CAP BIOINFORMATICS Su-Shing Chen CISE. 8/19/2005 Su-Shing Chen, CISE 1

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1 CAP BIOINFORMATICS Su-Shing Chen CISE 8/19/2005 Su-Shing Chen, CISE 1

2 Building Local Genomic Databases Genomic research integrates sequence data with gene function knowledge. Gene ontology to represent the knowledge in local genomic databases. Multiple organisms and gene products (e.g., proteins) with their functions.ncbi Entrez database with functions collected from other databases: Local SEED database, SWISS PROT, KEGG 8/19/2005 Su-Shing Chen, CISE 2

3 Midterm Project Page.jsp ry.fcgi /19/2005 Su-Shing Chen, CISE 3

4 4 ComparativeX Relational Tables Gene Id, Gene Name, Protein Id, Protein Name, Pathway Id, Pathway Name (multiples) Gene Id, Gene Name, Gene Function, Comments (multiples). Gene Id, Protein Id, Protein Function, Comments (multiples). Gene Id, Pathway Id, Pathway Function, Comments (multiples). Gene Id, GO Entries (multiples) 8/19/2005 Su-Shing Chen, CISE 4

5 Key Gene Ontology Features Where is a gene expressed? Spatial problem: organism s anatomy. What is the subcellular localization of a gene product? Subcellular anatomy. When is a gene expressed? Temporal problem:organism s ontogeny. What is the function of a gene product? Functional classification of gene products. 8/19/2005 Su-Shing Chen, CISE 5

6 Key Gene Ontology Features ussion.html Of what larger process is the gene product function a part? Process hierarchy. By what process is a gene s activities controlled? Regulatory hierarchy. Of what larger complex is this function a component? Parts-list of multicomponent complexes. What genes in species A have the function of gene X in species B? Functional classification of species A and B. 8/19/2005 Su-Shing Chen, CISE 6

7 Gene Ontology Consortium GO Consortium: SGD (Saccharomyces), FlyBase (Drosophila), MGD/GXD (Mouse), TAIR (Arabidopsis), Caenorhabditis elegans. Goals: 1. To compile a comprehensive structured vocabulary of terms, synonyms, biological dimensions (DNA metabolism, molecular function, cell). 2. To describe biological objects using these terms. 3. To provide tools for querying and manipulating vocabularies. 4. To provide tools to assign GO terms to biological objects (sequence, annotation, microarray, protein binding experiments). 8/19/2005 Su-Shing Chen, CISE 7

8 Three GO Ontologies Molecular function what a gene product does at the biochemical level (e.g., enzyme, transporter, ligand). Biological process a biological objective to which the gene product contributes (cell gowth and photosynthesis) Cellular component the place in the cell where a gene product is found (e.g., ribosome, nuclear membrane, Golgi apparatus). 8/19/2005 Su-Shing Chen, CISE 8

9 A GO Relational Schema Gene Ontology Database Schema Dependencies Diagram Dependency Diagram courtesy of Frank Schacherer - thanks! 8/19/2005 Su-Shing Chen, CISE 9

10 Ontology Structure & Standards The ontologies are structured vocabularies in the form of directed acyclic graphs (DAG s) that represent a network of childs and parents (is-a or part-of). See 8/19/2005 Su-Shing Chen, CISE 10

11 Database Management Systems A DBMS is a software for keeping computerized records about an enterprise and for querying information in the records. DBMS models: hierarchical, network, relational, and object-oriented. SQL (Structured Query Language) is a database language. Logical database design: Entity-relation and object-orientation. Physical database design: Indexing, storage, organization. 8/19/2005 Su-Shing Chen, CISE 11

12 A database is a set of named tables (relations) Columns (Attributes) Rows (Tuples) A relational schema = the set of attributes of a table 8/19/2005 Su-Shing Chen, CISE 12

13 DBMS Rules First normal form rule: Columns are not allowed to take multivalued attributes. Access rows by content only rule (there is no order on rows). The unique row rule: Two tuples in a relation can not be identical. The key rule: A key (a set of attributes) distinguishes two tuples. 8/19/2005 Su-Shing Chen, CISE 13

14 SQL SELECT FROM tables WHERE attributes = XXX. SELECT [all distinct] expr {, expr} FROM tablename [corr_name] {, tablename [corr_name]} WHERE [search_condition]. 8/19/2005 Su-Shing Chen, CISE 14

15 Entity-Relationship for Gene Product Metabolic Pathway Reaction Enzyme-Reaction Gene-Product Term Locus Species Genome Map Linkage-Group 8/19/2005 Su-Shing Chen, CISE 15

16 8/19/2005 Su-Shing Chen, CISE 16

17 Generalization Hierarchies Several types of entities with common attributes can be generalized into a higher-level entity type. Conversely an entity can be decomposed into lower-level entities. 8/19/2005 Su-Shing Chen, CISE 17

18 SUPERCLASS Eukaryote Categorization Classification CLASS Plant Animal Fungi SUBCLASS Hominidae Canidae SUB-SUB- CLASS Man Woman Dog Wolf Coyote 8/19/2005 Su-Shing Chen, CISE 18

19 Object Orientation Physical Object Represented by Procedures Information Content Digital Object Database Stored in Class of Objects 8/19/2005 Su-Shing Chen, CISE 19

20 Object Model - Biological Objects Genomic Objects Enzyme Objects Sequence Objects Structure Objects Experiment Objects Variation Objects Mapping Objects Citation - Literature + References Registry - People + Organizations External Links - Databases 8/19/2005 Su-Shing Chen, CISE 20

21 Dynamic Model Biochemical Processes Metabolic Pathways Signal Transduction Pathways Neural Networks 8/19/2005 Su-Shing Chen, CISE 21

22 DATA TYPES: An instance or object of the class contains values for the class attributes stored in the database Text (clone name) Number (insert size) Restricted Value (DNA type) List (people) Table (complex related attributes) Association (gene to gene-product: protein) Sequence Pointer (other databases) 8/19/2005 Su-Shing Chen, CISE 22

23 Locus Information A locus is often a gene, characterized by a mutant phenotype or by a DNA sequence, which has been either genetically mapped or localized (DNA sequence comparison or hybridization) to a particular spot in a genome. 8/19/2005 Su-Shing Chen, CISE 23

24 ORF (Open Reading Frame) An ORF corresponds to a stretch of DNA that can be translated into a polypeptide. It begins with an ATG start codon and terminates with one of the 3 stop codons. An ORF is a stretch of DNA that codes a protein of 1000 amino acids or more. An ORF is not considered equivalent to a gene or locus until it has a phenotype associated with a mutation in the ORF and/or an mrna transcript or a gene product generated. 8/19/2005 Su-Shing Chen, CISE 24

25 Object-oriented concepts Object and object identity Encapsulation Message passing Complex object Object class/type Inheritance Polymorphism and run-time binding Persistance 8/19/2005 Su-Shing Chen, CISE 25

26 Any thing (physical object, abstract concept, event, function, process) can be modeled as object. Public Interface OBJECT Private memory Data + Operation Operation Spec Data: instance variables, attributes, slots. Operations: methods, actions, behaviors. 8/19/2005 Su-Shing Chen, CISE 26

27 OBJECT CLASS Object type declaration CLASS protein DATA sequence structure OPERATION function Container of object instances Protein Class Protein instances 8/19/2005 Su-Shing Chen, CISE 27

28 ENCAPSULATION A Protein Object Intercellular action Information hiding Sequence search Data protein# protein_name Structure display Intracellular action 8/19/2005 Su-Shing Chen, CISE 28

29 Synthesis enzymes & peptide hormones Receptor proteins Substrate proteins DNA Protein kinases & phosphatases Proximal network mrnas Intracellular signals Intercellular signals Roger Smorgyi 8/19/2005 Su-Shing Chen, CISE 29

30 MESSAGE PASSING Return message A Source object (sender) Message= (objectb, methodx, parameter, return value) B Target object (receiver) 8/19/2005 Su-Shing Chen, CISE 30

31 COMPLEX OBJECT CLASS - Gene Product Class RNA Gene product protein gene Trypsin PRSS1 8/19/2005 Su-Shing Chen, CISE 31

32 COMPLEX OBJECT CLASS - (Biological) Polymorphism Class (Biological) Polymorphism Class Polymorphism Object Detection method Fragments in kb s Sizes detected in a polymorphism Allele Set Alleles Allele frequency Population 8/19/2005 Su-Shing Chen, CISE 32

33 Genetic & Physical Map Object Class Maps represent information contained in a chromosome. Maps are high-level summaries of the contents of a chromosome. Maps are used in large scale sequencing efforts. 8/19/2005 Su-Shing Chen, CISE 33

34 Map Object Type Assignment Tier Coordinate System Mapped Entity Position + Coordinates 8/19/2005 Su-Shing Chen, CISE 34

35 Type: Genetic map Physical map Contig map Transcript map Radiation hybrid map Cytogenetic map Mapped Entity: Amplimer Sequencing region Bin Syndromic region Breakpoint Syntenic region Chromosome Cell line Chromosome reagent Library Clone Contig CpG Island Cytogenetic marker EST Gene Gene element Regulatory region Repeat 8/19/2005 Su-Shing Chen, CISE 35

36 SUPERCLASS Eukaryote operations: exons, introns INHERITANCES exons introns chromosomey CLASS Plant operations: leaves Animal Fungi exons introns leaves SUBCLASS Hominidae Canidae SUB-SUB- CLASS Man Woman Dog Wolf Coyote operations: chromosomey 8/19/2005 Su-Shing Chen, CISE 36

37 Advantages of Inheritance Reuse of object type declaration. Reuse of software implementations. Modularization of complex problems. 8/19/2005 Su-Shing Chen, CISE 37

38 Object Oriented SQL SELECT genes FROM Genbank WHERE genes -> breast cancer SELECT results in objects. Support methods or operations in WHERE commands. Support link navigation across inter-object-relationships. 8/19/2005 Su-Shing Chen, CISE 38

39 Differences between OO-DBMS and Traditional DBMS Complex data structure System assigned object identity Integration of object structure and behavior Inheritance Simple data structure (tables) User defined identity (key) Separation of object structure and behavior No support of inheritance 8/19/2005 Su-Shing Chen, CISE 39

40 POLYMORPHISM - MUTATION Relation: aplimers from clones overlap genes nucleotide sequence gene aggregation Relation: aplimers are contained in genes clone Relation: aplimers are contained in clones amplimer (PCR primer) 8/19/2005 Su-Shing Chen, CISE 40

41 Class Libraries Design Tools Query Tools API page management, object locking, disk access, logging, recovery, transaction commit Object-Oriented DBMS Architecture Database Manager Object Manager Persistent Databases query, transaction, schema management, concurrency control, type management, versioning, object caching 8/19/2005 Su-Shing Chen, CISE 41

42 PHYLOGENETIC DATA next grouping is phylogenetic data [family/superfamily classification] [species]+[tissue]+[cell type]+[localization in cell]+[state of maturity(embryo, juvenile, adult, unspecified)] [genus] [phylum] [kingdom] [cdna sequence] [aa sequence] [bibliography for sequences] 8/19/2005 Su-Shing Chen, CISE 42

43 Kingdom Phylum cdna sequence bibliography species tissue Genus Super Family/ Family cell maturity PHYLOGENETIC DATA location 8/19/2005 Su-Shing Chen, CISE 43

44 MOLECULAR BIOLOGY next grouping is for dynamics of molecular biology [expression and its modulation] [degradation and its modulation] [turnover and its modulation] 8/19/2005 Su-Shing Chen, CISE 44

45 MOLECULAR DYNAMICS Expression Degradation Molecular Dynamics Turnover 8/19/2005 Su-Shing Chen, CISE 45

46 APPLICATIONS next grouping is for applications significance [human or veterinary health significance, if any known] [bibliography for human or veterinary health significance] [biotech significance, if any known] [bibliography for biotech significance] [agricultural significance, if any known] [bibliography for agricultural significance] 8/19/2005 Su-Shing Chen, CISE 46

47 Health Biotech Applications APPLICATIONS Agriculture 8/19/2005 Su-Shing Chen, CISE 47

48 PHARMACOLOGY next entry is for pharmacology [pharmacalogy -- toxin and other blocker sensitivity -- for each toxin or blocker for which there are experimental data, list toxin or blocker, Kd, Kon, Koff, whether it acts from inside or outside, are there anomalous effects to pure block (use dependence, etc.)?] [bibliography for pharmacalogy] 8/19/2005 Su-Shing Chen, CISE 48

49 Pharmacology blocker toxin Bibliography 8/19/2005 Su-Shing Chen, CISE 49

50 STRUCTURAL INFORMATION next set of entries is for structural information [experimentally determined structures] [bibliography for experimentally determined structures] [model-built structures] [bibliography for model-built structures] [partial structural information -- cd spectra, solution nmr, cysteine scanning, antibody labelling, identification of glycosylation or phosphorylation sites, etc.] [bibliography for partial structural information] 8/19/2005 Su-Shing Chen, CISE 50

51 Bibliography Partial Structure Information Structural Information Experimental Structures Bibliography Model Structures Bibliography STRUCTURAL INFORMATION 8/19/2005 Su-Shing Chen, CISE 51

52 8/19/2005 Su-Shing Chen, CISE 52

53 2002 Fall Homework 1 Due 9/26 Create an individual data set of 2 bacteria from NCBI Entrez Genome Database (See assignment). Create flat files. Include gene sequences (CDS regions), non coding regions, associated protein sequences. Include DDBJ/EMBL/GenBank Accession # and gi#. Include NCBI RefSeq. Include terms of NCBI NCBI Data Model. Use FASTA Format (>) for sequences. 8/19/2005 Su-Shing Chen, CISE 53

54 2002 Fall Homework 2 Due 10/17 Use BLAST to search similar gene sequences to your data set annotations to genes. Use BLAST to search similar protein sequences to your data set-annotations to proteins. Check CDS (coding regions) of annotated genes with annotated proteins. Any differences due to BLAST? 8/19/2005 Su-Shing Chen, CISE 54

55 2002 Fall Home Work 3 Due 11/7 Use NCBI Entrez structure database to get all structure (if available) coordinates data of your data set (2 bacteria and all BLAST annotations) Create flat files of structure data and visual data using Cn3D. 8/19/2005 Su-Shing Chen, CISE 55

56 RefSeq Protein Structure GO Databases Locus Gene Sequence CDS Protein Sequence Functions Functions Functions CAP 5510 Bacteria & Fungi Functional Database D/E/G BLAST Anno. G. Sequence BLAST CDS Anno. P. Sequence A. P. Structure 8/19/2005 Su-Shing Chen, CISE 56