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BCB 444/544

BCB 444/544. Lecture 1 What is Bioinformatics? (Genomics? Computational Biology?) #1_Aug20. Thanks to Mark Gerstein (Yale) & Eric Green (NIH) for many borrowed & modified PPTs. Instructors: Drena Dobbs ddobbs@iastate.edu Michael Terribilini terrible@iastate.edu

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BCB 444/544

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  1. BCB 444/544 Lecture 1 What is Bioinformatics? (Genomics? Computational Biology?) #1_Aug20 Thanks to Mark Gerstein (Yale) & Eric Green (NIH) for many borrowed & modified PPTs BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  2. BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  3. Instructors: Drena Dobbs ddobbs@iastate.edu Michael Terribilini terrible@iastate.edu Jae-Hyung Lee jhlee777@iastate.edu TAs: Jeff Sander jdsander@iastate.edu Pete Zaback petez@iastate.edu Lab: MBB 106, 4-4991 BCB 444/544 Introduction to Bioinformatics BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  4. BCB 444/544 - Website • http://bindr.gdcb.iastate.edu/bcb544 • Syllabus • Lecture & Lab Schedules • (with Homework Assignments) • Lecture PPTs • Lab Exercises • Practice Exams • Grading Policy • Project Guidelines, etc. • Links • Check regularly for updates! BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  5. BCB 444/544 - Computer Lab Meets in 1304 MBB every week EXCEPT this week: Current schedule: Thurs 1-3 PM Conflicts? Alternatives? 1st Lab meets in Library Rm 32 BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  6. BCB 444/544 - Required Textbook • Essential Bioinformatics • Jin Xiong, Cambridge, 2006 • ISBN-13: 9780521600828 • Textbook Companion Website: • Not much of one for Xiong: Xiong resources • but check out companion sites foroptional texts • (next slide - URLs also provided on class website) BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  7. BCB 444/544 - Optional Textbooks Please don't buy these yet! Completely optional, perhaps useful, references. All are available from ISU Bookstore but are cheaper from online booksellers. • Mount- good reference for both "biologists" and "computer scientists" - but a bit out of date; Online resources- include lists of applications with URLs • Pevsner- great overview, esp. for those with little biology background; Online resources-excellent: many links & PPTs. • Jones & Pevzner - good introduction to basic algorithms, esp. for biologists with little computer science background; Online resources- very good: problems, links & PPTs. BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  8. Required Reading (after today, must read before lecture) • Wed Aug 22 - for Lecture #2 • Xiong Textbook: • Chp 1 - Introduction • Chp 2 - Biological Databases • Thurs Aug 23 - for Lab #1: • Literature Resources for Bioinformatics Andrea Dinkelman, see Lab Schedule for URL • Fri Aug 24 • Genomics & Its Impact on Science & Society: Genomics & Human Genome Project Primer • see Lecture Schedule for URL BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  9. Xiong: Chps 1 & 2 SECTION I INTRODUCTION AND BIOLOGICAL DATABASES 1 Introduction What Is Bioinformatics? Goal Scope Applications Limitations New Themes Further Reading 2 Introduction to Biological Databases What Is a Database? Types of Databases Biological Databases Pitfalls of Biological Databases Information Retrieval from Biological Databases Summary Further Reading BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  10. Assignment #1: Tell us about you Due: Wed, Aug 22 1- Complete HW1_Aug20 for Drena BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  11. Assignment #2 (& for Fun): DNA Interactive "Genomes" http://www.dnai.org/c/index.html A tutorial on genomic sequencing, gene structure, genes prediction Howard Hughes Medical Institute (HHMI) Cold Spring Harbor Laboratory (CSHL) • Take the Tour • Read about the Project • Do some Genome Mining with: • Nothing to turn in - just do it! BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  12. What is Bioinformatics? Wikipedia: • Bioinformatics and computational biology involve the use of techniques including: applied mathematics informatics statistics computer science artificial intelligence chemistry & biochemistry (& engineering) to solve biological problemsusually on the molecular level • Research in computational biology often overlaps with • systems biology(& genomics) BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  13. What is Systems Biology? Genomics? Wikipedia: • Systems Biology - a term used very widely in the biosciences, particularly from the year 2000 onwards, and in a variety of contexts... • Genomics - is the study of an organism's entire genome Hmmm -- these aren't very useful! BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  14. What is Bioinformatics? Gerstein (Yale): • Bioinformatics is conceptualizing biology in terms of molecules & applying “informatics” techniques - derived from disciplines such as mathematics, computer science, and statistics - to organize and understand information associated with these molecules, on a large scale BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? Modified from Mark Gerstein

  15. Central Dogma of Molecular Biology DNA Sequence (1 gene) -> mRNA -> Protein -> Phenotype Molecules Sequence Structure Function Processes Mechanism Specificity Regulation Central Paradigm for Computational Biology DNA Sequence (entire genome) -> mRNA, rRNA, tRNA, snRNAs -> regulatory RNAs, e.g. miRNAs -> Proteins -> Phenotype Molecules & Systems Sequence, Structure, Function Interactions Pathways & Networks Large Amounts of Information Standardized ontologies Statistical analyses What is the Information?Biological Sequences, Structures, Processes BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? Modified from Mark Gerstein

  16. Explosion of "Omes" & "Omics!"Genome, Transcriptome, Proteome… • Genome - complete collection of DNA (genes and "non-genes") of an organism • Transcriptome - complete collection of RNAs (mRNAs & others) expressed in an organism* • Proteome - complete collection of proteins expressed in an organism* BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  17. Genome = Constant (more or less…) Transcriptome & Proteome = Variable • * Note: • AlthoughDNA is "identical" in all cellsof a single organism, bothtypes and amounts ofRNAs & proteins vary greatlyin different cells & tissues • Expression patterns depend on variables such as developmental stage, age, disease state, environmental conditions, etc. • Genome - complete collection of DNA (genes and "non-genes") of an organism • Transcriptome- complete collection of RNAs (mRNAs & others) expressed in an organism * • Proteome- complete collection of proteins expressed in an organism * BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  18. Molecular Biology Information: DNA & RNA Sequences DNA sequence: atggcaattaaaattggtatcaatggttttggtcgtat gcacaacaccgtgatgacattgaagttgtaggtattaa atggcttatatgttgaaatatgattcaactcacggtcg aaagatggtaacttagtggttaatggtaaaactatccg Gcaaacttaaactggggtgcaatcggtgttgatatcgctttaactgatgaaactgctcgtaaacatatcactgcaggcgcaaaaaaagtt RNA sequence has "U" instead of "T" Functions: • Genetic material • Information transfer (mRNA) • Protein synthesis (rRNA/tRNA) • Catalytic & regulatory activities (some very recently discovered!) Information: • 4 letter alphabet: A C G T of DNA nucleotides (nt) • ~ 1000 base pairs (bp) in avg gene (in bacteria) • ~ 3 X 109 bp in human genome • Where are the genes? • Which DNA sequences encode RNA? • Which genomic DNA is "junk"? • Which RNA sequences encode proteins? BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? Modified from Mark Gerstein

  19. Molecular Biology Information: Protein Sequences Functions:Most cellular functions are either performed by or regulated by proteins • Biocatalysis • Cofactor transport/storage • Mechanical motion/support • Immune protection • Regulation of growth and differentiation Information: • 20 letter alphabet: ACDEFGHIKLMNPQRSTVWY of amino acids (aa) • ~ 300 aa in an average protein (in bacteria) • > 3 X 106 known protein sequences Protein sequences: d1dhfa_ LNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTT d8dfr__ LNSIVAVCQNMGIGKDGNLPWPPLRNEYKYFQRMTS d4dfra_ ISLIAALAVDRVIGMENAMPWN-LPADLAWFKRNTL d3dfr__ TAFLWAQDRDGLIGKDGHLPWH-LPDDLHYFRAQTV • What is this protein? • Which amino acids are most important for folding, activity, or interaction with other proteins? • Which sequence variations are harmful (or beneficial)? BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? Modified from Mark Gerstein

  20. Molecular Biology Information:Macromolecular Structures DNA/RNA/Protein Structures • How does a protein (or RNA) sequence fold into an active 3-D structure? • Can we predict structure from sequence? • Can we predict function from structure (or perhaps, from sequence alone?) BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? Modified from Mark Gerstein

  21. We don't understand the protein folding code yet - but we try to engineer proteins anyway! BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? Modified from Mark Gerstein

  22. Molecular Biology Information:Biological Processes Genomics & Systems Biology • How do patterns of gene expression determine phenotype? • Which genes and proteins are required for differentiation during during development? • How do proteins interact in biological networks? • Which genes and pathways have been most highly conserved during evolution? BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  23. "On a Large Scale?"Whole Genome Sequencing 1st a complete bacterial genome, then yeast Genome sequences now accumulate so quickly that, in less than a week, a single laboratory can produce more bits of data than Shakespeare managed in a lifetime, although the latter make better reading. -- G A Pekso, Nature401: 115-116 (1999) BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? Modified from Mark Gerstein

  24. Genome Projects: Rapid Automated Sequencing Another recent improvement: rapid & high resolution separation of fragments in capillaries instead of gels E Yeung, Ames Lab, ISU More recently? Pyro-sequencing 454 sequencing http://www.454.com/ $ 1000 genomes? BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? Modified from Eric Green

  25. 1st Draft Human Genome: "Finished" in 2001 BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? Modified from Eric Green

  26. Human Genome Sequencing • Two approaches: • Public (government) - International Consortium • (mainly 6 countries, NIH-funded in US) • Hierarchical cloning & BAC-to-BAC sequencing • Map-based assembly • Private (industry) - Celera, Craig Venter, CEO • Whole genome random "shotgun" sequencing • Computational assembly • (took advantage of public maps & sequences, too) Guess which human genome they sequenced? Craig's • ~ 20,000 (Science, May 2007) How many genes? BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  27. Public Sequencing: International Consortium BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? Modified from Eric Green

  28. So, having a list of parts is not enough! BIG QUESTION? How do parts work together to form a functional system? SYSTEMS BIOLOGY What is a system? Macromolecular complex, pathway, network, cell, tissue, organism, ecosystem… BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  29. Is this Bioinformatics? YES • Creating digital libraries • Automated bibliographic search and text comparison • Knowledge bases for biological literature • Methods for structure determination • Computational X-ray crystallography • NMR structure determination • Distance geometry • Metabolic pathway simulation YES YES BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? Modified from Mark Gerstein

  30. Is this Bioinformatics? YES • Gene identification by sequence inspection • Prediction of splice sites, promoters, etc. • DNA methods in forensics • Modeling populations of organisms • Ecological Modeling • Genomic sequencing methods • Assembling contigs • Physical and genetic mapping • Linkage analysis • Linking specific genes to various traits YES YES YES YES BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? Modified from Mark Gerstein

  31. Is this Bioinformatics? • Rational drug design • RNA structure prediction • Protein structure prediction • Artificial life simulations • Artificial immunology • Computer security YES BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? Modified from Mark Gerstein

  32. So, this is Bioinformatics What is it good for? Just a few examples… BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics?

  33. Designing drugs • Understanding how proteins bind other molecules • Structural modeling & ligand docking • Designing inhibitors or modulators of key proteins Figures adapted from Olsen Group Docking Page at Scripps, Dyson NMR Group Web page at Scripps, and from Computational Chemistry Page at Cornell Theory Center). BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? Modified from Mark Gerstein

  34. Finding homologs of "new" human genes BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? Modified from Mark Gerstein

  35. Finding WHAT?Homologs - "same genes" in different organisms • Human vs Mouse vs Yeast • Much easier to do experiments on yeast to determine function • Often, function of an ortholog in at least one organism is known Best Sequence Similarity Matches to Date Between Positionally Cloned Human Genes and S. cerevisiae Proteins Human Disease MIM # Human GenBank BLASTX Yeast GenBank Yeast Gene Gene Acc# for P-value Gene Acc# for Description Human cDNA Yeast cDNA Hereditary Non-polyposis Colon Cancer 120436 MSH2 U03911 9.2e-261 MSH2 M84170 DNA repair protein Hereditary Non-polyposis Colon Cancer 120436 MLH1 U07418 6.3e-196 MLH1 U07187 DNA repair protein Cystic Fibrosis 219700 CFTR M28668 1.3e-167 YCF1 L35237 Metal resistance protein Wilson Disease 277900 WND U11700 5.9e-161 CCC2 L36317 Probable copper transporter Glycerol Kinase Deficiency 307030 GK L13943 1.8e-129 GUT1 X69049 Glycerol kinase Bloom Syndrome 210900 BLM U39817 2.6e-119 SGS1 U22341 Helicase Adrenoleukodystrophy, X-linked 300100 ALD Z21876 3.4e-107 PXA1 U17065 Peroxisomal ABC transporter Ataxia Telangiectasia 208900 ATM U26455 2.8e-90 TEL1 U31331 PI3 kinase Amyotrophic Lateral Sclerosis 105400 SOD1 K00065 2.0e-58 SOD1 J03279 Superoxide dismutase Myotonic Dystrophy 160900 DM L19268 5.4e-53 YPK1 M21307 Serine/threonine protein kinase Lowe Syndrome 309000 OCRL M88162 1.2e-47 YIL002C Z47047 Putative IPP-5-phosphatase Neurofibromatosis, Type 1 162200 NF1 M89914 2.0e-46 IRA2 M33779 Inhibitory regulator protein Choroideremia 303100 CHM X78121 2.1e-42 GDI1 S69371 GDP dissociation inhibitor Diastrophic Dysplasia 222600 DTD U14528 7.2e-38 SUL1 X82013 Sulfate permease Lissencephaly 247200 LIS1 L13385 1.7e-34 MET30 L26505 Methionine metabolism Thomsen Disease 160800 CLC1 Z25884 7.9e-31 GEF1 Z23117 Voltage-gated chloride channel Wilms Tumor 194070 WT1 X51630 1.1e-20 FZF1 X67787 Sulphite resistance protein Achondroplasia 100800 FGFR3 M58051 2.0e-18 IPL1 U07163 Serine/threoinine protein kinase Menkes Syndrome 309400 MNK X69208 2.1e-17 CCC2 L36317 Probable copper transporter BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? Modified from Mark Gerstein

  36. Comparative Genomics: Genome/Transcriptome/Proteome/Metabolome Databases, statistics • Occurrence of a specific genes or features in a genome • How many kinases in yeast? • Compare Tissues • Which proteins are expressed in cancer vs normal tissues? • Diagnostic tools • Drug target discovery BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? Modified from Mark Gerstein

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