the biological and social complexity of neurobiology. To understand the etiology and to influence the onset and progress of mental diseases remains of upmost importance, but despite the much improved care...

Plant small molecule UDP-glycosyltransferases (UGT) glycosylate a vast number of endogenous substances but also act in detoxification of metabolites produced by plant pathogenic microorganisms. The ability to inactivate the Fusarium graminearum mycotoxin deoxynivalenol (DON) into DON-3-O-glucoside is crucial for resistance of cereals. We analyzed t...

2353 Hematopoiesis is maintained throughout life by the constant production of mature blood cells from hematopoietic stem cells (HSC). One mechanism by which the number of HSC is maintained is self-renewal, a cell division in which at least one of the daughter cells is a cell with the same functional potential as the mother cell. The mechanisms of...

Background: Genome-wide association studies (GWAS) have provided a large set of genetic loci influencing the risk for many common diseases. Association studies typically analyze one specific trait in single populations in an isolated fashion without taking into account the potential phenotypic and genetic correlation between traits. However, GWA d...

Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we re...

Understanding mental disorders and their neurobiological basis encompasses the conceptual management of "complexity" and "dynamics". For example, affective disorders exhibit several fluctuating state variables on psychological and biological levels and data collected of these systems levels suggest quasi-chaotic periodicity leading to use concepts...

Motivation: Pairing between the target sequence and the 6–8 nt long seed sequence of the miRNA presents the most important feature for miRNA target site prediction. Novel high-throughput technologies such as Argonaute HITS-CLIP afford meanwhile a detailed study of miRNA:mRNA duplices. These interaction maps enable a first discrimination between fun...

The Munich Information Center for Protein Sequences (MIPS at the Helmholtz Center for Environmental Health, Neuherberg, Germany) has many years of experience in providing annotated collections of biological data. Selected data sets of high relevance, such as model genomes, are subjected to careful manual curation, while the bulk of high-throughput...

Selected examples of metabolites that were measured on multiple platforms; top row: alanine concentrations measured on Biocrates (FIA-MS), Chenomx (NMR), and Metabolon (GC-MS) platforms; middle row: proline concentrations measured on Biocrates (FIA-MS), Chenomx (NMR) and Metabolon (LC-MS) platforms; bottom row: 3-hydroxybutyrate measured on Chenomx...

List of top ranking associations. List of all associations with a p-value of association smaller than 10−6 for at least one of the tested metabolic traits. Reported are the SNP identifier (rs number), its chromosome (Chr.) and its chromosomal position (Position), the minor allele frequency (MAF), and the metabolic trait with the lowest p-value of a...

Influence of covariates on the association with all 482 metabolite concentrations. (0.58 MB XLS)

Schematic view of the role of FADS1 in the synthesis of phosphatidylcholine. Long-chain poly-unsaturated fatty acids have to be produced from the essential fatty acid linoleic acids (C18:2) in the omega-6 fatty acid synthesis pathway (top figure) and from alpha-linolenic acid (C18:3) in the omega-3 fatty acid synthesis pathway (not shown). Un- and...

Description of the metabolomics companies' QC processes. (0.16 MB PDF)

Associations of rs4775041 (LIPC) with metabolic traits. Metabolites associated (p<0.05) with genotype rs4775041 (LIPC) in the additive genetic model. In cases where alternative assignments of the metabolites are possible, these are indicated by a ‘*’. Full annotations can be found in the supporting online data files. Reported are the mean concentra...

Association data from metabolite concentration ratios with diabetes state. (0.86 MB XLS)

Metabolomics is the rapidly evolving field of the comprehensive measurement of ideally all endogenous metabolites in a biological fluid. However, no single analytic technique covers the entire spectrum of the human metabolome. Here we present results from a multiplatform study, in which we investigate what kind of results can presently be obtained...

The MIPS Fusarium graminearum Genome Database (FGDB) was established as a comprehensive genome database on one of the most devastating fungal plant pathogens of wheat, barley and maize. The current version of FGDB v3.1 provides information on the full manually revised gene set based on the Broad Institute assembly FG3 genome sequence. The results o...

An isolated defect of respiratory chain complex I activity is a frequent biochemical abnormality in mitochondrial disorders. Despite intensive investigation in recent years, in most instances, the molecular basis underpinning complex I defects remains unknown. We report whole-exome sequencing of a single individual with severe, isolated complex I d...

Understanding the synapse and its role in the development of psychiatric disorders is not only a demanding but a highly relevant challenge for neuroscience. With the advancement of modern high-throughput technologies, the amount of data collected becomes incomprehensible and the volume of information intractable for the individual scientist. Why Sy...

Serum metabolite concentrations provide a direct readout of biological processes in the human body, and they are associated with disorders such as cardiovascular and metabolic diseases. We present a genome-wide association study (GWAS) of 163 metabolic traits measured in human blood from 1,809 participants from the KORA population, with replication...

CORUM is a database that provides a manually curated repository of experimentally characterized protein complexes from mammalian organisms, mainly human (64%), mouse (16%) and rat (12%). Protein complexes are key molecular entities that integrate multiple gene products to perform cellular functions. The new CORUM 2.0 release encompasses 2837 protei...

The prediction of protein function as well as the reconstruction of evolutionary genesis employing sequence comparison at large is still the most powerful tool in sequence analysis. Due to the exponential growth of the number of known protein sequences and the subsequent quadratic growth of the similarity matrix, the computation of the Similarity M...

Recent developments in proteomics technology offer new opportunities for clinical applications in hospital or specialized laboratories including the identification of novel biomarkers, monitoring of disease, detecting adverse effects of drugs, and environmental hazards. Advanced spectrometry technologies and the development of new protein array for...

Localization of experimentally described miRNA target sites on human transcripts. The box plots show the distribution of the space from the target site towards the CDS end (upstream of the target site) and to the transcript end (downstream of the target site). Here, all miRNA target sites in 3′-UTRs on validated human RefSeq transcripts are shown....

Motif details. Text file containing the motif along with position probability and weight matrix. (0.02 MB TXT)

GC content and miRNA: mRNA duplex structure free energy. Shown is the percentage of the nucleotides guanine and cytosine (GC-content) in the predicted miRNA target site sequences versus the minimum free folding energy of the modeled miRNA: mRNA duplex structure for all 283,273 predicted target sites. It can be seen that no significant correlation e...

Tarbase's human transcript data set. Excel sheet describing all used miRNA targets. (0.09 MB XLS)

Schematic view of the analyzed mRNA transcript sequences with miRNA target sites. The complete remaining sequence downstream (i.e. in mRNA 3′ direction) of the target site were used with a spacer of 100 nucleotides. (0.15 MB TIF)

Motif matches in all Ensembl transcripts. Excel sheet with all human transcripts in which 3′-UTR the motif was found along with hit details. (3.69 MB XLS)

GeneSet2miRNA is the first web-based tool which is able to identify whether or not a gene list has a signature of miRNA-regulatory activity. As input, GeneSet2miRNA accepts a list of genes. As output, a list of miRNA-regulatory models is provided. A miRNA-regulatory model is a group of miRNAs (single, pair, triplet or quadruplet) that is predicted...

High-throughput metabolomics is a dynamically developing technology that enables the mass separation of complex mixtures at very high resolution. Metabolic profiling has begun to be widely used in clinical research to study the molecular mechanisms of complex cell disorders. Similar to transcriptomics, which is capable of detecting genes at differe...

The type III secretion system (TTSS) is a key mechanism for host cell interaction used by a variety of bacterial pathogens and symbionts of plants and animals including humans. The TTSS represents a molecular syringe with which the bacteria deliver effector proteins directly into the host cell cytosol. Despite the importance of the TTSS for bacteri...

Recent advances in experimental technologies allow for the detection of a complete cell proteome. Proteins that are expressed at a particular cell state or in a particular compartment as well as proteins with differential expression between various cells states are commonly delivered by many proteomics studies. Once a list of proteins is derived, a...

[This corrects the article on p. e1000376 in vol. 5, PMID: 19390696.].

Example alignment of N-termini. The first 30 residues of non-homologous effector proteins have been aligned using ClustalX with default parameters. (4.31 MB TIF)

Prediction results with EffectiveT3 trained without a certain taxonomic sub-set. EffectiveT3 has been trained without the positive and negative samples from the excluded taxonomic groups listed in this table. Testing EffectiveT3 on these effectors (E) and randomly chosen negative samples (R) resulted in true positive (+E), false negative (−E), fals...

EffectiveT3 predictions in complete proteomes. EffectiveT3 predictions for complete proteomes have been grouped by Archaea, Gram-positive and Gram-negative bacteria. Within each group, proteomes are sorted by their taxonomic lineage and species names. For each proteome, the absence (−) or presence (+) of a TTSS, the genomic G+C content, the number...

Example alignments between effector and non-effector orthologs. To investigate the evolutionary acquisition of the signal peptide, a pair wise sequence alignment study counting individual elongations and truncations between effectors and non-effector orthologs has been performed. This figure shows examples of these alignments. A) demonstrates elong...

Effector and TTSS sequences used in this study. Effector proteins are listed first, then the sequences of the TTSS system and few examples of TTSS related chaperones. The different sets are denoted as follows: A = animal pathogen set, P = plant symbiont set, T = type III secretion system, C = TTSS related chaperone. For each sequence, the first 25...

Orthologous groups of effector proteins. This table comprises effector proteins with individual experimental evidence for type III mediated transport which can be clustered into orthologous groups (clustered by homology and manual inspection). A sequence is added to a cluster, if it has at least Sratio> = 0.15 to one other cluster member. Sratio is...

Performance of the classifiers using the C-terminal end. To prove the concept of the N-terminal signal peptide, C-termini should have no predictive power. The performance for several classifiers has been evaluated using exactly the same feature selection, training and test procedure as used for the N-termini. 5 runs with different negative sets hav...

Groups of co-evolving effector and TTSS proteins and examples of co-localized effector proteins and chaperones based on the STRING database. For each group of co-evolving effector and TTSS proteins, gene names of the members are given. The right column indicates, whether the orthologous group comprises effectors, TTSS proteins or TTSS related chape...