Introduction to Bioinformatics October 13, 03

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1 Intrductin t Biinfrmatics Helge Weissig, Ph.D. helgew@biinfrmaticscurses.cm Intrductin t Biinfrmatics Helge Weissig, 2003 (1) Curse Objectives Prvide a brad verview f the field Intrduce sme f the mst cmmnly used nline Biinfrmatics tls Present basic algrithmic cncepts Practice query, retrieval and analysis f sequences and structures Intrductin t Biinfrmatics Helge Weissig, 2003 (2) Curse Schedule Lecture 1 Curse Intrductin NCBI Entrez Lecture 2 The BLAST Algrithm Using BLAST nline Lecture 3 ORF Finder GENSCAN Principles and use f PSI-BLAST Lecture 4 Multiple Sequence Alignments with ClustalW Prtein analysis (Prsite, Pfam, PRINTS, Blcks) Lecture 5 Databases and interface design Prgramming Languages Lecture 6 Structural Biinfrmatics primer Finding and analyzing structures with the PDB Intrductin t Biinfrmatics Helge Weissig, 2003 (3) 1

2 Intrductin t Biinfrmatics Lecture 1 q Curse Intrductin q NCBI Resurces Intrductin t Biinfrmatics Helge Weissig, 2003 (4) Textbk Biinfrmatics fr Dummies Jean-Michel Claverie & Cedric Ntredame Wiley Publishing, Inc. ISBN Intrductin t Biinfrmatics Helge Weissig, 2003 (5) What is Biinfrmatics? The systematic develpment and applicatin f cmputing systems and cmputatinal slutin techniques t the analysis f bilgical data btained by experiments, mdeling, database search, and instrumentatin Intrductin t Biinfrmatics Helge Weissig, 2003 (6) 2

3 What is Cmputatinal Bilgy? The systematic develpment and applicatin f cmputing systems and cmputatinal slutin techniques t mdels f bilgical phenmena Intrductin t Biinfrmatics Helge Weissig, 2003 (7) Cmpnents f Biinfrmatics Bilgical Data Cmputers Algrithms Outset? this that Intrductin t Biinfrmatics Helge Weissig, 2003 (8) Bilgical Data central dgma f mlecular bilgy DNA RNA Prtein Phentype Intrductin t Biinfrmatics Helge Weissig, 2003 (9) 3

4 Mlecular Bilgy and Cmputatinal Abstractins DNA RNA Prtein Phentype A string in a fur-letter alphabet A = a 1...a n, a x Œ A A = {A,C,G,T} Intrductin t Biinfrmatics Helge Weissig, 2003 (10) Mlecular Bilgy and Cmputatinal Abstractins [2] DNA RNA Prtein Phentype A string in a fur-letter alphabet B = b 1...b n, b x Œ B B = {A,C,G,U} Intrductin t Biinfrmatics Helge Weissig, 2003 (11) Mlecular Bilgy and Cmputatinal Abstractins [3] DNA RNA Prtein Phentype A string in a twenty-letter alphabet C = c 1...c n, c x Œ C C = { A -Y}, [B,J,O,U, X] œ C Intrductin t Biinfrmatics Helge Weissig, 2003 (12) 4

5 Mlecular Bilgy and Cmputatinal Abstractins [4] DNA RNA Prtein Phentype Infrmatin transfer Intrductin t Biinfrmatics Helge Weissig, 2003 (13) Infrmatin Transfer During Evlutin Phylgenetic Tree Evlutinary Distance Hrizntal Transfer Intrductin t Biinfrmatics Helge Weissig, 2003 (14) Infrmatin Thery Primer q Infrmatin is measured in bits q 1 bit := chice between tw equally pssible utcmes => DNA: 2 bits per base Intrductin t Biinfrmatics Helge Weissig, 2003 (15) 5

6 Infrmatin Thery Primer [2] q Infrmatin measured in bits q Is additive q Is well supprted mathematically q Measures sequence cnservatin q Is calculated as a decrease in uncertainty: n H = -Â p i lg 2 p i [bits] i=1 q Rate f infrmatin transmissin: R = -DH [bits/symbl] q Credits & details: Intrductin t Biinfrmatics Helge Weissig, 2003 (16) Infrmatin Grwth: Sequences 1.80E E E E E E E E E E E E E E E+09 Base Pairs Sequences 4.00E E E E+00 Year Intrductin t Biinfrmatics Helge Weissig, 2003 (17) Infrmatin Grwth: Genmes 1.E+10 1.E+09 1.E+08 Base Pairs Genes E E+06 1.E E Bacterium Eukarytic Cell Animal Human Intrductin t Biinfrmatics Helge Weissig, 2003 (18) 6

7 Infrmatin Grwth: Macrmlecular Structures Intrductin t Biinfrmatics Helge Weissig, 2003 (19) Infrmatin Cmplexity Intrductin t Biinfrmatics Helge Weissig, 2003 (20) Infrmatin Cmplexity [2] Eclgical Prcesses and Ppulatins Tissue and Organismal Physilgy Cmplexity Cellular & Develpmental Prcesses Bichemical Pathways & Prcesses Cmplete Genmes Genes, Prteins, RNAs, and thers Intrductin t Biinfrmatics Helge Weissig, 2003 (21) 7

8 Biinfrmatics Applicatins Eclgical Prcesses and Ppulatins Cmplexity Tissue and Organismal Physilgy Cellular & Develpmental Prcesses Bichemical Pathways & Prcesses Mrphgenesis and Develpment Mdeling Catalysis, Mlecular Dynamics Mdeling Structures f Multimlecular cmplexes Predicting Three-Dimensinal Structures f Prteins and RNAs Simulatin f Metablic and Signal Transductin Pathways Predicting Effects f Variatin Predicting Functins Cmplete Genmes Genes, Prteins, RNAs, and thers Sequence Variatin f Assembled Genmes Ppulatins Predicting Prtein Simulating and Understanding Gene Sequence Expressin Netwrks Recnstructing Phylgeny, Hmlgy, Genes and Gene Structures and Cmparitive Appraches Intrductin t Biinfrmatics Helge Weissig, 2003 (22) Biinfrmatics Applicatins [2] Eclgical Prcesses and Ppulatins Cmplexity Tissue and Organismal Physilgy Cellular & Develpmental Prcesses Experiment Bichemical Pathways & Prcesses Cmplete Genmes Genes, Prteins, RNAs, and thers Mrphgenesis and Develpment Simulatin f Metablic and Signal Transductin Pathways Mdeling Catalysis, Mlecular Dynamics Predicting Effects f Mdeling Structures f Cmputatin Multimlecular cmplexes Variatin Predicting Three-Dimensinal Predicting Functins Structures f Prteins and RNAs Sequence Variatin f Assembled Genmes Ppulatins Predicting Prtein Simulating and Understanding Gene Sequence Expressin Netwrks Recnstructing Phylgeny, Hmlgy, Genes and Gene Structures and Cmparitive Appraches Intrductin t Biinfrmatics Helge Weissig, 2003 (23) Biinfrmatics Applicatins: Genmic Scale Experiments Intrductin t Biinfrmatics Helge Weissig, 2003 (24) 8

9 Intrductin t Biinfrmatics Octber 13, 03 Biinfrmatics Applicatins: Genmic Scale Experiments [2] Others HAP1 - ROX1 + CYB CYC7 + GPD2 CYT1 Intrductin t Biinfrmatics Helge Weissig, 2003 (25) Biinfrmatics Applicatins: Prtemic Scale Experiments Intrductin t Biinfrmatics Helge Weissig, 2003 (26) Biinfrmatics Applicatin Areas Data archival and retrieval Crss-species cmparisns Databases, LIMS, experimental autmatin Experiments in yeast are easier than in mice where they are easier than in humans Whle Genme characterizatin Drug design Functinal anntatin! Prtein/ligand interactin studies Designing inhibitrs Dcking, structural mdeling Intrductin t Biinfrmatics Helge Weissig, 2003 (27) 9

10 Biinfrmatics challenges Bilgical Redundancy and multiplicity: Different sequences with similar structures Organisms with similar genes Multiple functins f single genes Gruping f genes in pathways Sequence redundancy in genmes Significance f relatinships and similarities Signal versus Nise Lack f Data Intrductin t Biinfrmatics Helge Weissig, 2003 (28) Intrductin t NCBI s Entrez Overview: Database structure Basic Searching Using related links/neighbrs Details, Limits, Preview. Entrez field qualifiers Advanced Blean queries Practical examples and hands-n wrk! Intrductin t Biinfrmatics Helge Weissig, 2003 (29) Intrductin t NCBI s Entrez [2] What is Entrez??? Why is Entrez imprtant??? Ë crss-disciplinary reference database Ë cnvenient query and retrieval capabilities Entrez allws the retrieval f mlecular bilgy data and bibligraphic citatins frm the NCBI's integrated databases. Intrductin t Biinfrmatics Helge Weissig, 2003 (30) 10

11 Intrductin t Biinfrmatics Helge Weissig, 2003 (31) Intrductin t Biinfrmatics Helge Weissig, 2003 (32) Intrductin t Biinfrmatics Helge Weissig, 2003 (33) 11

12 Entrez Databases NCBI Entrez's integrated databases include: PubMed: The bimedical literature (PubMed) Nucletide sequence database (Genbank) Prtein sequence database Structure: three-dimensinal macrmlecular structures Genme: cmplete genme assemblies PpSet: ppulatin study data sets OMIM: Online Mendelian Inheritance in Man Taxnmy: rganisms in GenBank Bks: nline bks PrbeSet: gene expressin and micrarray datasets 3D Dmains: dmains frm Entrez Structure UniSTS: markers and mapping data SNP: single nucletide plymrphisms CDD: cnserved dmains Intrductin t Biinfrmatics Helge Weissig, 2003 (34) Entrez Database Cnnectins PubMed Nucletide PpSet Prtein Structures Genmes Inter-database Links Intra-Database Links: Related Entries Intrductin t Biinfrmatics Helge Weissig, 2003 (35) Chse a database Intrductin t Biinfrmatics Helge Weissig, 2003 (36) 12

13 Click G Buttn Enter Query Term Intrductin t Biinfrmatics Helge Weissig, 2003 (37) Intrductin t Biinfrmatics Helge Weissig, 2003 (38) Details screen Exact query syntax Intrductin t Biinfrmatics Helge Weissig, 2003 (39) 13

14 Number f Entries/Page Intrductin t Biinfrmatics Helge Weissig, 2003 (40) Frmat, Neighbrs & Links Intrductin t Biinfrmatics Helge Weissig, 2003 (41) Links Pp-Up Intrductin t Biinfrmatics Helge Weissig, 2003 (42) 14

15 Entries added t Clipbard Intrductin t Biinfrmatics Helge Weissig, 2003 (43) Clipbard screen Intrductin t Biinfrmatics Helge Weissig, 2003 (44)!!!??? Intrductin t Biinfrmatics Helge Weissig, 2003 (45) 15

16 Same as withut qutes Intrductin t Biinfrmatics Helge Weissig, 2003 (46)??? Intrductin t Biinfrmatics Helge Weissig, 2003 (47)!!! Intrductin t Biinfrmatics Helge Weissig, 2003 (48) 16

17 Wildcard * Intrductin t Biinfrmatics Helge Weissig, 2003 (49) Indexed terms Intrductin t Biinfrmatics Helge Weissig, 2003 (50) Preview/Index screen Intrductin t Biinfrmatics Helge Weissig, 2003 (51) 17

18 Index fr kinase Intrductin t Biinfrmatics Helge Weissig, 2003 (52) Blean term inserted Intrductin t Biinfrmatics Helge Weissig, 2003 (53) Limits screen Intrductin t Biinfrmatics Helge Weissig, 2003 (54) 18

19 Database dependent fields Intrductin t Biinfrmatics Helge Weissig, 2003 (55) Careful!! Sticky!! Intrductin t Biinfrmatics Helge Weissig, 2003 (56) Field qualifier Intrductin t Biinfrmatics Helge Weissig, 2003 (57) 19

20 Advanced Blean Query Intrductin t Biinfrmatics Helge Weissig, 2003 (58) Histry screen Intrductin t Biinfrmatics Helge Weissig, 2003 (59) Intrductin t Biinfrmatics Helge Weissig, 2003 (60) 20

21 Intrductin t Biinfrmatics Helge Weissig, 2003 (61) Intrductin t Biinfrmatics Helge Weissig, 2003 (62) Basic Searching (Summary) Chse database Enter query term Hit G buttn Examples: camp activated prtein kinase camp activated prtein kinase camp activated prtein kinase camp dependent prtein kinase immunglb* Intrductin t Biinfrmatics Helge Weissig, 2003 (63) 21

22 Details, Limits, Preview Details: review Entrez s interpretatin f the query term Limits: ways t restrict a search t a defined subset f the database. Indexes: alphabetical lists f terms frm searchable database fields Histry: review, recall and cmbine past searches Clipbard: temprarily stre results Intrductin t Biinfrmatics Helge Weissig, 2003 (64) Entrez Field Qualifiers Frmat: term [qualifier] Where: Term is the string t search fr Qualifier specify the field t search in G G DB specific ne f WORD, TITL, MESH, MAJR, AUTH, JOUR, ECNO, GENE, DATE, PDAT, MDAT, PAGE, VOL, KYWD, ORGN, ACCN, PROT, SLEN, SQID, SUBS, PROP, FKEY, and PTYP Example: Burne PE [AUTH] Intrductin t Biinfrmatics Helge Weissig, 2003 (65) Entrez Field Qualifiers [2] ACCN accessin number AUTH authr name DATE publicatin year ECNO EC number FKEY feature key GENE gene name JOUR jurnal name KYWD keywrd MAJR MeSH majr tpic MDAT mdificatin date PAGE first page ORGN rganism PROP prperty PDAT publicatin/creatin date PTYP publicatin type PROT prtein name TITL title wrd SQID sequence id SLEN sequence length SUBS substance WORD text wrd VOL vlume Intrductin t Biinfrmatics Helge Weissig, 2003 (66) 22

23 Advanced Blean Queries Frmat: term [field] peratr term [field] Where Operatr is any f : AND (intersectin) OR (unin) BUTNOT (difference) Example: Taylr P [AUTH] AND prtein kinase Ranges: term1:term2 [field] Intrductin t Biinfrmatics Helge Weissig, 2003 (67) Using Related Links (aka Neighbrs ) PubMed Neighbrs Text & MeSH Prtein and Nucletide Neighbrs BLAST Macrmlecular Structure Neighbrs VAST Nn similarity based: references within text/anntatin VERY helpful in identifying related recrds Intrductin t Biinfrmatics Helge Weissig, 2003 (68) PubMed specific qualifier Intrductin t Biinfrmatics Helge Weissig, 2003 (69) 23

24 Intrductin t Biinfrmatics Helge Weissig, 2003 (70) Intrductin t Biinfrmatics Helge Weissig, 2003 (71) Exercises 1. Wrk thrugh the Entrez tutrial at 2. Find references abut shingles and facial paralysis. Display the recrds in the frmat that shws the abstract and the MeSH headings. Hw des PubMed map the term, shingles? 3. Find murine nucleic acid sequences invlved in apptsis and cancer. Display all f the retrieved recrds n ne Web page. 4. Find prtein sequences related t AIDS with publicatins in Nature. Save this search strategy s the search can be run again at a later date. 5. Find all muse r human nucletide sequences added t Entrez in Hw many structures crrespnd t yur result set? Intrductin t Biinfrmatics Helge Weissig, 2003 (72) 24

25 Reading Assignments Review Chapters 1 & 2 Study Chapters 3, 5, 7 & 8 Intrductin t Biinfrmatics Helge Weissig, 2003 (73) 25