FROM PATHWAYS DATABASES TO NETWORK MODELS

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FROM PATHWAYS DATABASES TO NETWORK MODELS
Baltazar D. Aguda Mathematical Biosciences
Institute Ohio State University,
USA bdaguda_at_mbi.osu.edu
Andrew B. Goryachev Centre for Integrative
Systems Biology University of Edinburgh,
UK andrew_goryachev_at_yahoo.com
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• I. Pathways databases and knowledgebases
• Pathguide
• Pathway data standards
• A modeling-focused use of pathways databases
• Repositories of models
• II. Network visualization and analysis
• Graphical representation of pathways
  and networks
• Methods and tools for network analysis and
  modelling
• Extracting and analyzing a biological model
• The G1-S transition in the mammalian cell
  cycle
• From a qualitative network to a kinetic model
• Computer simulation of the model

OUTLINE
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I.
Pathways databases and knowledgebases

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1. Protein-Protein Interactions (86) 2.
Metabolic Pathways (45) 3. Signaling Pathways
(45) 4. Pathway Diagrams (23) 5.
Transcription Factors/Gene Regulatory Networks
(30) 6. Protein-Compound Interactions (16) 7.
Genetic Interaction Networks (5) 8. Protein
Sequence Focus (12) 9. Other (13)
http//www.pathguide.org
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from Bader, Cary Sander, 2006
40 largest databases from PATHGUIDE
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Data coverage of pathway data formats
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The Modeling Problem G1 checkpoint
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www.geneontology.org
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Kyoto Encyclopedia of Genes and Genomes
www.kegg.jp
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Cell cycle network from KEGG
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www.reactome.org www.genmapp.org
G1-S network from REACTOME and GENMAPP
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www.biocarta.com
G1-S network from BIOCARTA
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Tyson cell cycle model from BIOMODELS
Biomodels Database at EBI www.ebi.ac.uk/biomode
ls/
Model repositories
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Hatzimanikatis G1-S model from CELLML
CellML at the Univ Auckland www.cellml.org
Model repositories
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II. Network visualization and analysis
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Graphical Representation of Pathways and Networks
Problem definition and challenges Math
perspective General kinetic
notation Metabocentric view
Biochemical/metabolic notation Genecentric view
Caltech notation Signalling views
Molecular Interaction Maps
Process Diagram
Notation
Edinburgh Pathway Notation Modular perspective
Patika Future unification and
standardization
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• Graphical Notation a necessity for the
  conceptual representation of biopathways

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• Stoichiometric Kinetic notation language of
  mathematical models (almost standard)

ODEs
Stochastic algorithms
Mandel et al, Brief. Bioinf. 5270 (2004)
JDesigner (H. Sauro)
Used in many simulators JDesigner, Copasi, etc.
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• Notations accepted in the field of metabolic
  biochemical pathways

EcoCyc
KEGG
Used in databases of metabolic pathways
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• Gene Regulatory Network notation
• (E. Davidson, H. Bolouri, A. Arkin, H. MacAdams)

activation in trans
self-activation
gene transcription
indirect activation
Davidson Erwin, Science 311796 (2006)
self-inhibition
Supported and extended by BioTapestry (H. Bolouri)
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Molecular Interaction Maps (K. Kohn, M. Aladjem)
Kohn, Chaos 1184 (2001)
Aladjem et al., Science STKE pe8 (2004)
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Process Diagram Notation (H. Kitano et al.)
Kitano et al., Nat. Biotech. 23961 (2005)
Supported by CellDesigner (SBI)
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Edinburgh Pathway Notation (I.Goryanin, P. Ghazal
et al.)
Meta-level notation
protein state
logical gate
state transition
Sorokin et al., ?. in press (2006)
Supported by Edinburgh Pathway Editor (UofE)
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PATIKA Abstract Pathway Notation (U. Dogrusoz,
E. Demir et al.)
complex
Demir et al., Bioinf. 20349 (2004)
Supported by PATIKA (Bilkent University, Turkey)
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• SBGN towards the unified graphics standard

SBGN
Graphic Notation Standards
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Methods and Tools for Network Analysis Modelling
Simulation versus analysis choice of strategy
and methods Multidimensional space of modeling
techniques Kinetic modeling with ODEs and
stochastic methods Petri Nets, Boolean and
Bayesian Networks Topological analysis of large
networks based on graph theory Stoichiometric
Network Analysis Metabolic Control
Analysis Qualitative stability analysis
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• Strategies simulate or analyse?
• (or rather what to do first)

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• Space of modeling methods

Boolean networks
Process calculi
Petri Nets
continuous ? discrete
stochsim
BaN
ODE
mechanistic ? symbolic
qualitative ? quantitative
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• Kinetic Modeling Deterministic Stochastic

species
reactions
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• Tools for simulation of kinetic models

BioSpice
V-CELL
M-Cell
E-CELL
SBW
CellX/Karyote
COPASI
Dizzy
DBsolve
SBToolbox
project size
PySCeS
MesoRD
JDesigner/Jarnak
Kinetikit
JigCell
BioNetS
XPPAUT
Cellware
Narrator
deterministic ?
stochastic
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• Many Flavors of Petri Nets

inhibitory arc
places
Hybrid Functional Petri Nets
Genomic Object Net
Stochastic Petri Nets
Mobius, TimeNET
test arc
Colored Petri Nets
Design/CPN, CPN tools
transitions
Mandel et al, Brief. Bioinf. 5270 (2004)
http//www.informatik.uni-hamburg.de/TGI/PetriNets
/
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• Boolean networks

Mandel et al, Brief. Bioinf. 5270 (2004)
Huang, Pharmacogenomics. 2 203 (2001)
Genetic Network Analyzer, Biocham
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• Bayesian Networks

Sachs, Science. 308 523 (2005)
Peer, Sci. STKE. pl4 (2005)
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• Topological analysis of network connectivity

Barabasi, Nat Rev Gen. 5 101 (2004)
Cytoscape/NetworkAnalyzer
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• Stoichiometric Matrix

Hofmeyr et al., Kinetics, Control and Regulation
of Metabolic Systems. ICSB02. (2002)
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• Stoichiometric Network Analysis

Hofmeyr et al., ICSB02. (2002)
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• Extreme pathways An example

Schilling Palsson, PNAS, 954193 (1998)
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• SNA Tools and Uses

• Network stability analysis
• Clarke, Adv. Chem. Phys. 431 (1980)
• Extraction of reduced
• models
• Aguda Clarke. J. Chem. Phys. 87
• 3461 (1987)
• Signal pathway analysis
• Papin Palsson. Bioph. J. 87 37
• (2004)
• Analysis of Ca oscillations
• Reidl et al. Bioph. J. 901147 (2006)

• METATOOL
• Pfeiffer et al. Bionf. 15251 (1999)
• FluxAnalyzer
• Klamt et al. Bionf. 19261 (2003)
• CellNetAnalyzer
• Klamt et al. BMC Bionf. 7 56 (2006)
• SNA toolbox
• Urbanzcik. BMC Bionf. 7 129 (2006)

extreme pathways
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• Metabolic Control Analysis

Local properties
Elasticities
Global properties
Response coefficients
Control coefficients
Hofmeyr et al., Kinetics, Control and Regulation
of Metabolic Systems. ICSB02. (2002)
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• MCA relates global to local properties

Summation theorems
Connectivity theorems
Control-matrix equation
Hofmeyr et al., Kinetics, Control and Regulation
of Metabolic Systems. ICSB02. (2002)
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• MCA-MFA enabled tools

JDesigner/Jarnak
BioSens
PySCeS
SBW
BioSpice
COPASI
DBsolve
SBToolbox
MetaFluxNet
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• MCA understanding the network function

Goryachev et al., PLOS Comp. Biol. 1 265 (2005)
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• Analysis of circuits and network stability

Tyson , J. Chem. Phys. 62 1010 (1975)
Thomas et al., Bul. Math. Biol. 57 247 (1995)
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• Extracting and analyzing a biological model

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consensus G1-S qualitative network
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Cycle strength
graph

Xi
1-cycle mii

Xi
Xj

2-cycle mijmji

Xi
Xj
3-cycle mijmjkmki


Xk
qNET graphs from Jacobian matrix M
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