Post on 28-Dec-2015
transcript
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 1
Lecture 1
What is Bioinformatics?(Genomics? Computational
Biology?)
#1_Aug20
BCB 444/544
Thanks to Mark Gerstein (Yale) & Eric Green (NIH)for many borrowed & modified PPTs
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 2
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 3
Introduction to Bioinformatics
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
8/20/07BCB 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!
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 5
Meets in 1304 MBB every weekEXCEPT this week:
Current schedule: Thurs 1-3 PMConflicts?Alternatives?
BCB 444/544 - Computer Lab
1st Lab meets in Library Rm 32
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 6
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 for optional texts (next slide - URLs also provided on class website)
BCB 444/544 - Required Textbook
8/20/07BCB 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• Mount - good reference for both "biologists" and "computer scientists" - but a bit out of date; Online resources - include lists of applications with URLs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.
8/20/07BCB 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
8/20/07BCB 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
8/20/07BCB 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
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 11
A tutorial on genomic sequencing, gene structure, genes prediction
Howard Hughes Medical Institute (HHMI)Cold Spring Harbor Laboratory (CSHL)
Assignment #2 (& for Fun): DNA Interactive
"Genomes"
1. Take the Tour2. Read about the Project3. Do some Genome Mining with: Nothing to turn in - just do it!
http://www.dnai.org/c/index.html
8/20/07BCB 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
informaticsstatisticscomputer scienceartificial intelligencechemistry & biochemistry (& engineering)
to solve biological problems usually on the molecular level
• Research in computational biology often overlaps with systems biology (& genomics)
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 13
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
What is Systems Biology? Genomics?
Hmmm -- these aren't very useful!
8/20/07BCB 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
Modified from Mark Gerstein
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 15
What is the Information?Biological Sequences, Structures, Processes
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
Modified from Mark Gerstein
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 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*
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 17
Genome = Constant (more or less…) Transcriptome & Proteome = Variable
• 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 *
* Note:
• Although DNA is "identical" in all cells of a single organism, both types and amounts of RNAs & proteins vary greatly in different cells & tissues
• Expression patterns depend on variables such as developmental stage, age, disease state, environmental conditions, etc.
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 18
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
Molecular Biology Information: DNA & RNA Sequences
DNA sequence:
atggcaattaaaattggtatcaatggttttggtcgtatgcacaacaccgtgatgacattgaagttgtaggtattaaatggcttatatgttgaaatatgattcaactcacggtcgaaagatggtaacttagtggttaatggtaaaactatccgGcaaacttaaactggggtgcaatcggtgttgatatcgctttaactgatgaaactgctcgtaaacatatcactgcaggcgcaaaaaaagtt
RNA sequence has "U" instead of "T"
Modified from Mark Gerstein
• Where are the genes?• Which DNA sequences encode RNA?• Which genomic DNA is "junk"? • Which RNA sequences encode proteins?
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 19
Molecular Biology Information: Protein Sequences
• 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_ LNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTd8dfr__ LNSIVAVCQNMGIGKDGNLPWPPLRNEYKYFQRMTSd4dfra_ ISLIAALAVDRVIGMENAMPWN-LPADLAWFKRNTLd3dfr__ TAFLWAQDRDGLIGKDGHLPWH-LPDDLHYFRAQTV
Functions: Most cellular functions are either performed by or regulated by proteins
• 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)?
Modified from Mark Gerstein
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 20
Molecular Biology Information:Macromolecular Structures
Modified from Mark Gerstein
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?)
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 21
We don't understand the protein folding code yet - but we try to engineer proteins anyway!
Modified from Mark Gerstein
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 22
Molecular Biology Information:Biological Processes
• 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?
Genomics & Systems Biology
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 23
"On a Large Scale?"Whole Genome Sequencing
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, Nature 401: 115-116 (1999)
Modified from Mark Gerstein
1st a complete bacterial genome, then yeast
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 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
QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
Modified from Eric Green
More recently? Pyro-sequencing454 sequencing http://www.454.com/$ 1000 genomes?
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 25
1st Draft Human Genome: "Finished" in 2001
QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
Modified from Eric Green
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 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'sHow many genes? ~ 20,000 (Science, May 2007)
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 27
Public Sequencing:International Consortium
QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
Modified from Eric Green
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 28
So, having a list of parts is not enough!
BIG QUESTION?
SYSTEMS BIOLOGY
How do parts work together to form a functional system?
What is a system? Macromolecular complex, pathway, network, cell, tissue, organism, ecosystem…
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 29
Is this Bioinformatics?
• 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
YES
Modified from Mark Gerstein
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 30
• 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
YES
Modified from Mark Gerstein
Is this Bioinformatics?
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 31
• Rational drug design• RNA structure prediction• Protein structure prediction• Artificial life simulations• Artificial immunology • Computer security
YES
Modified from Mark Gerstein
Is this Bioinformatics?
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 32
So, this is Bioinformatics
What is it good for?
Just a few examples…
8/20/07BCB 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).
Modified from Mark Gerstein
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 34
Finding homologs of "new" human genes
Modified from Mark Gerstein
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 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 ClonedHuman 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 proteinHereditary Non-polyposis Colon Cancer 120436 MLH1 U07418 6.3e-196 MLH1 U07187 DNA repair proteinCystic Fibrosis 219700 CFTR M28668 1.3e-167 YCF1 L35237 Metal resistance proteinWilson Disease 277900 WND U11700 5.9e-161 CCC2 L36317 Probable copper transporterGlycerol Kinase Deficiency 307030 GK L13943 1.8e-129 GUT1 X69049 Glycerol kinaseBloom Syndrome 210900 BLM U39817 2.6e-119 SGS1 U22341 HelicaseAdrenoleukodystrophy, X-linked 300100 ALD Z21876 3.4e-107 PXA1 U17065 Peroxisomal ABC transporterAtaxia Telangiectasia 208900 ATM U26455 2.8e-90 TEL1 U31331 PI3 kinaseAmyotrophic Lateral Sclerosis 105400 SOD1 K00065 2.0e-58 SOD1 J03279 Superoxide dismutaseMyotonic Dystrophy 160900 DM L19268 5.4e-53 YPK1 M21307 Serine/threonine protein kinaseLowe Syndrome 309000 OCRL M88162 1.2e-47 YIL002C Z47047 Putative IPP-5-phosphataseNeurofibromatosis, Type 1 162200 NF1 M89914 2.0e-46 IRA2 M33779 Inhibitory regulator protein
Choroideremia 303100 CHM X78121 2.1e-42 GDI1 S69371 GDP dissociation inhibitorDiastrophic Dysplasia 222600 DTD U14528 7.2e-38 SUL1 X82013 Sulfate permeaseLissencephaly 247200 LIS1 L13385 1.7e-34 MET30 L26505 Methionine metabolismThomsen Disease 160800 CLC1 Z25884 7.9e-31 GEF1 Z23117 Voltage-gated chloride channelWilms Tumor 194070 WT1 X51630 1.1e-20 FZF1 X67787 Sulphite resistance proteinAchondroplasia 100800 FGFR3 M58051 2.0e-18 IPL1 U07163 Serine/threoinine protein kinaseMenkes Syndrome 309400 MNK X69208 2.1e-17 CCC2 L36317 Probable copper transporter
Modified from Mark Gerstein
8/20/07BCB 444/544 F07 ISU Dobbs #1 - What is Bioinformatics? 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
Modified from Mark Gerstein