Vordiplom Mathematik at University of Osnabruck, Germany

Genetics Meets Metabolomics:
from Experiment to Systems Biology

• Summary: Unlike previous books published on metabolomics, this book switches the focus from experimental questions and technical challenges, to the application of metabolomics with an emphasis on the underlying genetics. The chapters provide a thorough basis for the understanding of the underlying experimental techniques, concepts and potential biomedical applications of this exciting field. The interdisciplinary approach of this book addresses a wide readership, and contains educational aids for anyone not familiar with a particular area of metabolomics. The area of research where genetics and metabolomics meet is likely to represent a field where systems biology shall prosper highly in the years to come.
• Content: Pre-conditions for high quality biobanking in large human epidemiological cohorts for metabolomics and other -omics studies.- Assay Tools for Metabolomics.- Statistical methods in genetic and molecular epidemiology and their application in studies with metabolic phenotypes.- Ultrahigh resolution mass spectrometry based non-targeted microbial metabolomics.- etabolomic systems biology of protozoan parasites.- Mouse genetics and metabolic mouse phenotyping.- Metabolomics in animal breeding.- Metabolomics applications in human nutrition.- Metabolomics for the individualized therapy of androgen deficiency syndrome in male adults.- Systems biology resources arising from the human metabolome project.- Understanding cancer metabolism through global metabolomics.- Genetic and metabolic determinants of fatty acid chain length and desaturation, their incorporation into lipid classes and their effects on risk of vascular and metabolic disease.- Mapping metabolomic quantitative trait loci (mQTL) – A link between metabolome-wide association studies and systems biology.- Metabolic traits as intermediate phenotype.- Genome-wide association studies with metabolomics.- Systems biology meets metabolism.

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Human metabolic individuality in biomedical and pharmaceutical research

• 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 report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10–60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn’s disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.

• Suhre K, Shin S-Y, Petersen A-K, Mohney RP, Meredith D, Wagele B, Altmaier E, CARDIoGRAM, Deloukas P, Erdmann J, Grundberg E, Hammond CJ, de Angelis MH, Kastenmüller G, Kottgen A, Kronenberg F, Mangino M, Meisinger C, Meitinger T, Mewes H-W, Milburn MV, Prehn C, Raffler J, Ried JS, Romisch-Margl W, Samani NJ, Small KS, Erich Wichmann H, Zhai G, Illig T, Spector TD, Adamski J, Soranzo N, Gieger C. Human metabolic individuality in biomedical and pharmaceutical research. Nature, 477:54-60, 2011.
• Suhre K, Gieger C, Genetic variation in metabolic phenotypes: study designs and applications. Nature Reviews Genetics, 13:759-769, 2012.

Establishing world leadership in date palm research in Qatar

• Weill Cornell Medical College in Qatar won the first award in the Qatar National Research Fund (QNRF) Exceptional Proposal program with Dr. Karsten Suhre, Professor of Physiology and Director of the Bioinformatics Core, and Dr. Joel Malek, Director of the Genomics Core, awarded a five-year grant of $US4.5 million for their project Establishing World Leadership in Date Palm Research in Qatar.
• The proposal combines two innovative technologies that are well established at WCMC-Q, genomics and metabolomics, in an interdisciplinary approach to date palm research, addressing major challenges of the field. WCMC-Q is collaborating with the Ministry of Environment’s Biotechnology Center in Qatar, the Helmholtz Centre in Munich, the French National Institute for Agricultural Research, and the European Institute for Research and Development.
• The goal of the project is to better understand date palm biology and link the genetics of the date palm to date palm characteristics such as fruit color, flavor and ability to resist disease or environmental stress.
• Go to the dactylifera.org web-site

Read the WCMC-Q press release

Read the QNRF press release

• At the Helmholtz Center Munich - German Research Center for Environmental Health (HMGU), I started a research program on genetically determined human metabotypes and their link to complex disease. Metabolomics studies in animal models, such as mice and bovine are used in complement to studies in a human population. As a bioinformatician, I combine data from different sources, many of them from HelmholtzMuenchen instruments, such as targeted quantitative metabolomics from a API Q TRAP 4000, non-targeted metabolomics from a Bruker 12 Tesla APEX FT-ICR, and genotyping information using Affymetrix 500k and 6.0 GeneChip arrays on the KORA population.
• I have set up a group in metabolic research, with partners from the Helmholtz Zentrum München institutes GAC (J. Adamski), EPI (T. Illig), and IOEC (P. Schmitt-Kopplin). Our group is providing different bioinformatics ressources, which are available through this metabolomics web server. On that site, a Wiki for the metabolic initiative MetaP is available for registered users.
• We have organized the conference Metabolomics & More : The Impact of Metabolomics on the Life Sciences, which will be held on March 10-12, 2010 in Freising-Weihenstephan, Germany.
• MassTRIX: Mass TRanslator into Pathways is a web server for the annotation of high precision mass spectrometry data. It is available at www.masstrix.org.

• REF1: Gieger et al., PLoS Genetics, 2008.
• REF2: Altmaier et al.,Endocrinology, 2008 [PDF].
• REF3: Suhre and Schmitt-Kopplin, Nucleic Acids Research, 2008.
• REF4: Wang-Sattler et al., PLoS One, 2008.
• REF5: Altmaier et al., Molecular Nutrition & Food Research, 2009.
• REF6: Suhre and Gieger, BioSpektrum, 2009.
• REF7: Illig, Gieger et al., Nature Genetics, 2010.
• REF8: Suhre et al., Nature Genetics, 2011.
• REF9: Suhre et al., Nature, 2011.

• The "Deutsches Zentrum fuer Diabetesforschung e.V." (DZD) is an intertdisciplinary cooperation of the Helmholtz Association and the Leibniz Association with strong contributions from the University of Tuebingen and the University Clinic Dresden. The managing office is at the Helmholtz Centre Munich.

• Greifswald Approach to Individualized Medicine (BMBF-research project). The objective of Gani_Med is to use state-of-the-art diagnostics and novel therapeutic interventions that take into account the specific requirements and characteristics of the individual patient in order to increase the effectiveness of treatments, avoid unwanted adverse reactions and significantly reduce health care costs.

• Systems Biology of Metabotypes (BMBF-research project). SysMBo is an interdisciplinary research consortium aiming to unravel the complex relations between genetic predisposition, environmental stimuli and disease. With the help of high-throughput metabolite profiling and powerful modelling tools, the researchers take a system based approach in order to understand the complex interplay between numerous factors leading to a pathophenotype.

• The Metabolomic Platform (metaP) is a scientific interdisciplinary cooperation of Institutes of the Helmholtz Zentrum München. The activities include both profiling (analyses of all measurable analytes to identify differences) and targeted analyses (quantification of a chosen set of analytes). These activities are possible by the unique contributions of participating Helmholtz Zentrum München institutes in the GAC.

Common genetic polymorphisms induce major differentiations in the metabolic make-up of the human population. We conducted a genome-wide association study with metabolomics, identifying genetic variants in genes involved in the breakdown of fats (Gieger et al., PLoS Genetics, 2008). The resulting differences in metabolic capacity can affect individuals' susceptibility to complex diseases such as diabetes and hyperactivity. In the rapidly evolving field of metabolomics, scientists aim to measure all endogenous metabolites in a cell or body fluid. These measurements provide a functional readout of the physiological state of the human body. Investigation into these so-called "genetically determined metabotypes" in their biochemical context may help determine the pathogenesis of common diseases and gene-environment interactions. We identified four single nucleotide polymorphisms (SNPs) located in genes coding for well-characterized enzymes of the lipid metabolism. Individuals with different genotypes in these genes have significantly different metabolic capacities with respect to the synthesis of some polyunsaturated fatty acids, the beta-oxidation of short- and medium-chain fatty acids and the breakdown of triglycerides. By simultaneous measurements of both SNPs and serum concentrations of endogenous metabolites, the researchers determined the metabolome of several hundred healthy individuals and compared it to their genetic inheritance. The results suggest that most individuals carry one or more risk alleles in their genetic inheritance that may determine a certain medical phenotype, the response to a given drug treatment, or the reaction to a nutritional intervention or environmental challenge. These findings may lead to more targeted approaches to health care based on a combination of genotyping and metabolic characterization. To achieve this goal, it will be necessary to identify the major genetically determined metabotypes and their association to complex diseases.

A much larger study has been published in Nature Genetics (Illig, Gieger et al., 2010). This study identifies a number of new genetically determined metabotypes.

• NORMA: normal mode fitting of crystal structures into EM densities using URO and NMA, presented at the EMBO Practical Course on Combination of Electron Microscopy and X-ray Crystallography in Structure Determination, Gif s/Yvette, France, 2005.
• Implementation of a Web-tool for protein normal mode analysis (NMA) using the elastic network model approximation (Tirion, 1996).
• We show three examples where NMA can be used to break difficult molecular replacement problems.
• At the example of the E. coli membrane channel proteins, we show how NMA can identify putative channel opening/closure conformational changes.
• REF1: Suhre and Sanejouand, Acta Cryst. D, 2004.
• REF2: Suhre and Sanejouand, NAR, 2004.
• REF3: Suhre, Sanejouand, Navaza, Acta Cryst. D, 2006.

• GFscore is a methodology to accelerate the process of High Throughput Screening (HTS). We have extended the principle of consensus scoring by using a Non-Linear Neural Network approach. This GFscore global scoring function is a combination of the five scoring functions from in the Cscore package from Tripos Inc.
• Click here to submit a job to the GFscore web-server
• Collaboration with Xavier Morelli and Stéphane Betzi.
• REF: Betzi et al., J. Chem. Inf. Model., 2006

• Mimivirus promoter elements (discovery of an exceptionally conserved AAAATTGA octamer in the Mimivirus genome).
• Mimivirus gene- and genome duplication (one third of the Mimivirus genes have a paralogue in the genome; an ancient segmental genome duplication event of about 200 kB was detected) [PDF, supplementary material].
• Mimivirus phylogenetic trees (reconstruction of all COG'ed Mimivirus genes; in collaboration with Hiro Ogata).
• Mimivirus phylogenomic profiling (part of PhD thesis work by Francois Enault).
• Mimivirus gene function analysis (B.Sc. level practical work of Delphine Potier).
• Structure determination of selected Mimivirus genes by X-ray crystallography.
• REF1: Abergel et al., Acta Cryst., 2005.
• REF2: Suhre, J. of Virology, 2005.
• REF3: Suhre et al., PNAS, 2005.
• REF4: Claverie et al., Virus Res., 2006.
• REF5: Fitzgerald et al., Virology, accepted, 2008.

• CaMBOT probing led to the isolation of a novel calmodulin binding protein cmbB in the social amoeba Dictyostelium discoideum. Structural and bioinformatic analyses reveal that the cmbB protein is almost entirely comprised of tandem repeats of an IP22 motif, which is a more precise representation of the previously identified FNIP repeat. cmbB also appears to share structural homology to YopM, from the plague bacterium Yersenia pestis, and its closest homologues are found in Mimivirus.
• Collaboration with Prof. Danton O'Day.
• REF: O'Day et al., BBRC, 2006.

• PhydBac is a Web-tool for comparative genomics of the E. coli proteome. It is currently extended to cover most bacterial genomes of interest in bio-technology, bio-defense and medical research.
• This is the PhD research work by Francois Enault
• Viral phylogenomic profiling (based on a new profile method).
• Phydbac "Gene Function predictor": a gene annotation tool based on genomic context analysis (automated gene function prediction).
• REF1: Enault et al., NAR, 2003.
• REF2: Enault et al., Bioinformatics, 2003.
• REF3: Enault et al., NAR, 2004.
• REF4: Enault et al., BMC Bioinformatics, 2005.

• CaspR is a web-server for automated molecular replacement by screening a large number of homology models for a potential solution.
• The method that is implemented in CaspR was first used to solve the crystal structure of the E. coli protein YecD (PDB-id 1J2R).
• The implementation of this method as a web-based server is part of the PhD research work of Jean-Baptiste Claude
• REF: Claude et al., NAR, 2004.

• 3D-Coffee is a web-server to compute multiple structure-sequence alignments.
• It is based on the T-Coffee engine and uses additional structure-sequence (FUGUE) and structure-structure (SAP) alignment methods.
• REF1: Notredame and Suhre, Current Protocols in Bioinformatics, 2004
• REF2: Poirot et al., NAR, 2004.
• REF3: O'Sullivan O et al., J. Mol. Biol., 2004.

• Microarray data analysis of a yeast delta-Set1 mutant under meiotic conditions.
• Transcriptional motif search (Gibbs sampling).
• Collaboration with Vincent Géli and Christophe de la Roche Saint André (LISM-IBSM).
• Microarray data access: http://www.ebi.ac.uk/arrayexpress/ (Username: e-mexp-41, Password: sP73X5h).
• REF1: Sollier et al., EMBO journal, 2004
• REF2: Bidaut et al., BMC Bioinformatics, 2006.

• X-ray data phasing using molecular replacement (AMoRe) based on homology models (MODELLER) and subsequent model building (TURBO-FRODO)
• Structure analysis (incl. molecular dynamics simulations)
• Crystal structure determination: E. coli protein yecD (1j2r), Mimivirus TyrRS (2j5b), M. tuberculosis thioredoxin reductase TrxB (2a87),
• PDB-id: YecD = 1j2r
• REF1: Abergel et al., J. Struct. Funct. Genomics, 2003
• REF2: Abergel et al., Acta Cryst. F, 2005.
• REF3: Akif et al., Acta Cryst. D, 2005.

• FusionDB is described in the Nucleic Acid Research 2004 database issue.
• We present an analysis of gene fusion events by multiple alignments and phylogenetic tree recontructuion.
• REF1: Suhre and Claverie, NAR, 2004
• REF2: Suhre, Methods Mol Biol., 2007

• Statistical (principal component) analysis of the amino acid composition of most sequenced bacterial genomes. We show that the CHA-POL criteria (replacement of polar by charges residues in thermophilic organisms) is an optimal criteria to discriminate meso-philic from thermophilic proteins.
• REF: Suhre and Claverie, J. Biol. Chem., 2003

• Genome evolution; Comparative genomics study of genome reduction processes (Tropheryma whipplei, Rickettsia, Wolbachia, ...).
• Tropheryma whipplei genome: NC_004572 / AE014184
• REF1: Raoult et al., Genome Research, 2003
• REF2: Crapoulet et al., Current genomics, 2005.
• REF3: Ogata et al., Trends in Microbiology, 2005.
• REF4: Fournier et al., International Journal of Systematic and Evolutionary Microbiology, 2006.
• REF5: Blanc et al., PLoS Genet., 2007

• Project management in the automobile industry, Wilhelm Karmann GmbH, R&D department

• Coupled physico-chemical modelling of ACE-1 and ACE-2 Lagrangian experiments
• Co-ordinator of the modelling activities in ACE-2 (IntegModel)
• Principal investigator in the ACE-2 EU project CloudyColumn
• Preparatory studies for Lagrangian experiments in ACE-Asia

• Troposphere-stratosphere exchange in the tropics
• Feasability studies of an aerosol measurement device for MOZAIC

• Responsible of the atmospheric chemistry module MesoNH-chemistry (MNHC)
• 3-D mesoscale and large eddy simulations of ACE-2 situations

• The Fermifield in an external electro-magnetic field will be defined as a sesquilinear form at one point without using test functions. It will be shown to satisfy the Dirac-equation and to be local in an appropriate sense. Moreover, based on the field at one point von-Neuman algebrae will be defined that are identical to the smeared field. This fact is not a straight forward deduction as the field is not translationally invariant. The twisted duality R(O) = R(O')t' will be proven in this work.