Reserach in the NGFNplus project at the Center for Bioinformatics Tübingen

NGFNplus is part of the national program of medical genome research and consists of 26 genome research networks. One of the research topics is the investigation of Parkinson's Disease (PD). In this project our research focuses at generating testable hypotheses regarding specific functional associations of PD. To this end, consequences of mutations and differential gene expression are deduced by systematically integrating genomic, transcriptional and protein-protein interaction datasets.


Official Homepage: http://www.ngfn.de/en/parkinson.html


In the core facility bioinformatics, analytic methods for the data analysis and management are developed and integrated into tailored software solutions. At the beginning of the project main focus is set on the inference of putative regulatory interactions based on transcription factor-gene links or SNP data. Deducing the effects of mutations and differential gene expression by systematically integrating genomic, transcriptional and protein-protein interaction (PPI) datasets constitutes one further goal of this project. The BowTieBuilder algorithm has been developed to identify the structure of signaling cascades based on PPI databases. In combination with the ModuleMaster algorithm, which unravels regulatory relationships among genes, integrative models of cellular processes can be created and complemented with information from KEGG. This algorithm was already successfully applied to data from the consortium. Finally, the SBMLsqueezer procedure equips these models with kinetic information. Exchange, storage, and annotation of these models can be achieved by the JSBML library developed in this project.

Hence, the bioinformatics platform ultimately aims at the integration and combined analysis of all biological measurement data of this consortium.


Figure 1: Example of a GWAS data analysis. The SNP data, i.e., genotype and affection status, is pre-filtered and fed into a Support Vector Machine (SVM). The best SVM parameters are determined through a grid search and then used to train a model, which is used to predict the disease risk of previously unseen samples. The prediction performance is estimated using a nested cross validation.

Project partners:

Subproject 1: Scientific administrative office
Prof. Dr. Thomas Gasser (Tübingen)
Subproject 2: Genomics of Parkinson's disease
Prof. Dr. Thomas Gasser, Prof. Dr. Daniela Berg (Tübingen)
Subproject 3: Mutations in recessive Parkinson's disease genes
Prof. Christine Klein (Lübeck)
Subproject 4: Genome-wide siRNA screen in an alpha-synuclein-based in vitro model of Parkinson's disease and in vivo target validation.
PD Dr. med. Günter U. Höglinger, Prof. Dr. Wolfgang H. Oertel (Marburg)
Subproject 5: Modifier screen in flies overexpressing the Drosophila homologue of LRRK2
Prof. Jörg B. Schulz, Dr. Aaron Voigt (Göttingen)
Subproject 6: Molecular mechanisms of pathogenic misfolding of α-synculein
Dr. Markus Zweckstetter, Prof. Dr. Christian Griesinger, Prof. Jörg B. Schulz (Göttingen)
Subproject 7: Biomarkers of the common Parkinson pathway: Autosomal recessive Parkinson shows alpha-Synuclein induction and synaptic pathology
Prof. Georg Auburger, Dr. Suzana Gispert (Frankfurt)
Subproject 8: Calpain cleavage of α-synuclein in the pathogenesis of Parkinson's disease by cell culture and animal models
Prof. MD Olaf Rieß (Tübingen)
Subproject 9: Regulation of Apoptosis Signal Regulating Kinase Pathways by DJ-1 and Parkin
Prof. Dr. Philipp Kahle (Tübingen)
Subproject 10: Mitochondrial stress response in neurodegeneration and aging - dissection of Omi/HtrA2 and DJ-1 mediated signalling pathways
Prof. Dr. med. Rejko Krüger (Tübingen)
Subproject 11: The physiological and pathological function of PINK1, parkin and LRRK2 in zebrafish and other models
PD Dr. Konstanze F. Winklhofer, Prof. Dr. Christian Haass (Munich)
Subproject 12: Functional characterization of LRRK2 in mammalian cells and tissues
Prof. Dr. Marius Ueffing (Munich)
Subproject 13: Dopaminergic dysfunction and molecular pathways to selective neurodegeneration: from mouse models to Parkinson disease.
Prof. Birgit Liss (Ulm)
Subproject 14: Characterization of genetic mouse models for Parkinson's disease
Prof. Dr. Günther Schütz (Heidelberg), Prof. Dr. W. Wurst (München-Neuherberg)
Subproject 15: High-performance proteome analysis for biomarker discovery and elucidation of pathomechanisms leading to neurodegeneration (Platform "Proteomics")
Prof. Dr. Katrin Marcus, Prof. Dr. Helmut E. Meyer (Bochum)
Subproject 16: Bioinformatics: data integration towards a systems level model of Parkinson's disease
Prof. Dr. Andreas Zell (Tübingen)

Contact: Office Phone E-Mail
Finja Büchel A306 +49-7071-29-78985 finja.buechel at informatik.uni-tuebingen.de
Andreas Dräger A313 +49-7071-29-78982 andreas.draeger at informatik.uni-tuebingen.de
Florian Mittag A306 +49-7071-29-78985 florian.mittag at informatik.uni-tuebingen.de

Publications

[1] Finja Büchel, Nicolas Rodriguez, Neil Swainston, Clemens Wrzodek, Tobias Czauderna, Roland Keller, Florian Mittag, Michael Schubert, Mihai Glont, Martin Golebiewski, Martijn van Iersel, Sarah M. Keating, Matthias Rall, Michael Wybrow, Henning Hermjakob, Michael Hucka, Douglas B Kell, Wolfgang Müller, Pedro Mendes, Andreas Zell, Claudine Chaouiya, Julio Saez-Rodriguez, Falk Schreiber, Camille Laibe, Andreas Dräger, and Nicolas Le Novère. Path2Models: large-scale generation of computational models from biochemical pathway maps. BMC Systems Biology, 7(1):116, November 2013. [ DOI | details | link | pdf ]
[2] Finja Büchel, Sandra Saliger, Andreas Dräger, Stephanie Hoffmann, Clemens Wrzodek, Andreas Zell, and Philipp J. Kahle. Parkinson's disease: dopaminergic nerve cell model is consistent with experimental finding of increased extracellular transport of α-synuclein. BMC Neuroscience, 14(136), November 2013. [ DOI | details | link | pdf ]
[3] Finja Büchel, Florian Mittag, Clemens Wrzodek, Andreas Zell, Thomas Gasser, and Manu Sharma. Integrative pathway-based approach for genome-wide association studies: identification of new pathways for rheumatoid arthritis and type 1 diabetes. PLoS ONE, 8(10), September 2013. [ DOI | link ]
[4] Clemens Wrzodek. Inference and integration of biochemical networks with multilayered omics data. PhD thesis, University of Tuebingen, Tübingen, Germany, June 2013. [ details | link ]
[5] Clemens Wrzodek, Finja Büchel, Manuel Ruff, Andreas Dräger, and Andreas Zell. Precise generation of systems biology models from KEGG pathways. BMC Systems Biology, 7(1):15, January 2013. [ DOI | details | link | pdf ]
[6] Peter Holmans, Valentina Moskvina, Lesley Jones, Manu Sharma, The International Parkinson's Disease Genomics Consortium (IPDGC), Alexey Vedernikov, Finja Büchel, Mohamad Sadd, Jose M. Bras, Francesco Bettella, Nayia Nicolaou, Javier Simón-Sánchez, Florian Mittag, J. Raphael Gibbs, Claudia Schulte, Alexandra Durr, Rita Guerreiro, Dena Hernandez, Alexis Brice, Hreinn Stefánsson, Kari Majamaa, Thomas Gasser, Peter Heutink, Nicholas W. Wood, Maria Martinez, Andrew B. Singleton, Michael A. Nalls, John Hardy, Huw R. Morris, and Nigel M. Williams. A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease. Human Molecular Genetics, December 2012. [ DOI | link | pdf ]
[7] Finja Büchel, Clemens Wrzodek, Florian Mittag, Andreas Dräger, Johannes Eichner, Nicolas Rodriguez, Nicolas Le Novère, and Andreas Zell. Qualitative translation of relations from BioPAX to SBML qual. Bioinformatics, 28(20):2648--2653, August 2012. [ DOI | details | link | pdf ]
[8] Florian Mittag, Finja Büchel, Mohamad Saad, Andreas Jahn, Claudia Schulte, Zoltan Bochdanovits, Javier Simón-Sánchez, Mike A Nalls, Margaux Keller, Dena Hernandez, Raphael Gibbs, Suzanne Lesage, Alexis Brice, Peter Heutink, Maria Martinez, Nicholas W Wood, John Hardy, Andrew B. Singleton, Andreas Zell, Thomas Gasser, and Manu Sharma. Use of Support Vector Machines for Disease Risk Prediction in Genome-Wide Association Studies: Concerns and Opportunities. Human Mutation, 33(12):1708--1718, June 2012. [ DOI | link ]
[9] Margaux F. Keller, Mohamad Saad, Jose M. Bras, Francesco Bettella, Nayia Nicolaou, Javier Simón-Sánchez, Florian Mittag, Finja Büchel, Manu Sharma, J. Raphael Gibbs, Claudia Schulte, Valentina Moskvina, Alexandra Durr, Peter Holmans, Laura L. Kilarski, Rita Guerreiro, Dena Hernandez, Alexis Brice, Pauli Ylikotila, Hreinn Stefánsson, Kari Majamaa, Huw R. Morris, Nigel Williams, Thomas Gasser, Peter Heutink, Nick Wood, John Hardy, Maria Martinez, Andrew B. Singleton, and Michael A. Nalls. Using genome-wide complex trait analysis 1 to quantify 'missing heritability' in parkinson's disease. Human Molecular Genetics, 21(22):4996--5009, 2012. [ DOI | link | pdf ]
[10] Finja Büchel, Clemens Wrzodek, Florian Mittag, Andreas Dräger, Adrian Schröder, and Andreas Zell. ProDGe: investigating protein-protein interactions at the domain level. Technical report, Nature Precedings, August 2011. [ DOI | details | link | pdf ]
[11] Clemens Wrzodek, Andreas Dräger, and Andreas Zell. KEGGtranslator: visualizing and converting the KEGG PATHWAY database to various formats. Bioinformatics, 27(16):2314--2315, June 2011. [ DOI | details | link | pdf ]
[12] Andreas Dräger. Computational Modeling of Biochemical Networks. PhD thesis, University of Tuebingen, Tübingen, Germany, January 2011. [ details | link ]
[13] Andreas Dräger, Adrian Schröder, and Andreas Zell. Systems Biology for Signaling Networks, volume 1 of Systems Biology, chapter Automating mathematical modeling of biochemical reaction networks, pages 159--205. Springer-Verlag, July 2010. [ DOI | details | link ]
[14] Clemens Wrzodek, Adrian Schröder, Andreas Dräger, Dierk Wanke, Kenneth W. Berendzen, Marcel Kronfeld, Klaus Harter, and Andreas Zell. ModuleMaster: A new tool to decipher transcriptional regulatory networks. Biosystems, 99(1):79--81, January 2010. [ DOI | details | link | pdf ]
[15] Jochen Supper, Lucía Spangenberg, Hannes Planatscher, Andreas Dräger, Adrian Schröder, and Andreas Zell. BowTieBuilder: modeling signal transduction pathways. BMC Systems Biology, 3(1):67, June 2009. [ DOI | details | link | pdf ]
[16] Andreas Dräger, Hannes Planatscher, Dieudonné Motsou Wouamba, Adrian Schröder, Michael Hucka, Lukas Endler, Martin Golebiewski, Wolfgang Müller, and Andreas Zell. SBML2LATEX: Conversion of SBML files into human-readable reports. Bioinformatics, 25(11):1455--1456, April 2009. [ DOI | details | link | pdf ]

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Funding:

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