FSU Logo

Research Projects

Friedrich-Schiller-University Jena, Department of Bioinformatics

BioInf Logo

Project 1. Metabolic Pathway Analysis
Project Metabolic Network Reconstruction and Analysis (since 2006)
Shortest EFM producing lysine in Escherichia coli when cofactors are set to external. Metabolic models increased in size and reached the genome-scale complexity. However, many metabolic models only make use of the stoichiometric information of networks instead of exploring the chemical space that can be extracted from databases. A step forward in this direction is required as many tools to analyze these large-scale models are already available. The main goal of this project is to design new methods to extract reaction rules from metabolic networks stored in databases and expand existing metabolic models in order to exploit a new chemical space. The study of these new metabolic models will be carried using elementary mode analysis, for which the applicability scope was recently enlarged.
Group members Luis Filipe Figueiredo Stefan Schuster
Links
Selected  publications
  1. C. Kaleta, L. F. de Figueiredo, J. Behre and S. Schuster. EFMEvolver: Computing elementary flux modes in genome-scale metabolic networks. In I. Grosse, S. Neumann, S. Posch, F. Schreiber, P. Stadler (editors), Lecture Notes in Informatics - Proceedings , volume P-157, Gesellschaft für Informatik, Bonn 2009, pp. 179-189. (ISBN:978-3-88579-251-2)
  2. L. F. de Figueiredo, A. Podhorski, A. Rubio, C. Kaleta, J. E. Beasley, S. Schuster and F. J. Planes. Computing the shortest elementary flux modes in genome-scale metabolic networks. Bioinformatics, accepted (doi: 10.1093/bioinformatics/btp564)
  3. L.F. de Figueiredo, S. Schuster, C. Kaleta, D.A. Fell: Can sugars be produced from fatty acids? A test case for pathway analysis tools. Bioinformatics 2008, 24 (22), 2615-2621
Funding

Systems Biology for Health in Old Age – GerontoSys (since 2009)


Continuous increase in life expectancy poses emerging challenges to society itself and particularly in public health care systems. Specifically, health in old age requires intensive research in its related processes and diseases. Although recent studies concluded a conserved phenotypic signature of ageing (see for instance Blagosklonny et al.), e.g. reduced stress resistance or altered metabolism, a profound molecular model that explains ageing in general, remains to be released.
Hence, besides investigating senescence (see also figure: mouse fibroblast cells before senescence (upper) and in senescent stage (lower)),  the main goal of this project will be the reconstruction and in depth analysis of age related metabolic networks in a multispecies approach. This will notably increase our understanding of age induced altered molecular events and aid further experimental design. To speed up reconstruction refinement and subsequent identification of particular fluxes, adequate techniques have to be used that are able to cope with or circumvent the noteworthy computational effort.

Group members Ines Heiland, Juliane Gebauer, Sascha Schäuble, Stefan Schuster

Selected  publications
from other groups
  1. M.V. Blagosklonny J. Campisi,D.A. Sinclair. Aging: past, present and future, Aging 2009, 1 (1), 1-5.
  2. C. J. Kenyon, 2010: The genetics of ageing, Nature, 464 (7288), 504-512.
  3. F. d'Adda di Fagagna, Reaper PM, L. Clay-Farrace, H. Fiegler, P. Carr , T.  von Zglinicki, G. Saretzki, N.P. Carter, S.P. Jackson: A DNA damage checkpoint response in telomere-initiated senescence. Nature 2003, 426 (6963),194-198.
  4. U. Herbig, M. Ferreira, L. Condel, D. Carey, J. M. Sedivy: Cellular senescence in ageing primates. Science 2006, 311 (5765),1257.
  5. T. Shlomi, M.N. Cabili, M.J. Herrgard, B.O. Palsson, E. Ruppin: Network-based prediction of human tissue-specific metabolism. Nature Biotechnology 2008, 26 (9), 1003-1010.
Funding
  Structural robustness of metabolic networks (2007-2009)
picture An important feature of living organisms is their homeostasis. They must be able to maintain their optimal conditions and thus to be robust against external perturbations (e.g. changes in temperature or food supply) or internal perturbations (e.g. spontaneous mutations). On the cellular level, one can distinguish between dynamic robustness for regulating metabolic fluxes and concentrations and structural robustness leading to redundant pathways to replace blocked parts of the metabolism (e.g. in the case of enzyme knockouts). In this project we are analysing the structural robustness of metabolic networks. Our analysis is based on the concept of elementary modes, which are the independent minimal fluxes through a metabolic network fulfilling the steady-state condition. Just taking their number as a measure of the structural robustness of a metabolic network does not fully reflect the change in its topology after the knockout of enzymes. Therefore we suggest a more sophisticated way of calculating the structural robustness. The measures we introduce are based on the relative number of elementary flux modes remaining after the knockout of enzymes. The calculations can be based on single or multiple knockouts. With the help of this robustnesses we are comparing metabolic networks of several different organisms.
Group members Jörn Behre Stefan Schuster
Links
Selected  publications
  1. T. Wilhelm ,J. Behre, S. Schuster: Analysis of structural robustness of metabolic networks. IEE Proceedings - Systems Biology 2004, 1, 114-120.
  2. J. Behre, T. Wilhelm, A. von Kamp, E. Ruppin and S. Schuster: Structural robustness of metabolic networks with respect to multiple knockouts. J. theor. Biol., 2008, 252 (3), 433–441
Collaboration
Funding
 General Analysis and Software Development (2005-2008)
picture Metabolic pathway analysis uses structural properties of metabolic networks in order to infer functional properties. We primarily use elementary modes analysis, which enumerates all independent minimal steady-state fluxes through a metabolic network. Elementary modes can be regarded as possible metabolic pathways. For calculation we develop and maintain the program Metatool, which is available for download. Apart from using elementary modes for identifying pathways, they can also be applied to calculate the maximal yield of a network, to make predictions about the effects of reaction knock-outs and to evaluate the robustness of the whole network.
Group members Jörn BehreAnja Schroeter , Stefan Schuster, Axel von Kamp, Dimitar Kenanov
Links
Selected publications
  1. D. Deutscher, I. Meilijson, S. Schuster, E. Ruppin: Can single knockouts accurately single out gene functions?  BMC Systems Biology 2008, 2, 50, http://www.biomedcentral.com/1752-0509/2/50
  2. S. Schuster, T. Pfeiffer and D.A. Fell: Is maximization of molar yield in metabolic networks a universal principle? J. theor. Biol. 2008, 252 (3), 497–504
  3. S. Schuster , A. von Kamp, M. Pachkov: Understanding the roadmap of metabolism by pathway analysis. In: Metabolomics, Methods and Protocols (W. Weckwerth, ed.) Humana Press, Totowa (NJ), 2007, 199-226.
  4. A. von Kamp, S. Schuster: Metatool 5.0: fast and flexible elementary modes analysis. Bioinformatics 2005, 22 (15),1930-1931.
  5. J. Stelling, S. Klamt , K. Bettenbrock, S. Schuster, E.D. Gilles: Metabolic network structure determines key aspects of functionality and regulation. Nature 2002, 420 (6912), 190-193.
  6. S. Schuster, D. A. Fell and T.  Dandekar: A general definition of metabolic pathways useful for systematic organization and analysis of complex metabolic networks. Nature Biotechnology 2000, 18(3) 326-332
Collaboration Variability of metabolic networks in genetically identical populations.
Funding
Modeling of Human erythrocyte metabolism and E. Coli lipid metabolism (2005-2008)
picture Both the projects below concern modeling and studying/simulating of biochemical networks using the concept/method of Elementary Flux Modes. This term refers to minimal group of enzymes that can operate at steady state with all the irreversible reactions used in the right direction. This concept is useful for study of enzyme deficiencies or estimating redundancy of the systems for example.
Project 1: Modeling of Human erythrocyte metabolism. The project investigated the redundancy and yield of purine salvage pathways in human erythrocytes. We included three pathways in the model - glycolysis, pentose phosphate pathway and purine metabolism. The model had to show us how ATP could be regenerated in the erythrocyte and especially we wanted to see if the reported bypass of AK through SAHH is possible. The model showed us positive result.
Project 2: Modeling of E. coli lipid metabolism - in progress. This project is aimed at modeling the lipid metabolis of E. coli with respect to Lipid-A synthesis. The model will include pathways responsible for metabolism of several types of lipids.
Group members Stefan Schuster, Dimitar Kenanov
Links
Selected  publications
  1. S. Schuster , D.Kenanov: Adenine and adenosine salvage pathways in erythrocytes and the role of S-adenosylhomocysteine hydrolase. A theoretical study using elementary flux modes. FEBS Journal 2005, 272 (20), 5278-5290. Full text
Selected  publications
from other groups
  1. R.T. Smolenski, K. Fabianovska-Majewska, C. Montero, J.A. Duely, L.D. Fairbanks, M. Marlewski, H.A. Simmonds: A nouvel route of ATP synthesis. Biochemical Pharmacology 1992, 43 (10), 2053–2057
Collaboration
Funding
Project 2. Modelling of Biological Oscillations
Modelling the Circadian Clock of Chlamydomonas reinhardtii and Its Influences on Nitrogen Use and Photosynthetic Capacity (since 2008)
Project5 This project is devoted to the study of the circadian clock of the unicellular green alga Chlamydomonas reinhardtii by asystems biological approach combining modern experimental techniques with modelling and computer simulations. In particular, the project is aimed at producing genetically modified strains of C. reinhardtii that show an improved nitrogen use and photosynthetic capacity specifically during day-phase. We aim to establish an in silico model that allows one to better understand the circadian clock of C. reinhardtii. Based on simulations with that model, regulatory genes that are involved in nitrogen metabolism and photosynthesis will be selected forgenetic manipulation. Thereby, the translation of their mRNAs will be put under the control of the circadian clock. This combined experimental and modelling approach will lead to a systems-theoretical view on this part of green algae physiology and will be instrumental in simulating, analyzing and interpreting the underlying complex metabolic and genetic systems. Within the research initiative in systems biology (FORSYS), three closely collaborating partners participate in the project which in consequence consists of three workpackages (WP). The experimental WP1 carried out at the Institute of General Botany and Plant Physiology headed by M. Mittag investigates techniques for improvement of photosynthetic efficiency in connection with nitrogen metabolism by considering and modulating the circadian control of these processes. The dynamic model of photosynthetic processes and the Calvin cycle in C. reinhardtii to be established in the Ebenhaeh group (Max Planck Institute of Molecular Plant Physiology) can be coupled with the circadian oscillator model to be established in WP3. In WP3, we will, moreover, focus on simulating the effect of circadian rhythms on photosynthesis and nitrogen metabolism. Therefore, the cooperation will allow one to derive valuable predictions on the increase of ammonium uptake and photosynthetic productivity.
Group members Ines Heiland, Thomas Hinze, Stefan Schuster
Links
  • FORSYS
  • GoFORSYS
  • GoFORSYS Chlamy Project Page
  • Chlamy Center 
  • Chlamydomonas reinhardtii genome version 3.0 
  • CellDesigner 
  • Selected publications
    1. B. Knoke, M. Marhl, M. Perc, Schuster S.: Equality of average and steady-state level in some nonlinear models of biological oscillations. Theory Biosci. 2008, 127(1),1-14.
    2. M. Schmidt, G. Gessner, M. Luff, I. Heiland, V. Wagner, M. Kaminski, S. Geimer, N. Eitzinger, T. Reissenweber, O. Voytsekh, M. Fiedler, M. Mittag, G. Kreimer : Proteomic analysis of the eyespot of Chlamydomonas reinhardtii provides novel insights into its components and tactic movements. Plant Cell 2006, 18(8),1908-1930.
    Selected  publications
    from other groups
    1. J.C. Locke, A.J. Millar, M.S. Turner: Modelling genetic networks with noisy and varied experimental data: the circadian clock in Arabidopsis thaliana. J. Theor Biol. 2005, 234 (3), 383-393.
    2.  D. Mergenhagen, E. Mergenhagen:The biological clock of Chlamydomonas reinhardtii in space. Eur. J. Cell Biol. 1987, 43 (2), 203-207.
    Collaboration
    Funding
    • BMBF (Projektträger Jülich)
    The advantage of Ca2+ oscillations (since 2003)
    Project 2.3. It is a long standing question what the advantage of Ca2+ oscillations compared to a constant steady state signal is. In the behaviour of the oscillation generating system, there exist two regimes depending on a bifurcation parameter: an unstable steady state and a stable limit cycle. The question is why the latter behaviour (which imposes additional energy costs) has been chosen in evolution. By considering the average of the oscillating Ca2+ and activated target proteins one can show that under certain conditions oscillations indeed are beneficial compared to the steady state signal: first by lowering the average Ca2+ concentration in the cytosol and second by resulting in a stronger average activation of target proteins (cellular response, CR). However, both features crucially depend on nonlinear, convex Ca2+ binding kinetics (e.g. by cooperativity).
    Group members Stefan Schuster, Christian Bodenstein
    Selected  publications
    1. B. Knoke, M. Marhl, M. Perc and S. Schuster. Equality of average and steady-state level in some nonlinear models of biological oscillations. Theory in Biosciences 2008, 127 (1), 1-14.
    2. C. Bodenstein. A simple model for decoding of calcium oscillations: analytic solution and analysis of frequency sensitivity, oscillation benefit and finiteness resonance. Diploma thesis 2008,1-84.
    Selected  publications
    from other groups
    1. C. Salazar, A. Z. Politi, T. Höfer. Decoding of calcium oscillations by phosphorylation cycles: analytic results. Biophysical Journal 2008, 94 (4), 1203-1215.
    2. D. Gall, E. Baus, G. Dupont. Activation of the liver glycogen phosphorylase by Ca2+ oscillations: a theoretical study. Journal of Theoretical Biology 2000, 207 (4), 445-454.
    3. R. E. Dolmetsch, K. Xu, R.S. Lewis. Calcium oscillations increase the efficiency and specificity of gene expression. Nature 1998, 392 (6679), 933-936.
    Collaboration

     Decoding of Ca2+ oscillations: analytic approach (since 2008)

    decoding of calcium oscillations

    The extracellular information (e.g. hormonal stimulation) encoded into Ca2+ oscillations needs to be decoded by downstream target proteins into the appropriate cellular response (e.g. upregulation of gene expression). Generally it is assumed that the information is present in the frequency of the oscillation (frequency modulation (FM)), which is more robust to noise than amplitude modulation (AM). Several models involving phosphorlyation cascades (kinase and counteracting phosphatase) known from intracellular signal transduction have been proposed. Common to all models is a Ca2+ regulated protein kinase at the first level. It has been shown that a simple Ca2+ dependent on-off mechanism of the kinase is able to decode an infinite signals frequency. Moreover, finite oscillations do show an interesting resonance phenomenon termed as 'finiteness resonance' where a given frequency activates a specific protein. Most of the proposed decoding models are analysed numerically in this project and thus an analytical approach can lead to new insights.

    Group members

    Stefan Schuster, Christian Bodenstein

    Selected  publications
    1. M. Marhl, M. Perc, S. Schuster. A minimal model for decoding of time-limited Ca2+ oscillations. Biophys. Chem. 2006, 120 (3), 161-167.
    2. M. Marhl, M. Perc and S. Schuster.  Selective regulation of cellular processes via protein cascades acting as band-pass filters for time-limited oscillations. FEBS Letters 2005, 579 (25), 5461-5465.
    3. C. Bodenstein. A simple model for decoding of calcium oscillations: analytic solution and analysis of frequency sensitivity, oscillation benefit and finiteness resonance. Diploma thesis 2008,1-84.
    Selected  publications
    from other groups
    1. C. Salazar, A. Z. Politi, T. Höfer. Decoding of calcium oscillations by phosphorylation cycles: analytic results. Biophysical Journal 2008, 94 (4), 1203-1215.
    2. G. Dupont, A. Goldbeter. Protein phosphorylation driven by intracellular calcium oscillations: a kinetic analysis. Biophysical Chemistry 1992, 42 (3), 257-270.
    Collaboration

    Selective regulation of protein activity by complex Ca2+ oscillations (2003-2007)

    picture

    As Ca2+ connects several input signals to several target processes in the cell, the question arises how one second messenger can transmit more than one signal simultaneously (bow-tie structure of signalling). For decoding, the frequency of simple spiking Ca2+ oscillations enables a selective activation of a specific protein and herewith a specific cellular process, so how can two or more classes of proteins be selectively regulated at the same time ?
    To investigate if a complex Ca2+ signal like bursting could selectively regulate two calcium-binding proteins (one being subject to biphasic regulation), several bursting patterns with simplified square pulses were applied. It could be shown that besides the selective activation of one or both proteins, also one protein can be activated while the other one is deactivated concomitantly, in dependence on the bursting pattern. Thus, the two proteins, which could be linked to two different cellular processes, can be regulated independently.

    Group members

    Stefan Schuster, Beate Knoke

    Selected  publications
    1. B. Knoke, M. Marhl, S. Schuster.   Selective Regulation of Protein Activity by Complex Ca2+ Oscillations: A Theoretical Study. In: "Mathematical Modeling of Biological Systems", Vol. I. (A. Deutsch, L. Brusch, H. Byrne, G. de Vries and H.-P. Herzel, eds.), Birkhäuser, Boston, 2007, 11-24. 
    2. S. Schuster, B. Knoke, M. Marhl. Differential regulation of proteins by bursting calcium oscillations - A theoretical study. BioSystems 2005, 81 (1), 49-63.
    Collaboration
    • Marko Marhl at the Biophysics group, University of Maribor, Slovenia
    Project 3. Evolutionary Game Theory and Individual-Based Modelling

    Population dynamics of yeasts studied from a game-theoretic perspective (since 2007)
    Population dynamics of yeasrs
    Population dynamics of microorganisms, like bacteria and fungi, but also viruses are influenced by social interactions. Those microbes and viruses do not have any consciousness and therefore are not able to act rationally. Nevertheless, changes in metabolism and habit due to mutations allow for different patterns of action, associated to strategies. Thus, the individuals can be assigned to players in a game.
    Strategies like ‘cooperation’ and ‘cheating’ can be observed in yeasts. Examples are ATP production and the external hydrolysis of sucrose by invertase secretion.
    Group members Anja Schroeter, Stefan Schuster
    Links
    Selected  publications
    1. S. Schuster, J.-U. Kreft, A. Schroeter and T. Pfeiffer: Use of game-theoretical methods in biochemistry and biophysics, J. Biol. Phys. 2008, DOI 10.1007/s10867-008-9101-4
    2. S. Schuster, T. Pfeiffer and D.A. Fell: Is maximization of molar yield in metabolic networks a universal principle? J. theor. Biol., 2008, 252 (3), 497–504
    3. T. Pfeiffer,S.  Schuster:  Game-theoretical approaches to studying the evolution of biochemical systems. Trends Biochem. Sci. 2005,  30 (1), 20-25.
    4. T. Frick,S. Schuster: An example of the prisoner's dilemma in biochemistry. Naturwissenschaften 2003,  90 (7), 327-331.
    Selected  publications
    from other groups
    1. R.C. MacLean, I. Gudelj: Resource competition and social conflict in experimental populations of yeast. Nature 2006 , 441, 498-501.
    2. D. Greig, M. Travisano: The Prisoner's Dilemma and polymorphism in yeast SUC genes. Proceedings of the Royal Society of London. Series B, Biological sciences 2004, 271 (Suppl.), S25-S26.
    Collaboration
    Mathematical modelling of communication between micro-organisms (since 2008)
    Mathematical modelling of communications

    In nature there are various forms of intra- and inter-species signalling between micro-organisms. A specific example are the communication processes during the sexual mating of fungi (in particular, Mucorales). The pheromone trisporic acid has been previously identified as a key player in these processes.
    An absorbing point to be researched is mutual exchange of intermediates between mating types during the trisporic acid production. Not only the synthesis of trisporic acid is interesting but also its effect on mating and fusion parasitism.
    For the analysis of this system we use various methods from mathematical biology and bioinformatics, e.g. evolutionary game theory and individual based modelling.

    Group members Sarah Werner, Anja Schroeter, Stefan Schuster

    Selected  publications
    1.   S. Schuster, J.-U. Kreft, A. Schroeter and T. Pfeiffer: Use of game-theoretical methods in biochemistry and biophysics, J Biol Phys.  2008, 34(1-2),1-17.
    Selected  publications
    from other groups
    1. Schultze, K., Schimek, C., Wöstemeyer, J., Burmester, A. Sexuality and parasitism share common regulatory pathways in the  fungus Parasitella parasitica. Gene 2005, 348, 33-44.
    2. J. Wöstemeyer,C. Schimek: Trisporic Acid and Mating in Zygomycetes. In: Sex in Fungi: Molecular Determination and Evolutionary Implications, ASM Press, Washington D.C.,2007, 431-443.
    Collaboration
    Funding
    Modeling the early stages of biofilm formation (since 2010)

    The formation of bacterial biofilms plays an important role in nosocomial infections of implants in hospitals. A large amount of this bacterial centered infections leads to a total replacement of the affected implants. In this regard the early stages of biofilm formation (first seconds to hours), particularly the adhesion of the bacterial cells are of extended interest. At this timescale the surface properties such as topography, surface energy or surface chemistry of an implant material are crucial parameters influencing bacterial adhesion.

    The aim of the project is to identify and characterize the most important material surface properties influencing the bacterial adhesion as well as to understand the bacterial interaction parameters and dynamics at the early stages of biofilm formation using multiscale individual based modeling approaches.

    This contribution could help to develop special surface designs of implant materials inhibiting the formation of biofilms and promoting the tissue integration of the implant.

    Group members

    Daniel Siegismund, Anja Schroeter, Stefan Schuster

    Selected  publications

    1. D. Siegismund, Keller T. F., Jandt K. D., Rettenmayr M.: Fibrinogen adsorption on biomaterials - a numerical study, Macromolecular Bioscience, in press.

    Collaboration

    Institute of Materials Science and Technology (FSU Jena), Department of Metallic Materials, Markus Rettenmayr

    Funding

    Jena School for Microbial Communication (ProExzellenz)

    Rock Scissors Paper Game among Bacteria (2004-2006)
    picture Three-player game: "RSP" - rock beats scissors, scissors beats paper and paper beats rock. For each subpopulation, the Competitive Exclusion Principle holds while for all together, a permanent cyclic coexistence is observed. Example from microbiology: Bacteriocin producing bacteria: Producers win against sensitives, resistant win against producers (because of lower metabolic costs), sensitives win against resistants (even lower costs). Can be modelled by competitive Lotka-Volterra equations.
    Group members Gunter Neumann, Stefan Schuster
    Links
    Selected  publications
    1. G. Neumann,S. Schuster: Modelling the rock - scissors - paper game between bacteriocin producing bacteria by Lotka-Volterra equations, Discrete and Continuous Dynamical Systems, Series B 2007, 8 (1), 2007-228.
    2. G. Neumann, S. Schuster: Continuous model for the rock-scissors-paper game between bacteriocin producing basteria. J. Math. Biol. 2007, 54 (6), 815-846. 
    Selected  publications
    from other groups
    1. B. Kirkup, M.A. Riley: Antibiotic-mediated antagonism leads to a bacterial game of rock-paper-scissors in vitro. Nature 2004, 428 (6981), 412-414.
    Project 4. Alternative Splicing
    Alternative Splicing at competitive tandem donor splice sites (since 2003)
    picture We investigate the phenomena of short alternatively spliced eukaryotic transcripts with variations of length L < 20 between two consecutive donor splice sites. In particular alternative exons which are spliced to the same downstream acceptor -A5E (defined as Exon that is alternatively spliced at the downstream donor = 5'splice site) tend to show a strong bias on a length variation of 4 nucleotides which define in that way a splice site within a splice site. Such cases comprise about 8% of the totally observed A5E events and thus make up only one fourth of the observed 30% of short NAGNAG variations at alternative acceptor sites reported by Hiller et al.. Our results indicate about 85 % of these tetramer variations to be candidates for nonsense mediated mRNA decay. The remaining 15% constitute a special class of alternative splicing regulation that we are currently investigating.
    Group members
    Former member of staff
    Martin Pohl Stefan Schuster
    Jeanice Kielbassa, Ralf Bortfeldt
    Links
    Selected  publications
    1. R. Bortfeldt, S. Schindler, K. Szafranski, S. Schuster and D. Holste: Comparative analysis of sequence features involved in the recognition of tandem splice sites. BMC Genomics, 2008, 9, 202.
    Selected  publications
    from other groups
    1. M. Hiller, K. Huse,K. Szafranski, N. Jahn, J. Hampe, S. Schreiber,R. Backofen, M.Platzer: Widespread occurrence of alternative splicing at NAGNAG acceptors contributes to proteome plasticity. Nature Genetics 2004, 36 (12), 1255-1257.
    2.  L.E. Maquat: Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nature reviews. Molecular cell biology 2004, 5 (2), 89-99.
    3. M. Zavolan, S. Kondo, C. Schonbach, J. Adachi, D.A. Hume, Y. Hayashizaki, T. Gaasterland: Impact of alternative initiation, splicing, and termination on the diversity of the mRNA transcripts encoded by the mouse transcriptome. Genome Research 2003, 13 (6B), 1290-1300.
    Collaboration
    • Dirk Holste (Austrian Research Centers, Vienna)  and the group of M. Platzer at the FLI Jena

    Alternative Splicing in the fungal domain (since 2008)


    picture

    Some fungal species splice their mRNA during gene expression in an alternative manner [1]. But how widely is this cellular process spread in the fungal domain and which processes in the microbial lifestyle are affected? One can imagine that the switch from peaceful mutualism to pathogen behaviour may involve regulated alternative splicing [2].

    To address the mentioned issues, we apply different bioinformatics approaches. On the one hand, we align transcript sequences (expressed sequence tags) to genome sequences of various fungi [3]. Detected alternatively spliced genes are put in a cell biological context. We study conservation of these genes, investigate phylogenetic distribution and draw conclusions on evolution.

    The other approach is ab initio prediction of splice variants. For transcripts of rare developmental and other phenotypic stages this is the method of choice [4]. Genomic DNA is searched for potential splicing signals. We develop an algorithm for classification of pseudo and real splice sites tailored to fungal sequence features.

    Group members

    Konrad Grützmann, Martin Pohl, Stefan Schuster

    Selected  publications
    from other grpups
    1. M. Irimia, J.L.Rukov, D.Penny, S.W.Roy: Functional and evolutionary analysis of alternatively spliced genes is consistent with an early eukaryotic origin of alternative splicing, BMC Evolutionary Biology 2007, 7, No.188.
    2. K. Wang, D.W. Ussery, S. Brunak: Analysis and prediction of gene splice sites in four Aspergillus genomes, Fungal Genetics and Biology 2009, 46 (Suppl. 1), S14-S18.
    3. J.W.S. Hoi, C. Herbert, N.Bacha, R. O'Connell, C. Lafitte, G. Borderies, M.Rossignol, P.Rouge, B. Dumas: Regulation and role of a STE12-like transcription factor from the plant pathogen Colletotrichum lindemuthianum, Molecular Microbiology 2007, 64 (1), 68-82.
    4. M.  Zhang, W. Gish: Improved spliced alignment from an information theoretic approach, Bioinformatics 2006, 22 (1), 13-20.

    Collaboration
    Mutually Exclusive Splicing (since 2008)

    picture

    We investigate the phenomenon of alternatively spliced eukaryotic transcripts with mutual exclusion of exons.

    A peculiarity of mutually exclusive splicing is that two (or more) splicing reactions are not independent as in other alternative splicing subtypes. Two processes must be executed or disabled in a coordinated manner.

    The mechanism of exchanging complete exons enables the encoding of a whole class of proteins with similar scaffold but different subdomains and, thus, with highly specific functionality.

    Here we search and analyse mutually exclusive exons (MXEs) in the human and mouse genome.

    Our data suggests that ~4% of human protein coding genes are affected by mutually exclusive splicing with a high variation from the basic adjacent splicing pattern shown at the left.
    Group members Martin PohlKonrad Grützmann, Stefan Schuster
    Selected  publications
    from other groups
    1. C.W.J. Smith: Alternative splicing--when two's a crowd. Cell 2005, 123 (1), 1-3.
    2. M. Soom, G. Gessner, G, H. Heuer, T. Hoshi, S.H.  Heinemann: A mutually exclusive alternative exon of slo1 codes for a neuronal BK channel with altered function. Channels (Austin) 2008, 2 (4), 278-282.
    3. M. Sammeth, S. Foissac, R. Guigó: A general definition and nomenclature for alternative splicing events. PLoS Computational Biology 2008, 4 (8), e1000147.
    Collaboration
    • Dirk Holste (Austrian Research Centers, Vienna)
    • Ralf Bortfeldt (Humboldt University, Berlin)
      Alternative splicing at tandem acceptors NAGNAG and donors GYNGYN (2006-2008)
    E/I transcript Alternative splicing is a key to understand complexity in higher organisms. We focus on the two frequent forms of the alternative splice sites:
    • alternative 5' splice site GYNGYN
    • alternative 3' splice site NAGNAG
    Where N stands for A, G, C, and T, and Y means C or T.
    Our first goal is to find special patterns in nucleotide sequences that cause the forms E(xonic), I(ntronic), and both. To answer this question, we accumulated extensive data about alternative splice events at GYNGYN donors and NAGNAG acceptors in the Tandem Splice Site DataBase TassDB: TAndem Splice Site DataBase. In the figure you can see transcript annotation of acceptor NAGNAG: E/I transcripts.
    Links TassDB: Tandem Splice Site DataBase
    Selected  publications
    1. M. Hiller, K. Szafranski, R. Sinha, K. Huse, S. Nikolajewa, P. Rosenstiel, S. Schreiber, R. Backofen, and M. Platzer: Assessing the fraction of short-distance tandem splice sites under purifying selection. RNA 2008, 14 (4), 616-629.
    2. M. Hiller, S. Nikolajewa, K. Huse, K. Szafranski , P. Rosenstiel, S. Schuster, R. Backofen, M.  Platzer: TassDB- a database of alternative tandem splice sites. Nucleic Acids Research 2006, Vol. 00, Database Issue D1-D5.
    Selected  publications
    from other groups
    1. M. Hiller, K. Huse, K. Szafranski, N. Jahn, J. Hampe, S. Schreiber, R. Backofen, M. Platzer: Widespread occurrence of alternative splicing at NAGNAG acceptors contributes to proteome plasticity. Nature Genetics 2004, 36 (12), 1255-7.
    Group members Swetlana Nikolajewa, Stefan Schuster
    Collaboration
    A PETRI NET approach to the modeling of alternative splicing pathways (2003-2008)
    picture Here we concentrate on the most important hub for the execution of alternative splicing decision the SPLICEOSOME. This protein assembly is one of the largest complexes in the eukaryotic nucleus involving more than 300 protein factors in its maturation and function. For the annotation and theoretical analysis of this large interaction network we are developing a PETRI NET model, taking advantage of the methods abstraction-, visualisation- and mathematical capabilities. Furthermore the graph theoretical representation allows for testing different strategies of model validation based on the calculation of the semi positive minimal T-INVARIANTS
    Group members

     Stefan Schuster, Ralf Bortfeldt
    Links
    Selected  publications
    1. R. Bortfeldt, S. Schuster, I. Koch: Exhaustive analysis of the modular structure of the spliceosomal assembly network - a Petri net approach. In Silico Biology 2010,10, 0007, http://www.bioinfo.de/isb/2010/10/0007/.
    2. J. Kielbassa, R. Bortfeldt, S. Schuster, I. Koch: Modeling of the U1 snRNP assembly pathway in alternative splicing in human cells using Petri nets. Computational Biology and Chemistry 2009, 33(1):46-61.
    Selected  publications
    from other groups
    1. M. Peleg, D. Rubin, R.B. Altman: Using Petri Net tools to study properties and dynamics of biological systems. Journal of the American Medical Informatics Association (JAMIA) 2005, 12 (2), 181-199.
    2. Koch I, Heiner M.: Qualitative Modelling and Analysis of Biochemical Pathways with Petri Nets. Tutorial Notes, 5th Int. Conference on Systems Biology - ICSB 2004, Heidelberg/Germany.
    Collaboration
    • Ina Koch at Johann Wolfgang Goethe-University Frankfurt a. Main