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Overview of the Pathway Tools Software and Pathway/Genome Databases

Overview of the Pathway Tools Software and Pathway/Genome Databases. Introductions. BRG Staff Peter Karp Tomer Altman Joe Dale Fred Gilham John Myers Suzanne Paley Markus Krummenacker Ingrid Keseler Ron Caspi Alex Shearer Carol Fulcher Attendees Where from, what genome?

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Overview of the Pathway Tools Software and Pathway/Genome Databases

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  1. Overview of the Pathway Tools Software and Pathway/Genome Databases

  2. Introductions • BRG Staff • Peter Karp • Tomer Altman • Joe Dale • Fred Gilham • John Myers • Suzanne Paley • Markus Krummenacker • Ingrid Keseler • Ron Caspi • Alex Shearer • Carol Fulcher • Attendees • Where from, what genome? • What do you hope to get out of the tutorial?

  3. SRI International • Private nonprofit research institute • No permanent funding sources • 1300 staff in Menlo Park • Founded in 1946 as Stanford Research Institute • Separated from Stanford University in 1970 • Name changed to SRI International in 1977

  4. SRI Organization Information and Computing Sciences Bioinformatics Research Group Biopharmaceuticals And Pharmaceutical Discovery Engineering Systems And Sciences Physical Sciences Education and Policy

  5. Research in the SRIBioinformatics Research Group • BioCyc Database Collection • EcoCyc • MetaCyc • Pathway Tools • BioWarehouse

  6. Outline for Tutorial • Monday • Introduction • Pathway/Genome Navigator • Introduction to Pathway/Genome Editors • Tuesday • PathoLogic tutorial • PathoLogic lab session – Build initial version of PGDB • Pathway hole filler lecture+lab • Wednesday • PathoLogic: Creating protein complexes, operon predictor, transport inference parser • Pathway Tools Schema • Model organism database projects • Thursday • Advanced Pathway/Genome Editors • Friday • Overviews and Omics Viewers • Comparative analysis • Structured Advanced Query Form • Metabolite Tracing • Regulation

  7. Tutorial Goals • General familiarity with Pathway Tools goals and functionality • Ability to create, edit, and navigate a new PGDB • Create new PGDB for genome(s) you brought with you • Familiarity with information resources available about Pathway Tools to continue your work

  8. SRI’s Support for Pathway Tools • NIH grant finances software development and user support • Additional grants finance other software development • Email us bug reports, suggestions, questions • Comprehensive bug reports are required for us to fix the problem you reported • Keep us posted regarding your progress

  9. Administrative Details • Please wear badge at all times • Escort required outside this room/hallway • Let us know when you are leaving • Use E-Bldg Entrance • Phone numbers to call from entrance • Meals • Restrooms

  10. Tutorial Format • Questions welcome during presentations • Lab sessions will take different amounts of time for different people • Refine your PGDB • Read Pathway Tools manuals • Computer logins • Internet connectivity

  11. Pathway/Genome Database Pathways Reactions Compounds Sequence Features Proteins RNAs Operons Promoters DNA Binding Sites Regulatory Interactions Genes Chromosomes Plasmids CELL

  12. BioCyc Collection of Pathway/Genome Databases • Pathway/Genome Database (PGDB) – combines information about • Pathways, reactions, substrates • Enzymes, transporters • Genes, replicons • Transcription factors/sites, promoters, operons • Tier 1: Literature-Derived PGDBs • MetaCyc • EcoCyc -- Escherichia coli K-12 • Tier 2: Computationally-derived DBs, Some Curation -- 20 PGDBs • HumanCyc • Mycobacterium tuberculosis • Tier 3: Computationally-derived DBs, No Curation -- 349 DBs

  13. Terminology –Pathway Tools Software • PathoLogic • Predicts operons, metabolic network, pathway hole fillers, from genome • Computational creation of new Pathway/Genome Databases • Pathway/Genome Editors • Distributed curation of PGDBs • Distributed object database system, interactive editing tools • Pathway/Genome Navigator • WWW publishing of PGDBs • Querying, visualization of pathways, chromosomes, operons • Analysis operations • Pathway visualization of gene-expression data • Global comparisons of metabolic networks Bioinformatics 18:S225 2002

  14. 1000+ licensees: 75+ groups applying software to 150+ organisms Saccharomyces cerevisiae, SGD project, Stanford University pathway.yeastgenome.org/biocyc/ Mouse, MGD, Jackson Laboratory dictyBase, Northwestern University Under development: CGD (Candida albicans), Stanford University Drosophila, P. Ebert in collaboration with FlyBase C. elegans, P. Ebert in collaboration with WormBase Planned: RGD (Rat), Medical College of Wisconsin Arabidopsis thaliana, TAIR, Carnegie Institution of Washington Tomato and Potato, Cornell University GrameneDB, Cold Spring Harbor Laboratory Medicago truncatula, Samuel Roberts Noble Foundation Pathway Tools Software: PGDBs Created Outside SRI

  15. NIAID BRCs: BioHealthBase (M. tuberculosis, F. tuleremia), PATRIC, ApiDB (Cryptosporidium) F. Brinkman, Simon Fraser Univ, Pseudomonas aeruginosa V. Schachter, Genoscope, Acinetobacter M. Bibb, John Innes Centre, Streptomyces coelicolor G. Church, Harvard, Prochlorococcus marinus, multiple strains E. Uberbacher, ORNL and G. Serres, MBL, Shewanella onedensis R.J.S. Baerends, University of Groningen, Lactococcus lactis IL1403, Lactococcus lactis MG1363, Streptococcus pneumoniae TIGR4, Bacillus subtilis 168, Bacillus cereus ATCC14579 Matthew Berriman, Sanger Centre, Trypanosoma brucei, Leishmania major Herbert Chiang, Washington University, Bacteroides thetaiotaomicron Sergio Encarnacion, UNAM, Sinorhizobium meliloti Gregory Fournier, MIT, Mesoplasma florum Mark van der Giezen, University of London, Entamoeba histolytica, Giardia intestinalis Michael Gottfert, Technische Universitat Dresden, Bradyrhizobium japonicum Artiva Maria Goudel, Universidade Federal de Santa Catarina, Brazil, Chromobacterium violaceum ATCC 12472 Kenneth J. Kauffman, University of California, Riverside, Desulfovibrio vulgaris Pathway Tools Software: PGDBs Created Outside SRI

  16. Pathway Tools Software: PGDBs Created Outside SRI • Mike McLeod, University of British Columbia, Rhodococcus sp. RHA1 • Robert S. Munson, Children's Research Institute, Ohio, Haemophilus ducreyi, Haemophilus influenzae 86-026NP • John Nash, Canadian NRC, Campylobacter jejuni • Christopher S. Reigstad, Washington University, Escherichia coli UTI89 • Haluk Resat, Pacific Northwest Lab, Rhodobacter sphearoides • Gary Xie, Los Alamos Lab, Bacillus cereus • Large scale users: • C. Medigue, Genoscope, 107 PGDBs • G. Burger, U Montreal, 48 PGDBs • Bart Weimer, Utah State University, Lactococcus lactis, Brevibacterium linens, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus johnsonii, Listeria monocytogenes • Partial listing of outside PGDBs at BioCyc.org

  17. Terminology • “Database” = “DB” = “Knowledge Base” = “KB” = “Pathway/Genome Database” = “PGDB”

  18. Why Create PGDBs? • Extract more information from your genome • Create an up-to-date computable information repository about an organism • Perform analyses on the genome and pathway complement of the organism • Analyses of omics data • Analyses of cellular systems (dead-end metabolites) • Reports generated by Pathway Tools • Perform comparative analyses with other organisms • Generate a genome poster and metabolic wall chart

  19. Sequence Project Workflow Raw Sequence PathoLogic Phred P/G Editors Pathway Tools Phrap P/G Navigator GeneMark/Glimmer WWW Publishing Analyses BLAST, BLOCKS

  20. EcoCyc Project – EcoCyc.org • E.coli Encyclopedia • Review-level Model-Organism Database for E. coli • Tracks evolving annotation of the E. coli genome and cellular networks • The two paradigms of EcoCyc • “Multi-dimensional annotation of the E. coli K-12 genome” • Positions of genes; functions of gene products – 76% / 66% exp • Gene Ontology terms; MultiFun terms • Gene product summaries and literature citations • Evidence codes • Multimeric complexes • Metabolic pathways • Regulation of transcription initiation Karp, Gunsalus, Collado-Vides, Paulsen Nuc. Acids Res. 35:7577 2007ASM News 70:25 2004 Science 293:2040

  21. Paradigm 1:EcoCyc as Textual Review Article • All gene products for which experimental literature exists are curated with a minireview summary • Found on protein and RNA pages, not gene pages! • 3257 gene products contain summaries • Summaries cover function, interactions, mutant phenotypes, crystal structures, regulation, and more • Additional summaries found in pages for operons, pathways • EcoCyc cites 15,880 publications

  22. Paradigm 2: EcoCyc as Computational Symbolic Theory • Highly structured, high-fidelity knowledge representation provides computable information • Each molecular species defined as a DB object • Genes, proteins, small molecules • Each molecular interaction defined as a DB object • Metabolic reactions • Transport reactions • Transcriptional regulation of gene expression • 220 database fields capture extensive properties and relationships

  23. EcoCyc Procedures • DB updates performed by 5 staff curators • Information gathered from biomedical literature • Enter data into structured database fields • Author extensive summaries • Update evidence codes • Corrections submitted by E. coli researchers • Four releases per year • Quality assurance of data and software • Evaluate database consistency constraints • Perform element balancing of reactions • Run other checking programs

  24. MetaCyc: Metabolic Encyclopedia • Describe a representative sample of every experimentally determined metabolic pathway • Describe properties of metabolic enzymes • Literature-based DB with extensive references and commentary • Pathways, reactions, enzymes, substrates • Jointly developed by • P. Karp, R. Caspi, C. Fulcher, SRI International • L. Mueller, A. Pujar, Cornell Univ • S. Rhee, P. Zhang, Carnegie Institution Nucleic Acids Research2008

  25. MetaCyc Data -- Version 11.6

  26. Taxonomic Distribution ofMetaCyc Pathways

  27. Family of Pathway/GenomeDatabases EcoCyc CauloCyc AraCyc MtbRvCyc HumanCyc MetaCyc

  28. Comparison of BioCyc to KEGG:The Data • KEGG approach: Static collection of pathway diagrams that are color-coded to produce organism-specific views • KEGG vs MetaCyc: Resource on literature-derived pathways • KEGG pathway maps are composites of pathways in many organisms -- do not identify what specific pathways elucidated in what organisms • KEGG pathway maps encompass multiple biological pathways; are 2-4 times the size of MetaCyc pathways • KEGG has no literature citations, no summaries, less enzyme detail • KEGG vs BioCyc organism-specific PGDBs • KEGG re-annotates entire genome for each organism • KEGG does not curate or customize pathway networks for each organism

  29. Comparison of Pathway Tools to KEGG: The Software • KEGG has no pathway hole filler or transport inference parser or operon predictor • KEGG has no interactive editing tools – you cannot refine a KEGG pathway DB • KEGG has no algorithmic visualization tools – pathway diagrams are pre-drawn • May become out of date • Cannot show pathways at multiple detail levels • KEGG genome browser has very limited functionality • KEGG has one overview diagram with limited functionality • KEGG has no metabolite tracing tool • KEGG has no Structured Advanced Query Tool

  30. Overviews and Omics Viewers • Genome-scale Visualizations • Metabolic map • Transcriptional regulatory network • Genome map • Overlay gene expression, proteomics, metabolomics data • Obtain pathway based visualizations of omics data • Numerical spectrum of expression values mapped to a color spectrum • Steps of overview painted with color corresponding to expression level(s) of genes that encode enzyme(s) for that step

  31. Environment for Computational Exploration of Genomes • Powerful ontology opens many facets of the biology to computational exploration • Global characterization of metabolic network • Analysis of interface between transport and metabolism • Nutrient analysis of metabolic network

  32. Pathway Tools Implementation Details • Allegro Common Lisp • Sun, Linux, Windows, Macintosh platforms • Ocelot object database • 370,000+ lines of code • Lisp-based WWW server at BioCyc.org • Manages 370+ PGDBs

  33. The Common Lisp ProgrammingEnvironment • Gatt studied Lisp and Java implementation of 16 programs by 14 programmers (Intelligence 11:21 2000)

  34. Survey • Please complete survey at end of each day

  35. PGDB(s) That You Build • Before you leave • Tar up your PGDB directory and FTP it home, email it home, or copy it to flash disk • We will create a backup copy of your PGDB directory if the directory is still there at the end of the tutorial • Delete the PGDB directory if you don’t want us to back it up • We will not give the backed up data to anyone else

  36. Information Sources • Pathway Tools User’s Guide • /root/aic-export/pathway-tools/ptools/11.5/doc/manuals/userguide.pdf • NOTE: Location of the aic-export directory can vary across different computers • Pathway Tools Web Site • Publications, FAQ, programming examples, etc. • http://bioinformatics.ai.sri.com/ptools/ • BioCyc Publications Page • http://biocyc.org/publications.shtml • MetaCyc Guide • http://metacyc.org/MetaCycUserGuide.shtml • Slides from this tutorial • http://bioinformatics.ai.sri.com/ptools/tutorial/ • BioCyc Webinars • http://biocyc.org/webinar.shtml

  37. Reporting Pathway Tools Problems • ptools-support@ai.sri.com • Tell us: • What platform you are running on • What version of Pathway Tools you are running • The error message • Result of [1] EC(2) :zoom :count :all • What operation were you performing when the error occurred? • New patches automatically downloaded and loaded with PTools starts up • Auto-Patch • Tools -> Instant Patch -> Download and Activate All Patches

  38. Summary • Pathway Tools and Pathway/Genome Databases • Not just for pathways! • Computational inferences • Operons, metabolic pathways, pathway hole fillers • Editing tools • Analysis tools: Omics data on pathways • Web publishing of PGDBs • Main classes of users: • Develop PGDB to extract more information from genome for genome paper • Develop a model-organism DB for the organism that is updated regularly and published on the web

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