Introduction BIOINFORMATICS - Gerstein Lab

1 1(c) Mark Gerstein , 1999, Yale, Gerstein , Yale (c) Mark Gerstein , 1999, Yale, +3(c) Mark Gerstein , 1999, Yale, isBioinformatics? (Molecular)Bio-informatics One idea for a definition? BIOINFORMATICS is conceptualizingbiology in terms ofmolecules(in the sense of physical-chemistry) andthen applying informatics techniques(derivedfrom disciplines such as applied math, CS, andstatistics) to understand andorganize theinformation associatedwith these molecules,on alarge-scale. BIOINFORMATICS is MIS for Molecular BiologyInformation4(c) Mark Gerstein , 1999, Yale, Biology: an Information Science Central Dogmaof Molecular BiologyDNA-> RNA-> Protein-> Phenotype-> DNA Molecules Sequence, Structure, Function Processes Mechanism, Specificity, Regulation Central Paradigmfor BioinformaticsGenomic Sequence Information-> mRNA (level)-> Protein Sequence-> Protein Structure-> Protein Function-> Phenotype Large Amounts of Information Standardized Statistical(idea from D Brutlag, Stanford, graphics from S Strobel) Genetic material Information transfer (mRNA) Protein synthesis (tRNA/mRNA) Some catalytic activity Most cellular functions are performed orfacilitated by proteins.

2 Primary biocatalyst Cofactor transport/storage Mechanical motion/support Immune protection Control of growth/differentiation5(c) Mark Gerstein , 1999, Yale, Biology Information - DNA Raw DNA Sequence Coding or Not? Parse into genes? 4bases:AGCT ~1 Kinagene,~2 M in genomeatggcaattaaaattggtatcaatggttttggtc gtatcggccgtatcgtattccgtgcagcacaacaccgtga tgacattgaagttgtaggtattaacgacttaatcgacgtt gaatacatggcttatatgttgaaatatgattcaactcacg gtcgtttcgacggcactgttgaagtgaaagatggtaactt agtggttaatggtaaaactatccgtgtaactgcagaacgt gatccagcaaacttaaactggggtgcaatcggtgttgata tcgctgttgaagcgactggtttattcttaactgatgaaac tgctcgtaaacatatcactgcaggcgcaaaaaaagttgta ttaactggcccatctaaagatgcaacccctatgttcgttc gtggtgtaaacttcaacgcatacgcaggtcaagatatcgt ttctaacgcatcttgtacaacaaactgtttagctccttta gcacgtgttgttcatgaaactttcggtatcaaagatggtt taatgaccactgttcacgcaacgactgcaactcaaaaaac tgtggatggtccatcagctaaagactggcgcggcggccgc ggtgcatcacaaaacatcattccatcttcaacaggtgcag cgaaagcagtaggtaaagtattacctgcattaaacggtaa attaactggtatggctttccgtgttccaacgccaaacgta tctgttgttgatttaacagttaatcttgaaaaaccagctt cttatgatgcaatcaaacaagcaatcaaagatgcagcgga aggtaaaacgttcaatggcgaattaaaaggcgtattaggt tacactgaagatgctgttgtttctactgacttcaacggtt gtgctttaacttctgtatttgatgcagacgctggtatcgc attaactgattctttcgttaaattggtatc.

3 Caaaaatagggttaatatgaatctcgatctccattttgtt catcgtattcaacaacaagccaaaactcgtacaaatatga ccgcacttcgctataaagaacacggcttgtggcgagatat ctcttggaaaaactttcaagagcaactcaatcaactttct cgagcattgcttgctcacaatattgacgtacaagataaaa tcgccatttttgcccataatatggaacgttgggttgttca tgaaactttcggtatcaaagatggtttaatgaccactgtt cacgcaacgactacaatcgttgacattgcgaccttacaaa ttcgagcaatcacagtgcctatttacgcaaccaatacagc ccagcaagcagaatttatcctaaatcacgccgatgtaaaa attctcttcgtcggcgatcaagagcaatacgatcaaacat tggaaattgctcatcattgtccaaaattacaaaaaattgt agcaatgaaatccaccattcaattacaacaagatcctctt tcttgcacttgg6(c) Mark Gerstein , 1999, Yale, Biology Information:Protein Sequence 20 letter alphabet ACDEFGHIKLMNPQRSTVWYbut notBJOUXZ Strings of ~300 aa in an average protein (in bacteria)

4 ,~200 aa in a domain ~200 K known protein sequencesd1dhfa_LNCIVAVSQNMGIGKNGDLPWPPL RNEFRYFQRMTTTSSVEGKQ-NLVIMGKKTWFSId8dfr_ _LNSIVAVCQNMGIGKDGNLPWPPLRNEYKYFQRMTSTSH VEGKQ-NAVIMGKKTWFSId4dfra_ISLIAALAVDRVIG MENAMPWN-LPADLAWFKRNTL--------NKPVIMGRHT WESId3dfr__TAFLWAQDRDGLIGKDGHLPWH-LPDDLH YFRAQTV--------GKIMVVGRRTYESFd1dhfa_ LNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTTSSV EGKQ-NLVIMGKKTWFSId8dfr__LNSIVAVCQNMGIGK DGNLPWPPLRNEYKYFQRMTSTSHVEGKQ-NAVIMGKKTW FSId4dfra_ISLIAALAVDRVIGMENAMPW-NLPADLAW FKRNTLD--------KPVIMGRHTWESId3dfr__TAFLW AQDRNGLIGKDGHLPW-HLPDDLHYFRAQTVG-------- KIMVVGRRTYESFd1dhfa_ VPEKNRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKL TEQPELANKVDMVWIVGGSSVYKEAMNHPd8dfr__ VPEKNRPLKDRINIVLSRELKEAPKGAHYLSKSLDDALAL LDSPELKSKVDMVWIVGGTAVYKAAMEKPd4dfra_ ---G-RPLPGRKNIILS-SQPGTDDRV-TWVKSVDEAIAA CGDVP------EIMVIGGGRVYEQFLPKAd3dfr__ ---PKRPLPERTNVVLTHQEDYQAQGA-VVVHDVAAVFAY AKQHLDQ----ELVIAGGAQIFTAFKDDVd1dhfa_-PEK NRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKLTEQP ELANKVDMVWIVGGSSVYKEAMNHPd8dfr__ -PEKNRPLKDRINIVLSRELKEAPKGAHYLSKSLDDALAL LDSPELKSKVDMVWIVGGTAVYKAAMEKPd4dfra_ -P--KRPLPERTNVVLTHQEDYQAQGA-VVVHDVAAVFAY AKQHLD----QELVIAGGAQIFTAFKDDV7(c) Mark Gerstein , 1999, Yale, Biology Information:Macromolecular Structure DNA/RNA/Protein Almost all protein(RNA Adapted From D Soll Web Page,Right Hand Top Protein from M Levitt web page)8(c) Mark Gerstein , 1999, Yale, Biology Information.

5 Protein Structure Details Statistics on Number of XYZ triplets 200 residues/domain->200 CA atoms, separated by A Avg. Residue is Leu: 4 backbone atoms + 4 sidechain atoms, 150 cubic A =>~1500 xyz triplets (=8x200) per protein domain 10 K known domain, ~300 foldsATOM 1 C ACE 0 1 GKY 67 ATOM 2 O ACE 0 1 GKY 68 ATOM 3 CH3 ACE 0 1 GKY 69 ATOM 4 N SER 1 1 GKY 70 ATOM 5 CA SER 1 1 GKY 71 ATOM 6 C SER 1 1 GKY 72 ATOM 7 O SER 1 1 GKY 73 ATOM 8 CB SER 1 1 GKY 74 ATOM 9 OG SER 1 1 GKY 75 ATOM 10 N ARG 2 1 GKY 76 ATOM 11 CA ARG 2 1 GKY 77 ATOM 12 C ARG 2

6 1 GKY 1444 CB LYS 186 1 GKY1510 ATOM 1445 CG LYS 186 1 GKY1511 ATOM 1446 CD LYS 186 1 GKY1512 ATOM 1447 CE LYS 186 1 GKY1513 ATOM 1448 NZ LYS 186 1 GKY1514 ATOM 1449 OXT LYS 186 1 GKY1515 TER 1450 LYS 186 1 GKY15169(c) Mark Gerstein , 1999, Yale, theWorld ofSequencesBacteria, , ~1600genes[Science269: 496]Eukaryote,13 Mb, ~6 Kgenes[Nature387:1]199519971998 Animal, ~100Mb, ~20 Kgenes[Science282: 1945]Human, ~3Gb, ~100 Kgenes[???]2000?10(c) Mark Gerstein , 1999, Yale, BiologyInformation:Whole Genomes The Revolution Driving EverythingFleischmann, ,Adams, ,White,O.

7 ,Clayton, ,Kirkness, ,Kerlavage, A. R., Bult, C. J., Tomb, J. F., Dougherty, B. A., Merrick, J. M., McKenney, K.,Sutton, G., Fitzhugh, W., Fields, C., Gocayne, J. D., Scott, J., Shirley, R., Liu, L. I., Glodek, A.,Kelley, J. M., Weidman, J. F., Phillips, C. A., Spriggs, T., Hedblom, E., Cotton, M. D.,Utterback, T. R., Hanna, M. C., Nguyen, D. T., Saudek, D. M., Brandon, R. C., Fine, L. D.,Fritchman, J. L., Fuhrmann, J. L., Geoghagen, N. S. M., Gnehm, C. L., McDonald, L. A., Small, ,Fraser, ,Smith, , (1995)."Whole-genomerandom sequencing and assembly ofHaemophilusinfluenzae rd."Science269: 496-512.(Picture adapted from TIGR website, ) Integrative Data1995, HI (bacteria): Mb & 1600 genes done1997, yeast: 13 Mb & ~6000 genes for yeast1998, worm: ~100Mb with 19 K genes1999: >30 completed genomes!

8 2003, human: 3 Gb & 100 K sequence nowaccumulate so quickly that,in less than a week, asingle laboratory canproduce more bits of datathan Shakespearemanagedinalifetime,although the latter makebetter G A Pekso,Nature401: 115-116 (1999)11(c) Mark Gerstein , 1999, Yale, ExpressionDatasets: theTranscriptosomeAlso: SAGE;Samson andChurch, Chips;Aebersold,ProteinExpressionYoung/L ander, Chips,Abs. , array,Rel. Exp. overTimecourseSnyder,Transposons,Protein (c) Mark Gerstein , 1999, Yale, data (courtesy of J Hager)Yeast Expression data inAcademia:levels for all 6000 genes!Can only sequence genomeonce but can do an infinitevariety of these arrayexperimentsat 10 time points,6000 x 10 = 60K floatstelling signal frombackground13(c) Mark Gerstein , 1999, Yale, Whole-GenomeExperimentsSystematic KnockoutsWinzeler, E.

9 A., Shoemaker, D. D.,Astromoff, A., Liang, H., Anderson, K.,Andre, B., Bangham, R., Benito, R.,Boeke, J. D., Bussey, H., Chu, A. M.,Connelly, C., Davis, K., Dietrich, F., Dow,S. W., El Bakkoury, M., Foury, F., Friend,S. H., Gentalen, E., Giaever, G.,Hegemann, J. H., Jones, T., Laub, M.,Liao, H., Davis, R. W. & et al. (1999).Functional characterization of the genome by gene deletion andparallel , 901-62 hybrids, linkage mapsHua, S. B., Luo, Y., Qiu, M., Chan, E., Zhou, H. &Zhu, L. (1998). Construction of a modular yeasttwo-hybrid cDNA library from human EST clones forthe human genome protein linkage ,143-52 For yeast:6000 x 6000 / 2~18 Minteractions14(c) Mark Gerstein , 1999, Yale, Biology Information.

10 Other Integrative data Information tounderstand genomes Metabolic Pathways(glycolysis), traditionalbiochemistry Regulatory Networks Whole OrganismsPhylogeny, traditionalzoology Environments, Habitats,ecology The Literature(MEDLINE) The (Pathway drawing from P Karp s EcoCyc, Phylogenyfrom S J Gould, Dinosaur in a Haystack)15(c) Mark Gerstein , 1999, Yale, of data Matchedby Development of ComputerTechnology CPU vs Disk & Net As important as theincrease in computerspeed has been, theability to store largeamounts ofinformation oncomputersisevenmore crucial DrivingForceinBioinformatics(Internet picture adaptedfrom D Brutlag, Stanford)0500100015002000250030003500400 0450019801985199019950204060801001201401 97919811983198519871989199119931995 CPU InstructionTime (ns) (c) Mark Gerstein , 1999, Yale, is born!