GINsim user manual
Contents
1. J positive o I negative negative score 42 Ci f 0 OR 1 gt 1 Analyse Circuits When this first step is completed the second dialog shows the list of circuits and enables to run the analysis When the analysis is completed new categories appear to show which circuits are functional or more specifically positive or negative When a circuit is selected its functionality context is shown in the bottom panel of the dialog The analysis can be performed on the wild type or on any defined mutant 23 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement Petri Net Export Regulatory graphs can be exported into Petri net using the method described in Chaoutya2006 Mutant Selection e contour cance un The Petri Net export dialog allows to select the export format the initial markup and the mutant to apply before exporting The initial markup can be taken from an existing initial state of the model modifications made in this dialog are also applied to the simulation settings only the first state is used Analysing the state transition graph Strongly connected component GINsim allows to compute the graph of the Strongly Connected Components SCC graph see http en wikipedia org wiki Strongly connected component of an existing graph through the SCC graph option of the Actions menu The SCC graph is an acyclic graph abstracted from the origi2. pe eS an sess C20 1 Max F e OOO TENETE M ec 0 C20 a ax i 5 m Show animation The logical parameter panel showing all parameters for C1 e While logical parameters can be numerous usually many of them take the value zero To shorten parameter definition only non zero parameters have to be defined in GINsim e Adding the same set of interactions twice 1s impeded e The set of interactions associated to a logical parameter can be modified select the parameter and the corresponding set of interactions will be selected in the right list This set can then be modified and the lt lt button applies changes If the new interaction set is already defined in the list of logical parameters nothing is changed e To add a new logical parameter when an existing one 1s already selected select the empty line at the bottom of the list Interactions When a single arc is selected the Modelling Attributes tab allows to define its properties E Ea w E Properties of the Cro N arc in the lambda4 model As a gene can have different effects on another one depending on its activity level an arc can contain several interactions listed on 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement the left e The button adds an interaction e The X button deletes the selected interaction e Properties of the selected interaction can de
3. EEEE EEEE SEEE EEEE CIELE NEAPEL ESETE AEAEE EEIE NENESE AEAEE AESF IAEE SEAE ERE Cre errr IEN ENEE EAE LESE EEEE EIENEN EEAEA EAEE AEE IAEA errr AE EAEI reer Terre Perera s Figure 8 Ring layout example 7 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement Both the level and ring layouts have an inversed counterpart The secondary window This window which is originally attached to the main frame offers a bird view of the graph and 3 tabs 1 Modelling Attributes this name changes according to the context 2 Graphical Attributes 3 Graph Attributes The Modelling Attributes and Graph Attributes tabs are specitic to the type of graph and will be detailed later on Active tab change depending on the current selection e if nothing is selected only the Graph Attributes tab is active e if one node or one edge is selected the first two tabs are active e if several nodes or several edges are selected only the Graphical Attributes tab is active e if the selection contains both nodes and edges all tabs are inactive Graphical Attributes The Graphical Attributes tab in the secondary window allows to change the visual properties of the graph elements e Nodes o background and foreground color o shape and size Figure 9 Graphical attributes for nodes 8 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc
4. be used and thus should not be defined The simulation Once a regulatory model has been defined a simulation can be launched through the Run Simulation option of the Action menu This option triggers a dialog box allowing to choose simulation settings Figure 17 P EEEE AA E E A A A AO N E E E E N A AEE A E E E ae A a eet naa E E EE E E E eee deen eae Figure 17 Simulation settings 14 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement e Construction of the state transition qraph Simulation Settings Construction Strategy Size limits O Synchronous Depth Asynchronous Number of States C Breadth First Mutant Selection Depth First O With Priority Classes Configure Initial States This dialog box allows to configure and run the simulation Simulation Parameters The left part of this dialog allows to manage a set of simulation settings several simulation settings can be created allowing to switch quickly from one to another These settings will be saved and restored with the graph if the extended save is selected otherwise they are lost when opening again The right part of the dialog box enables the definition of the selected setting Construction Strategy In a given state of the system one or several genes are called to change their values When several changes are pending different construction strategies lead to different su
5. defined o Min and Max define its range of activity The interaction is active when the activity level of its source gene is in this range o Sign is this interaction an activation an inhibition or unknown This is only a visual hint the real effect of interactions is defined through logical parameters Model integrity GINsim keeps the definition of regulatory graphs consistent e When an interaction is deleted all logical parameters in which it was involved are also deleted e When the max value of a node is decreased interactions and logical parameters are checked and if necessary updated silently to avoid inconsistencies These automatic changes are necessary to keep the model valid but they can alter it Keep in mind that you need to double check parameters after performing such changes A Important When a gene has several actions on another one the activation ranges of these interactions should usually be disjoint but GINsim does not check this property Checking activation intervals of interactions and the correctness of logical parameters is left to the user as adding more controls generates more annoyances than real help Invalid logical parameters are highlighted to ease their detection Keep in mind that a change in the activation range of one of the interactions can turn a valid logical parameter into an impossible one A parameter involving interactions from the same source with disjoint activity ranges would never
6. graph ignoring all graphical attributes or to save only the position of nodes The default is to save all graphical attributes position size color shape The graph is saved in the XML based GINML format e Save Subgraph to save the current selection as a new graph e Export to save the current graph using another format GINsim can export all kinds of graphs using several generic visualisation formats These exports only retain the graph structure and visual appearance The following export formats are available under the File export submenu o Graphviz Graphs can be exported to the dot format used by the graph visualisation software Graphviz http www graphviz org This export considers only the graph structure graphical attributes are lost It enables the display of large state transition graphs that can not be viewed within GINsim o BioLayout graphs can also be exported to the BioLayout format http www biolayout org Like in graphviz format graphical attributes are lost o SVG the Scalable Vector Graphic SVG format is an XML based format for representing vector graphics http www w3 org Graphics SVG Tools like Inkscape http inkscape org can be used to display modify and export SVG files to virtually any image format The regulatory graph can additionally be exported to Petri net e Quit close all graphs and exit the GINsim application Some of these actions New Open and Save are also available fr
7. to all simulation modes excepting the asynchronous breadth first one where no information on depth is stored Warning When considering several initial states some of them can be reached while running the simulation from an other state In this case no new search will be triggered for them and the depth counter will not be reinitialised 1 e the depth limit for these initial states will be shorter State transition graph with all reachable states from the state 0111 The same simulation with a depth limit set to 2 keeps only the initial state and the nodes at a distance of two or less 1 e the six white states Vasseeansesteausesteansesteausesteausestuausesesausestausesesauseseseusestsauaeseuausesesausesesausestsauaesesausestsausestsausestuauaestuaussstsausesesausestsauaestsaassesauaestuauaestseuasstunuasseseuasseseuasseseuasseseuaeseseuaeseseuaestseuasseseuaeseseauseseuaeseseuasstseasstueasseseuasstsesasseseuasseseuasseseuasstsesaestseuaustseaustsesaustsasasstseuasstseuausesesauseseuasseueasseseuauseseuasstsesoustseaustsesasseseuaustseuaustseuaustueuasseseuasstueuaustueuasstseuasseseuanstseuanseseuauseseuaustueuanstseuasstseanseseuanstueeauseueearseseearseeeeanseseeanseeteansteetanseeeanse The limit on the total number of states apply to all simulation modes Under the asynchronous assumption this limit has slightly different effects on depth first and breadth first search Figure 24 Limitation of the size depth first and breadth firs
8. Enseignement Modelling Attributes Graphical Attributes Graph Attributes Shape Rectangle w Height25 Set as Default Background Colon Width55 Apply to All Foreground Color pply e Arcs o line color o line width o intermediate points they can be either automatically or manually placed o drawing method straight from one point to the next one or following a bezier curve When the option for intermediate points is set to Manual the points can be added by right clicking on an arc As the underlying drawing tool does not support ctr click to emulate right click on Mac OSX an additional toolbar button allows to insert them with a normal click Figure 10 Graphical attributes for arcs l Modelling Attributes Graphical Attributes Graph Attributes Line Color Intermediate Points Manual v Set as Default Line Width 2 Drawing MethodCurve w Apply to All Tip Buttons on the right side of the tab allow to apply the selected graphical attributes to additional elements e Apply to All apply the selected attributes those for which the checkbox is selected to all nodes or edges of the graph Note that if several elements are selected the selected attributes are only applied to the selection e Set as Default use the selected attributes as default for elements that will be created in the future Bird view The bird view offers an overview of the graph a red rectangle highlighting the viewed pa
9. GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement 1 sur 29 GINsim user manual Table of Contents Introduction About GINsim Availability Running GINsim Overview of the manual New in GINsim 2 3 The User Interface The GINsim window File menu Edit menu View menu Actions menu The secondary window Processing a new graph Editing the regulatory graph Notes Gene order Gene attributes Interactions Model integrity The simulation Simulation Parameters Construction Strategy Initial states Mutant Definition Depth and size limitations Running the simulation Analysing the regulatory graph Stable State Search Functionality of Regulatory Circuits Petri Net Export Analysing the state transition graph Strongly connected component Path finder Animation plugin Trajectory visualization with gnuplot References Introduction About GINsim GINsim is a tool supporting the definition the simulation and the analysis of regulatory graphs based on a multilevel logical formalism This formalism leans on the definition of two types of graphs regulatory graphs which model regulatory networks and state transition graphs which represent their dynamical behaviour for given initial state s and under specific updating assumptions Availability GINsim 2 3 is freely available under the terms of the General Public License The GINsim website http gin univ mrs fr GINsim contains up to date infor
10. ccessor states and thus to different state transition graphs Synchronous mode In this mode all changes are performed simultaneously This simplification may generate artefacts in the state transition graph Each state has at most one successor state which encompass all updating calls on gene activity levels Asynchronous mode In this mode all changes are performed independantly It will generate a state transition graph taking into account any possible trajectories This mode is chosen by default Each state can have several successor states each of them encompassing a single updating on one gene activity level In this mode the graph transition state can be generated depth first or breadth first The same state transition graph will be built except if interrupted for illustration see depth and size limitation Figure 18 Construction strategy synchronous versus asynchronous 15 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement 0x10 ASYNCHRONOUS SYNCHRONOUS 0x10 0210 6210 _ O a a B N i _ as gt i 0100 Gama _ 0309 0311 _ wp 0211 cer 0100 Gas gy 0300 4 Le 0211 0111 ha g i x lt A a We mien osaa 0301 a j f 5 P 5 i p Jo301 NS d Vere 0101 Samples of simulation results for the lambda4 model applying synchronous and asynchronous strategies to the same initial states all states where C1 0 and Cro gt 0 Dotte
11. ch gene in the corresponding table cell Allowed expression levels are defined as semicolon separated list of values or intervals denoted by a dash The special value m denotes the max value of the gene examples 0 2 4 means 0 or values between 2 and 4 0 m means any expression level The default denoted by a is to not define any set it is thus the same as 0 m To be used for the current simulation setting a line must be selected using checkboxes in the second column If no line is selected all possible states are considered resulting to the full state transition graph otherwise only the states corresponding to the selected line s are considered The simulation will start with every selected initial states unless they have already been reached by a previous simulation i e from another initial states Note The X button deletes the selected row of initial states The reset button unselects all selected rows Mutant Definition GINsim allows the definition of mutants which can then be selected before running the simulation A mutant is a set of restrictions on the evolution of the activity levels The Configure button of the Mutant panel in the simulation dialog box but also in some other places opens a dialog box allowing to specify minimal and maximal activity levels for some genes Once the activity level of a gene enters the specified interval it can not leave it anymore 1 e transitions pushing
12. d arcs denote that several transitions are triggered simultaneously Priority classes This strategy allows the user to group components into different classes and to assign a priority level to each of these classes In case of concurrent transition calls GINsim first updates the gene s belonging to the class with the highest ranking For each class the user can further specify the desired updating assumption which then determines the treatment of concurrent transition calls inside that class When several classes have the same ranking concurrent transitions are treated under an asynchronous assumption no priority By default all transitions belong to the same asynchronous class Running a simulation without further configuration is thus the same as using the asynchronous assumption The left part of the configuration dialog box shows a list of priority classes see Figure 19 The name of a class can be edited and a checkbox allows to change its internal mode from asynchronous unchecked to synchronous checked Buttons enable to add delete X order using the arrows and group ungroup G them The central column lists transitions that belong to the currently selected class and the column on the right lists all other transitions belonging to other classes To add transitions to the selected class choose them in the right list an click on the lt lt button The gt gt button removes the transition selected in the central
13. e part Actions menu Figure 6 The Actions menu Actions Help Layout H Level Layout SCC graph Level Layout Gdnverted Run Simulation Ring Layout Functional Circuits Ring Layout inverted Stable States 6 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement The Action menu for a regulatory graph Some actions can be performed from this menu depending on the type of graph Individual actions are detailed in the relevant part of this manual Currently available actions are e for all graphs o layout algorithms o determination of the Strongly Connected Components SCC of a graph e for regulatory graphs o simulation i e determination of the state transition graph o analyse of the functionality of regulatory circuits o determination of stable states e for state transition graphs o path search o graphical path construction animation Layout algorithms Elements of the graph can be placed automatically mainly useful for graphs constructed by GINsim like state transition graphs e Level layout nodes are placed on rows nodes without any incoming arc being placed on top and nodes without any outgoing arc at the bottom PEEVES ERE RESET PERERA CE REET REPEAT EEE EPA TERETE Pe ePr Tae eet ceri REE a PEER EET ERE TDAP CTR REPT CPE AE EAEAN err AEE EEEIEE EEA AEAEE ENESE EEEE IELE AEAEE AEI AENEA EAEE Rea Creare err RcT RE AEE LEANE ENEA
14. ement The search tool has found a path from the state 0770 to 0311 involving four steps Animation plugin The animation tool is launched through the Animate option of the Action menu of a state transition graph It allows to interactively follow a trajectory in the state transition graph Genes of the regulatory graph are highlited according to the selected state 26 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement Figure 30 The animation plugin E GINsim unnamed EA GINsim File Edit View Actions Help Actions Help all f SS Show animation To follow a trajectory in the state transition graph select a starting state It is then colorized in blue and added to the trajectory listed in the animation dialog box Its successor states are highlited and can be added to the trajectory upon selection which changes the available successors To build another trajectory select a state in the dialog and press the lt lt button to remove it and all of its successors To view the defined trajectory select the starting state and press the gt button Trajectory visualization with gnuplot Path created with the animation plugin or found by the path finder can be visualized using gnuplot The GP button in the path finder and in the animator box opens the gnuplot export box Figure 31 Gnuplot export box 27 sur 29 16 09 2008 14 38 GINsim us
15. er has no effect on the regulatory graph itself but may affect the partial simulation and the state transition graph the same order being used in the states names The gene order can be modified on the left side of the Graph Attributes tab Figure 13 Changing gene order Modelling Attributes Graphic Attributes Graph Attributes Name lambda4 DTD Atte gin univ mrs tr GiNsim GINML_ 2 _ 1 dte eee The left part of the Graph Attributes tab of a regulatory graph lists all genes of the model and allows to modify their order The up and down buttons move selected genes in the list O In all lists several elements can be selected using the ctrl apple on Mac OS X or shift keys Several lists can be reordered using the up and down buttons Gene attributes When a single gene is selected the Modelling Attributes tab allows to define its properties 11 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement e Name long name of the gene optional e Jd identifier of the gene appears in the graph and must be unique e Max value the maximal expression level of the gene The default value is 1 boolean case and it can be increased for multi valued genes e Basal value the value towards which the node tends when none of its regulators is active The default value is 0 e Logical parameters define the dynamical evolution of the expression level de
16. er manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement m Export the path E Mode Selected C1 ro anow The gnuplot export box allows to select genes that should appear on the graph First select nodes that should appear in the graph selecting many nodes badly affects the graphs Then select the kind of graph to create see bellow Finally click export and choose a place to save your plot Note that two files will be created but only the first file name will be asked to the user If you saved it as myplot gnuplot the second file will then be named myplot data the graph can be obtained by running gnuplot and typing the load thygraph gnuplot tommand at the gnuplot prompt 0 0 1 2 6 16000 0 901744 6 16000 8 45054 Examples of the two kinds of gnuplot graphs available The first one uses arrows of different colors to show changes in the expression levels The second one show separate subgraphs for each gene 28 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement References Chaouiya2003 Claudine Chaouiya Elisabeth Remy Brigitte Moss and Denis Thieffry Qualitative analysis of regulatory graphs a computational tool based on a discrete formal framework Lectures Notes in Control and Information Sciences 2003 294 119 126 Chaoutya2006 Claudine Chaouiya Elisabeth Remy and Denis Thieffry Qualitative Petri N
17. et Modelling of Genetic Networks Lecture Notes in Computer Science 2006 4220 95 112 10 1007 11880646_5 Gonzalez2006 Aitor Gonzalez Gonzalez Aur lien Naldi Lucas Sanchez Denis Thieffry and Claudine Chaoutya G Nsim a software suite for the qualitative modelling simulation and analysis of regulatory networks Biosystems 2006 84 91 100 10 1016 j biosystems 2005 10 003 Naldi2007 Aur lien Naldi Denis Thieffry and Claudine Chaoutya Decision Diagrams for the Representation and Analysis of Logical Models of Genetic Networks LNCS LNBI 2007 4695 2007 233 247 10 1007 978 3 540 75140 3 16 29 sur 29 16 09 2008 14 38
18. lected clicking on the graph panel adds a new gene Interaction insertion mode when selected interactions are added by dragging from one gene to another The interactions must be complemented by the definition of the logical parameters for the target variable see below The three buttons allow to add different kinds of interactions activation inhibition or undefined Note The terms gene and interaction are used through this document but nodes of the regulatory graph can represent a variety of regulatory components like protein concentration or qualitative state of the cell Similarly arcs can denote gene regulation but also protein phosphorylation degradation complex formation Notes Notes can be attached to the different components of the regulatory graph e the graph itself e genes e interactions 10 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement A note is composed of a textual comment and a list of URLs Figure 12 Notes Modelling Attributes Graphical Attributes Graph Attributes Namellambca DTD Hite gin univ mrs frfGlNsim GiIWWML_2_ 1 dtd URL Controlling the lysis hsogeny decision hitp ligin univ mrs fr GlNsim repositary jin the phage lambda The same Note panel is used for all elements supporting notes This screenshot shows this panel in the Graph Attributes tab Gene order Genes are ordered in the regulatory graph This ord
19. list from the current class and add them to the first class in the list Finally a choice list on the bottom left allows to apply some predefined settings Figure 19 Definition of Priority classes 16 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement Construction of the state transition graph Priority Classes Content of the Selected Class Content of Other Classes One unique class Show animation Figure 20 Priority Class example result Fi Example of simulation by priority classes Two priority classes have been created the highest ranked one is synchronous and contains C1 C2 and Cro The other class contains only N The resulting state transition graph is splited into two parts N expressed vs N not expressed DEAE A A E A E A E A E A A A E E E A A E A E E E E E Initial states 17 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement The bottom part of the dialog box is dedicated to the definition and the selection of the initial states of the simulation see Figure 17 The main part is a table allowing to define initial states Note that initial states are defined outside of the simulation setting and can thus be shared between several simulation settings Each row of the table corresponds to a set of states This set is defined by the specification of allowed expression levels for ea
20. mations along with the latest official version of the software and its documentation Running GINsim 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement GINsim is a Java application and thus should run on any system offering a Java virtual machine version 1 4 or later If Java is not already installed on your computer it can be downloaded e from sun Java page for Windows Solaris and Linux 1386 and AMD64 e from apple Java page for Mac OS X users e from IBM Java page for some other systems AIX linux powerpc Other system requirements depend heavily on model size To work confortably a computer with at least 512Mo of RAM is required A screen resolution of at least 1024x768 1s recommended GINsim is available in two forms e A single jar file On a properly configured system double click on the file to launch the application otherwise run it with the command java jar GINsim version jar e An archive zip or tar gz format Uncompress it and run the included launcher script runginsim bat for windows runginsim sh for UNIX like systems and runginsim command for Mac OS X This version includes the documentation tutorial and user manual and can be extended through plugins Tip Large models may require an increase of the amount of RAM available to the Java virtual machine This can be done e for the jar file with the command java Xmx300M jar GINsim version ja
21. nal one each node of the SCC graph is a cycle or a set of intertwined cycles of the original graph This makes it easier to follow trajectories as the resulting graph 1s more compact Figure 28 Strongly Connected Components graph 24 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement GINsim unnamed File Edit View Actions Help fe Selection Attributes Graphic Attributes g 1 a210 0214 Example of Strongly Connected Component Graph The original state transition graph is on top The Selection Attribute tab in the bottom panel shows the content of the selected SCC i e the list of nodes in the original graph Note that the SCC Graph tool can also be applied to regulatory graphs Path finder The search path action allows to find a path between different states of the state transition graph Selecting the search a path action in the action menu opens the configuration dialog This dialog allows to specify the starting state the target state and intermediate states using the and X buttons to add remove them GINsim then performs a shortest path search If several paths exist between these states the result is thus the first encountered shortest path Figure 29 Search for a path in the state transition graph 25 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseign
22. ns It is composed of three sections copy paste graph editing tools and selection management Copy paste The edit menu offers classical Copy Paste entries Note Copy and Paste actions are specific to GINsim copying the graph and pasting it into an external application is not supported These actions are only available for regulatory graphs Graph elements can be copied and pasted from one GINsim window to another Pasted elements are automatically selected to ease their move The Copy action does not test selected interactions it will automatically select ALL interactions between selected genes To avoid naming conflict the identifiers of pasted genes will be changed by adding 1 2 Logical parameters are also copied and cleaned up logical parameters involving not copied nodes are suppressed The resulting graph is consistent but these new parameters may need to be checked Graph editing tools e Delete to delete all selected elements e Edit to select and move genes and arcs default editing mode e Add Node to add a node This submenu lists the node insertion modes When one of these modes is selected clicking in the graph panel creates a new node e Add Arc to add an arc This submenu lists the arc insertion modes When one of these modes is selected dragging from a node to another adds an arc between them Toolbar buttons show the selected editing mode and allow to change it 16 09 2008 14 38 GINsim
23. om the toolbar Figure 3 The save dialog a save a lSlciBE i ap 1_else O_wtginml B gapE ginml arabidopsis ginml gapC ginml boolean_cell_cycle ginml phage2 ginml All Graphical Attributes 7 L gapA ginm phage4 ginml _ Extended Save File Name phage ginml Files of Type z ginml files X The Java Save dialog allows to browse and create folders as well as to choose their location By default only folders and GINML files are shown other files can be seen by removing the GINML Files filter The choice list box on the right side allows to choose which graphical attributes to save The ExtendedSave checkbox allows to enable or disable extended save save as archive containing the graph and related data 4 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement 5 sur 29 Tip If the Extended Save option is selected the file is saved in an archive zip file with a zginml extension instead of a xml file with a ginml extension This allows to save related data such as simulation parameters or mutant definitions along with the model These files need GINsim 2 3 or later to be opened Edit menu Figure 4 The Edit menu Edit View Actions Help Copy Ctrl C Paste Ctrl V Del Delete Delete E Edit Ctrl Escape Add an Arc Add a Node Select All Ctrl A Invert Selection The Edit menu allows the selection of some editing optio
24. pending on the active incoming interactions Figure 14 Attributes of a gene GIiNsim phage4 ginml File Edit View Actions Help ECOG Shiki Modelling Attributes Graphic Attributes Graph Attributes C10 2 Max Id EN mim Basal Bo Properties of the gene Cro as defined in the lambda4 model Note The Modelling Attributes tab is divided into two parts The Notes and Parameters buttons bottom left respectively select notes and logical parameters editing Logical parameters When a gene is selected logical parameters defined for this gene can be configured in the right part of the Modelling Attribute tab The panel dedicated to the definition of logical parameters is divided into three parts e On the left a table lists all defined logical parameters showing their values and related interactions e On the right the list of all incoming interactions on the selected gene e The central part contains the following buttons o lt lt assigns the set of selected incoming interactions from the right list to the selected logical parameter o X deletes the selected logical parameter s 12 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement 13 sur 29 o up and down arrows reorder the selected logical parameters Figure 15 Definition of non zero parameters for Cl Modelling Attributes Graphical Attributes Graph Attributes
25. r replace 300 by the amount of RAM you want in Mo e for the archive by changing the value of the JAVAMAXMEM variable in the launcher script Overview of the manual The next section covers the Graphical User Interface of GINsim mostly through the presentation of the main menu options Section 3 presents the editing tools dedicated to regulatory graphs Section 4 is dedicated to simulation i e the generation of state transition graphs Finally section 5 and 6 present analysis tools For a first introduction to GINsim the GINsim tutorial may be a better starting point This manual uses as much as possible the same examples and figures New in GINsim 2 3 Noteworthy improvements e extended save option when saving a file e redesign of the simulation dialog box e mutants definition replace transition blocking and can be stored when using extended save New features e Petri net e analytic determination of the stable states of a regulatory graph e analysis of the functionality of regulatory circuits The User Interface The GINsim window When GINsim is launched its main window opens see Figure 1 This window is divided into three parts e the menu and toolbar on the top e the graph panel as the main central part e the secondary panel on the bottom 2 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement fein ine unnamed Modelling At
26. rt It also offers some navigation facilities e click on it to change the viewed part e resize the red square using the bottom right corner to change the zoom factor Processing a new graph When a graph is generated state transition graph or graph of the strongly connected components the user can choose to display it to 9 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement perform some actions on it or to save it through the What to do dialog box Processing the New Graph EJ What do you want to do with this graph Size of the graph 1 Display alan o levattaveu x C Save O Export O Launch an Action For state transition graphs the number of stable states appears at the top right corner Clicking on the OK button performs the selected action This dialog box remains available to perform different actions on the graph This dialog is closed when the graph is displayed as all actions can then be performed through the Actions menu of the GINsim window Editing the regulatory graph Regulatory graphs can be interactively modified genes and interactions can be added removed and their properties defined Elements can be added depending on the current editing mode Available editing modes for regulatory graphs Deletion option selected items are deleted Default editing mode allows to select and move objects Gene insertion mode when se
27. s after the optional selection of a mutant The result is shown in a table in the same dialog allowing to launch it again for another mutant A in the table denotes that the state is stable for every value of the corresponding variable 21 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement Mutant Selection Functionality of Regulatory Circuits Regulatory circuits have a crucial role in the dynamical behaviour of a system In particular positive circuits are required for the existence of several attractors and negative circuits for the presence of cyclic attractors We presented in Naldi2007 a method to analyse circuits of the regulatory graph An implementation described in Figure 26 of this analysis is available in GINsim in the Circuits Functionality option of the Action menu Figure 26 Finding and analysing regulatory circuits Functional Circuits a aoe 72 2 vaxa E ee T S R a E E E s tE E E a ee O The first dialog enables to select which circuits will be analysed by specifying constraints on the length of the circuits or on the involved actors By default all circuits are considered 22 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement Functional Circuits Mutant Selection congue C2 C1 Cro C1 Cro C2 C1 Cro WN CZ C1WN C1 Cro J functional B Cro 4 C1 cro
28. t search construction 20 sur 29 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement The limit on the total number of nodes has different effects on depth first and breadth first state transition graphs These examples show the graph of Figure 23 limited to 6 states The first state transition graph was obtained using the depth first construction whereas the second results from the breadth first one Running the simulation While the simulation is running the bottom left corner indicates the size of the generated state transition graph The simulation can be interrupted using the Cancel button without loosing the calculated part of the state transition graph At the end of the simulation the user can choose what he wants to do with the resulting state transition graph see processing a new graph The result are shown in a table the same dialog allowing to launch the analysis again for another mutant A in the result table denotes that the state 1s stable for every value of the corresponding variable Analysing the regulatory graph Stable State Search The Stable States option of the Actions menu allows the analytic i e without running a simulation determination of stable states of the model All stable states are determined regardless of their reachability using an algorithm described in Naldi2007 The stable states dialog box see Figure 25 allows to run the analysi
29. the gene outside of the interval are ignored This enables the definition of common mutants knockouts or ectopic expressions for one or several genes as an extension of the model The simulation of more subtle mutants conditional knockouts still requires modifications of the logical parameters Warning These representation of mutants blocks some transitions but does not affect trajectories where the activity level of the gene is outside of this range Completely locking the expression level of a gene requires to set its initial values properly 18 sur 29 16 09 2008 14 38 file D Utilisateurs Adama Documents Travail Postdoc Enseignement GINsim user manual Construction of the state transition graph B Mutants A 1 1 Select a gene Dialog box for the definition of mutants Show animation Result of an asynchronous simulation where the expression level for Cro has been blocked at 1 The state transition graph is the same as the original asynchronous one but all transitions where Cro leaves this value have been suppressed This state transition graph is now composed of two disconnected parts with a new stable state 16 09 2008 14 38 19 sur 29 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement Depth and size limitations An option is also offered to limit the search depth and or the total number of states generated The limit on depth applies
30. tributes Graphic Attributes Graph Attributes Name default_name DTDhttp gin univ mrs fr GINsim GINML_2_ 1 dtd In the following the contents of the menus are described File menu 3 sur 29 B New Open Ctrl 0 Recent Files b Merge Graph Close Etri W el Save Ctrl s Save as Ctrl Shift Save Subgraph Graphviz BioLayout SVG The File menu offers all the classical options to open save a file to open close a window and to quit the application 16 09 2008 14 38 GINsim user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement The File menu provides the following options e New to create a new graph This will open a new window unless the current graph is empty e Open to load a graph from a file This will open a new window unless the current graph is empty e Recent Files to open a recently used graph This submenu lists the more recently opened graphs e Merge graph to open a graph and merge it with the current one This option works only for regulatory graphs e Close to close the current graph If other windows are opened it will simply close the current one otherwise it will last with an empty window e Save and Save as to save the current graph If the file is new or if the Save as option has been selected a file selection dialog appears Figure 3 which allows to choose the graphical attributes to save it is possible to save only the structure of the
31. user manual file D Utilisateurs Adama Documents Travail Postdoc Enseignement The selection of non default editing modes is transient by default once the action has been performed GINsim switches back to the default mode E GINsim can be locked in any mode by double clicking on the corresponding toolbar button These options are not available when visualizing a state transition graph Multiple Selection e Select All select all elements of the graph e Invert Selection unselect all selected elements and select all others View menu Figure 5 The View menu View Actions Help Zoom In Ctrl NumPad Zoom Out Ctrl NumPad Normal Size Ctrl Equals J Split Tool Window J Arc Names H Nodes to front l Grid I Grid Active Bird View The View menu allows to control the zoom factor and to set some display options The View menu contains e Zoom In Out and Normal Size to control the zoom factor e Split Tool Window to put the secondary panel in a separate window e Arc Names to display or hide arc names the source and target nodes e Nodes to front to move all nodes to front above arcs or to back makes selection easier e Grid to display or hide the grid in the graph panel e Grid Active to make the grid magnetic e Bird View to display or hide the bird view miniature of the graph in the secondary window The bird view gives an overview for large graphs and enables the selection of the visibl
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