1. Overview of Genome Databases Peter D. Karp, Ph.D. SRI International pkarp@ai.sri.com www-db.stanford.edu/dbseminar/seminar.html

2. Talk Overview Definition of bioinformatics Motivations for genome databases Issues in building genome databases

3. Definition of Bioinformatics Computational techniques for management and analysis of biological data and knowledge l Methods for disseminating, archiving, interpreting, and mining scientific information Computational theories of biology Genome Databases is a subfield of bioinformatics

4. Motivations for Bioinformatics Growth in molecular-biology knowledge (literature) Genomics 1. Study of genomes through DNA sequencing 2. Industrial Biology

5. Example Genomics Datatypes Genome sequences l DOE Joint Genome Institute u 511M bases in Dec 2001 u 11.97G bases since Mar 1999 Gene and protein expression data Protein-protein interaction data Protein 3-D structures

6. Genome Databases Experimental data l Archive experimental datasets l Retrieving past experimental results should be faster than repeating the experiment l Capture alternative analyses l Lots of data, simpler semantics Computational symbolic theories l Complex theories become too large to be grasped by a single mind l The database is the theory l Biology is very much concerned with qualitative relationships l Less data, more complex semantics

7. Bioinformatics Distinct intellectual field at the intersection of CS and molecular biology Distinct field because researchers in the field must know CS, biology, and bioinformatics Spectrum from CS research to biology service Rich source of challenging CS problems Large, noisy, complex data-sets and knowledge-sets Biologists and funding agencies demand working solutions

8. Bioinformatics Research algorithms + data structures = programs algorithms + databases = discoveries Combine sophisticated algorithms with the right content: l Properly structured l Carefully curated l Relevant data fields l Proper amount of data

9. Reference on Major Genome Databases Nucleic Acids Research Database Issue http://nar.oupjournals.org/content/vol30/issue1/ l 112 databases

10. Questions to Ask of a New Genome Database

11. What are Database Goals and Requirements? What problems will database be used to solve? Who are the users and what is their expertise?

12. What is its Organizing Principle? Different DBs partition the space of genome information in different dimensions Experimental methods (Genbank, PDB) Organism (EcoCyc, Flybase)

13. What is its Level of Interpretation? Laboratory data Primary literature (Genbank) Review (SwissProt, MetaCyc) Does DB model disagreement?

14. What are its Semantics and Content? What entities and relationships does it model? How does its content overlap with similar DBs? How many entities of each type are present? Sparseness of attributes and statistics on attribute values

15. What are Sources of its Data? Potential information sources l Laboratory instruments l Scientific literature u Manual entry u Natural-language text mining l Direct submission from the scientific community u Genbank Modification policy l DB staff only l Submission of new entries by scientific community l Update access by scientific community

16. What DBMS is Employed? None Relational Object oriented Frame knowledge representation system

17. Distribution / User Access Multiple distribution forms enhance access Browsing access with visualization tools API Portability

18. What Validation Approaches are Employed? None Declarative consistency constraints Programmatic consistency checking Internal vs external consistency checking What types of systematic errors might DB contain?

19. Database Documentation Schema and its semantics Format API Data acquisition techniques Validation techniques Size of different classes Coverage of subject matter Sparseness of attributes Error rates Update frequency

20. Relationship of Database Field to Bioinformatics Scientists generally unaware of basic DB principles l Complex queries vs click-at-a-time access l Data model l Defined semantics for DB fields l Controlled vocabularies l Regular syntax for flatfiles l Automated consistency checking Most biologists take one programming class Evolution of typical genome database Finer points of DB research off their radar screen Handfull of DB researchers work in bioinformatics

21. Database Field For many years, the majority of bioinformatics DBs did not employ a DBMS l Flatfiles were the rule l Scientists want to see the data directly l Commercial DBMSs too expensive, too complex l DBAs too expensive Most scientists do not understand l Differences between BA, MS, PhD in CS l CS research vs applications l Implications for project planning, funding, bioinformatics research

22. Recommendation Teaching scientists programming is not enough Teaching scientists how to build a DBMS is irrelevant Teach scientists basic aspects of databases and symbolic computing l Database requirements analysis l Data models, schema design l Knowledge representation, ontologies l Formal grammars l Complex queries l Database interoperability

23. BioSPICE Bioinformatics Database Warehouse Peter Karp, Dave Stringer-Calvert, Tom Lee, Kemal Sonmez SRI International http://www.BioSPICE.org/

24. Project Goal Create a toolkit for constructing bioinformatics database warehouses that collect together a set of bioinformatics databases into one physical DBMS

25. Motivations Important bioinformatics problems require access to multiple bioinformatics databases Hundreds of bioinformatics databases exist l Nucleic Acids Research 30(1) 2002 – DB issue l Nucleic Acids Research DB list: 350 DBs at http://www3.oup.co.uk/nar/database/a/ Different problems require different sets of databases

26. Motivations Combining multiple databases allows for data verification and complementation Simulation problems require access to data on pathways, enzymes, reactions, genetic regulation

27. Why is the Multidatabase Approach Not Sufficient? Multidatabase query approaches assume databases are in a DBMS Internet bandwidth limits query throughput Most sites that do operate DBMSs do not allow remote SQL access because of security and loading concerns Control data stability Need to capture, integrate and publish locally produced data of different types Multidatabase and Warehouse approaches complementary

28. Scenario 1 BioSPICE scientist wants to model multiple metabolic pathways in a given organism l Enumerate pathways and reactions l What enzymes catalyze each reaction? l What genes code for each enzyme? l What control regions regulate each gene?

29. Approach Oracle and MySQL implementations Warehouse schema defines many bioinformatics datatypes Create loaders for public bioinformatics DBs l Parse file format for the DB l Semantic transformations l Insert database into warehouse tables Warehouse query access mechanisms l SQL queries via Perl, ODBC, OAA

30. Example: Swiss-Prot DB Version 40.0 describes 101K proteins in a 320MB file Each protein described as one block of records (an entry) in a large text file Loader tool parses file one entry at a time Creates new entries in a set of warehouse tables

31. Warehouse Schema Manages many bioinformatics datatypes simultaneously l Pathways, Reactions, Chemicals l Proteins, Genes, Replicons l Citations, Organisms l Links to external databases Each type of warehouse object implemented through one or more relational tables (currently 43)

32. Warehouse Schema Databases on our wish list: l Genbank (nucleotide sequences) l Protein expression database l Protein-protein interactions database l Gene expression database l NCBI Taxonomy database l Gene Ontology l CMR

33. Warehouse Schema Manages multiple datasets simultaneously l Dataset = Single version of a database Support alternative measurements and viewpoints Version comparison Multiple software tools or experiments that require access to different versions Each dataset is a warehouse entity Every warehouse object is registered in a dataset

34. Warehouse Schema Different databases storing the same biological types are coerced into same warehouse tables Design of most datatypes inspired by multiple databases Representational tricks to decrease schema bloat l Single space of primary keys l Single set of satellite tables such as for synonyms, citations, comments, etc.

35. Warehouse Schema Examples l Protein data from Swiss-Prot, TrEMBL, KEGG, and EcoCyc all loaded into same relational tables l Pathway data from MetaCyc and KEGG are loaded into the same relational tables

36. Example: Swiss-Prot DB ID 1A11_CUCMA STANDARD; PRT; 493 AA. AC P23599; DT 01-NOV-1991 (Rel. 20, Created) DT 01-NOV-1991 (Rel. 20, Last sequence update) DT 15-DEC-1998 (Rel. 37, Last annotation update) DE 1-AMINOCYCLOPROPANE-1-CARBOXYLATE SYNTHASE CMW33 (EC 4.4.1.14) (ACC DE SYNTHASE) (S-ADENOSYL-L-METHIONINE METHYLTHIOADENOSINE-LYASE). GN ACS1 OR ACCW.

37. How Swiss-Prot is Loaded into The Warehouse Register Swiss-Prot in Datasets table Create entry in Entry and Protein tables for each Swiss-Prot protein Satellite tables store l Protein synonyms, citations, comments, accession numbers, organism, sequence features, subunits/complexes, DB links

38. Protein Table CREATE TABLE Protein ( WID NUMBER --The warehouse ID of this protein Name VARCHAR2(500) --Common name of the protein AASequence VARCHAR2(4000),--Amino-acid sequence for this protein Charge NUMBER, --Charge of the chemical Fragment CHAR(1), --Is this protein a fragment or not, T or F MolecularWeightCalc NUMBER, --Molecular weight calculated from sequence. Units: Daltons. MolecularWeightExp NUMBER, --Molecular Weight determined through experimentation. Units: Daltons. PICalc VARCHAR2(50), --pI calculated from its sqeuence. PIExp VARCHAR2(50), --pI value determined through experimentation. DataSetWID NUMBER --Reference to the data set from which the entity came from );

39. Database Loaders Loader tool defined for each DB to be loaded into Warehouse Example loaders available in several languages Loaders l KEGG (C) l BioCyc collection of 15 pathway DBs (C) l Swiss-Prot (Java) l ENZYME (Java)

40. Terminology Model Organism Database (MOD) – DB describing genome and other information about an organism Pathway/Genome Database (PGDB) – MOD that combines information about l Pathways, reactions, substrates l Enzymes, transporters l Genes, replicons l Transcription factors, promoters, operons, DNA binding sites BioCyc – Collection of 15 PGDBs at BioCyc.org l EcoCyc, AgroCyc, YeastCyc

41. Loader Architecture Grammar for Swiss-Prot Parser for SwissProt ANTLR Parser Generator Swiss-Prot Datafile SQL Insert Commands Oracle Loadable File

42. Current Warehouse Contents KEGGENZYMESwissProtBsubCycWarehouse Total Chemicals 7,2842,952057610,812 Genes 5,714088,6054,22198,540 Organisms 600103,8071103,868 Proteins 3,8293,870101,6024,150113,451 Enzymatic Reactions 3,509007174,226 Pathways 4,517001384,655 Pathway Reactions 36,2710053036,801

43. Example Warehouse Uses Check completeness of data sources Count reactions in ENZYME database with (and without) associated protein sequences in SWISS-PROT database: 3870 reactions in ENZYME 1662 reactions (43%) with a sequence in SWISS-PROT 2208 reactions (57%) without a sequence in SWISS-PROT Count #of distinct non-partial EC numbers in SWISS-PROT: 1554 distinct EC numbers in SWISS-PROT (non-partial)