1. In silico systems biology:network reconstruction, analysis and network based modelling EMBO practical course 10-13 April 2010, Hinxton, UK

19. Integration of genomic data with biological networks state of the art and future challenges Laura I. Furlong Integrative Biomedical Informatics Group, Research Unit on Biomedical Informatics (GRIB)

20. SNP Phenotypic effect Disease association Functional effect (e.g. loss of binding site) Network modelling Bauer-Mehren A, Furlong L, Rautschka M, Sanz F: From SNPs to pathways: integration of functional effect of sequence variations on models of cell signalling pathways. BMC Bioinformatics 2009, 10(Suppl 8):S6. Network visualization Integration of SNPs and their effects with networks

21. Prediction of pathogenic effect of mutations and SNPs

23. EntrezGene dbSNP Cytoscape node attribute file MySQL DB SNP, mutagenesis information Association to disease Functional effect Mapping to dbSNP Mapping to NCBI Gene Identification of GO concepts A data integration approach

24. Biological network data More than 200 pathway repositories and over 60 specialized on reactions in human More than 200 curated models

25. Manually curated information on nsSNPs, mutations Association to disease Results from mutagenesis experiments Broad collection of SNPs and short range sequence variants dbSNP Sequence variation data

27. Visualization

28. 28/64

29. S->A mutation at position 218 leads to protein inactivation Modelling the impact of sequence variation

30. Birtwistle MR, Hatakeyama M, Yumoto N, Ogunnaike BA, Hoek JB, Kholodenko BN (2007) Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses. Mol Syst Biol 3: 144. Modelling the impact of sequence variation

31. Concerning sequence variations Too few have been functionally characterized Synonymous (“silent”) mutations can also alter function, e.g. through modulation of splicing or altering protein folding Need of tools for prediction of the impact of coding and non coding SNPs on gene/protein function (and even on biological process) Challenges

32. The IntAct project

33. 1.Define a standard for the representation and annotation of molecular interaction data 2.provide a public repository 3.populate the repository with experimental data from project partners and curated literature data 4.provide modular analysis tools 5.provide portable versions of the software to allow installation of local IntAct nodes. IntAct goals & achievements - Curation manual available from home page - Member of the International Molecular interaction Exchange consortium (IMEx) http://www.ebi.ac.uk/intact ftp://ftp.ebi.ac.uk/pub/databases/intact 4200+ distinct publications, 209,000+ binary interactions, 63,000+ proteins imported from UniProt Known installation: AstraZeneca, GSK, MERCK, MINT, Proteome Center of Shanghai search & advanced search, hierarchView, pay-as-you-go, MiNe…

34. Master headline “Lifecycle of an Interaction” Publication (full text) CVs Curation manual. abstract annotate p1 p2 I exp curator Super curator check IMEx MatrixDB Mint DIP reject Public web site FTP site accept Sanity Checks (nightly) report IntAct Curation

35. Public data All data is manually curated by expert curators Curation manual rigorously followed All curated data is reviewed by a senior curator All data is made available on FTP site: (!) data updated every week (!) format available: ftp://ftp.ebi.ac.uk/pub/databases/intact Data

36. Controlled vocabularies Why do we use them ? e.g. far too many ways to write: yeast two hybrid, Y2H, 2H, two-hybrid, … Full integration of PSI-MI ontology Over 1,500 terms, fully defined and cross-referenced

37. How to deal with Complexes Some experimental protocol do generate complex data: Eg. Tandem affinity purification (TAP) One may want to convert these complexes into sets of binary interactions, 2 algorithms are available: Both are somewhat wrong, spoke is said to generated 3 times less false positive (Bader et al.).

38. The IntAct web site

39. http://www.ebi.ac.uk/intact IntAct: Home page

40. UniProt TaxonomyPubMedMethod (PSI-MI CV) Interaction details Complex ? Interactors IntAct: Search and results IMEx data Other PSICQUIC services

41. IntAct: Search and results Export Custom columns Filters

42. IntAct: Browse

43. IntAct: Advanced search: Ontologies

44. IntAct > Advanced search: Fields Filtering options Add more filtering options

45. IntAct > Advanced search: MIQL Molecular Interaction Query Language

46. IntAct > Chemical search 1. Draw your compound 2. View matching molecules 3. View known interactions

47. IntAct > Interaction details

48. IntAct > Interaction details > More..

49. IntAct > Interaction details > Find similar interactions We search for similar interaction by looking for interactions sharing the same participants. Interactions having the most in commons are shown first. So far all hits are shown, we will work at speeding up that view as it can be rather slow when many participants exist in the original interaction.

50. IntAct > List of interactors

51. IntAct > List of interactors > Compounds

52. IntAct > Graph view

53. IntAct > Linking to Cytoscape

54. Molecular Interaction Standards

55. Engineering 1850 Nuts and bolts fit perfectly together, but only if they originate from the same factory Standardisation proposal in 1864 by William Sellers It took until after WWII until it was generally accepted, though … Proteomics 2003 Proteomics data are perfectly compatible, but only if they are from the same lab / database / software “Publish and vanish” by data producers Collecting all publicly available data requires huge effort Urgent need for standardisation

56. Community standard for Molecular Interactions XML schema and detailed controlled vocabularies Jointly developed by major data providers: BIND, CellZome, DIP, GSK, HPRD, Hybrigenics, IntAct, MINT, MIPS, Serono, U. Bielefeld, U. Bordeaux, U. Cambridge, and others Version 1.0 published in February 2004 The HUPO PSI Molecular Interaction Format - A community standard for the representation of protein interaction data. Henning Hermjakob et al, Nature Biotechnology 2004. Version 2.5 published in October 2007 Broadening the horizon - Level 2.5 of the HUPO-PSI format for molecular interactions. Samuel Kerrien et al., BMC Biology 2007. PSI-MI XML format

57. 57 IntAct specific columns (+11): Experimental role(s) of interactors Biological role(s) of interactors Properties (CrossReference) of interactors Type(s) of interactors HostOrganism(s) Expansion method(s) Dataset name(s) Standard columns (15): ID(s) interactor A & B Alt. ID(s) interactor A & B Alias(es) interactor A & B Interaction detection method(s) Publication 1st author(s) Publication Identifier(s) Taxid interactor A & B Interaction type(s) Source database(s) Interaction identifier(s) Confidence value(s) + PSIMITAB Format Standardization in progress !!

58. 58 PSI-MI Data format Data distribution Control vocabulary Data submission Website Search Interactions Interaction details Interactors Molecular view Graph view Standard format Tools PSICQUIC PSI-MI CV Reporting guideline MIMIx Tools PSI-MI XML PSI-MITAB XML Java API MITAB Java API XMLMakerFlattener Semantic Validator RPsiXML (Bioconductor) PSI-MI XML files PSI Excel Sheet PSI Web Form Data Servers Registry Clients

59. MIMIx Experiments Interaction detection method (eg. Yeast two hybrid) Participant detection method (eg. Mass Spectrometry) Host organism Interactions Interactors Identifiers from public database Species of origin Biological/experimental roles (eg. enzyme,target / bait,prey) Confidence

60. IMEx: The International Molecular Exchange Consortium Group of major public interaction data providers sharing curation effort: DIP, IntAct, MINT, MPact, MatrixDB, MPIDB and BioGRID Independent molecular interaction resources Common curation standards for detailed curation Common data formats (PSI-MI XML, PSICQUIC) Common accession number space Coordinated & non-redundant curation In production mode since February 2010 Since 3/2009 supported by the European Commission under PSIMEx, contract number FP7-HEALTH-2007-223411, with additional partners Vital-IT, Nature, Wiley, BiaCore (GE), U. Maryland, CSIC, TU Munich, MIPS, SCBIT (Shanghai) Imex.sf.net

61. IMEx website Imex.sf.net

62. Getting access to more data is easy !!

63. Data distribution: PSICQUIC Proteomics Standards Initiative Common QUery InterfaCe. Community effort to standardise the way to access and retrieve data from Molecular Interaction databases. Widely implemented by independent interaction data resources. Based on the PSI standard formats (PSI-MI XML and MITAB) Not limited to protein-protein interactions, also e.g. Drug-target interactions Simplified pathway data A registry listing resources implementing PSICQUIC Documentation: http://psicquic.googlecode.com

64. PSICQUIC implementation ….…. …..... ….…. …..... PSICQUIC Sample Observation error Interaction databases Publications PSICQUIC sources Annotation error User PSICQUIC Registry PSICQUIC client

65. 19.05.201565 Service broker Service consumer Service provider Service Contract... Interact Publish Find Service Oriented Architecture PSI-MI... PSICQUIC Registry DAS Clients PSICQUIC Clients Format PSICQUIC sources PSICQUIC sources PSICQUIC sources PSICQUIC implementation PSICQUIC Server (SOAP/REST web service) PSICQUIC Registry PSICQUIC Clients PSICQUIC view Cytoscape Envision2 …

66. PSICQUIC Registry http://www.ebi.ac.uk/Tools/webservices/psicquic/registry/registry?action=STATUS 1.693.000 binary interactions !

67. What can I do with PSICQUIC User can query the registry to get a list of available services Registry supports tagging Users can script against these services using pretty much any programming language (SOAP / REST) Easy to parse MITAB to extract data of interest Data can be loaded in cytoscape to visualize a network

68. PSICQUIC limitations Currently users can only download MITAB format We are planning to enable PSI-MI XML download too so users can get the original complex We are currently working on adding additional data formats: BioPax (only in IntAct’s PSICQUIC so far) SBML

69. S ystems B iology M arkup L anguage

70. Overview of SBML  A machine-readable format for representing computational models in systems biology  Tool-neutral exchange language for software applications

71.  Declares model not procedure  Independent of modelling formalism Overview of SBML

72.  Expressed in XML  Not really meant for humans to read

73. SBML structure and syntax

74. <sbml xmlns="http://www.sbml.org/sbml/level3/version1/core" level="3" version="1"> SBML structure and syntax

75. <sbml xmlns="http://www.sbml.org/sbml/level3/version1/core" level="3" version="1">...... SBML structure and syntax

76. <sbml xmlns="http://www.sbml.org/sbml/level3/version1/core" level="3" version="1">...... SBML structure and syntax

77. <sbml xmlns="http://www.sbml.org/sbml/level3/version1/core" level="3" version="1">... <species …... SBML structure and syntax

78. Compartment SBML structure and syntax a container of finite size for well-stirred substances <compartment id="cell" spatialDimensions="3" size="2.3" units="litre" constant="true"/>

79. Species SBML structure and syntax a pool of a chemical substance <species id="s" compartment="cell" initialAmount="4.6" substanceUnits="mole" hasOnlySubstanceUnits="false" boundaryCondition="false" constant="false"/>

80. Parameter SBML structure and syntax a quantity of whatever type is appropriate <parameter id="p1" value="3000" constant="false"/> <parameter id="p2" value="8000" constant="true"/>

81. Reaction SBML structure and syntax a statement describing some transformation, transport or binding process that can change one or more species Reactants R Products P Modifiers M ‘Kinetic law’: v = f(R, P, M, parameters)

82. SBML structure and syntax S0S1 S2 rate law: k * S0 * S2

83. SBML structure and syntax

84. SBML structure and syntax

85. comp1 k S0 S2 ‘id’ of other elements SBML structure and syntax

86. comp1 k S0 S2 SBML structure and syntax

87. S0S1 S2 rate law: k * S0 * S2 dS0/dt = - k * S0 * S2 * comp dS1/dt = + k * S0 * S2 * comp

88. Rule SBML structure and syntax a mathematical expression that is added to the model equations assignmentRule rateRule algebraicRule x = f(y) dx/dt = f(y) f(x,y) = 0

89. … 1 SBML structure and syntax At specific pointt > 30 flag = 1

90. Model Compartment Reaction Species Rule Unit Parameter Level 1 Version 1 Level 1 Version 2 Function Event Level 2 Version 1 Initial Assignment Constraint Compartment Type Species Type Level 2 Version 2 Level 2 Version 3 Level 2 Version 4 SBML structure and syntax

91. SBML Level 3 additional information spatial qual Submodel 1Submodel 2 comp layoutcore mathematically necessary for correct interpretation possibly necessary

92. SBML Resources 181 applications (that we know about)

93. SBML Resources

94. Online validator

95. SBML Resources

96. Online Test Suite

97. SBML Resources

101. MathSBML Mathematica SBMLToolbox MATLAB Octave

102. SBML Resources

103. converters BioPAX

104. SBML Resources

111. Conclusions No idea how to integrate discrete models No optimal solution how to fit data to the model for discrete modelling We are at the beginning of in silico systems biology New modelling, data analysis, integration approaches and tools are needed