8/22/07bcb 444/544 f07 isu dobbs #2 - biological databases1 finish: lecture 1- what is...

8/22/07BCB 444/544 F07 ISU Dobbs #2 - Biological Databases 1

Finish: Lecture 1- What is Bioinformatics?

Lecture 2

Biological Databases&

ISU Resources

#2_Aug22

BCB 444/544


BCB 444/544 - Website

http://bindr.gdcb.iastate.edu/bcb544

• Updated Syllabus • Lecture & Lab Schedules

(with Homework Assignments) • Lecture PPTs & PDFs• Lab Exercises• Practice Exams• Grading Policy• Project Guidelines, etc.• Links

• Check regularly for updates!

Hyperlink


Meets in 1304 MBB every weekEXCEPT this week:

Current schedule: Thurs 1-3 PMConflicts? See Drena

BCB 444/544 - Computer Lab

1st Lab meets in Library Rm 32


Assignment #1: Tell us about you

Due: Today - Wed, Aug 22

1- Complete HW1_Aug20 for Drena


Required Reading (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


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


#1- What is Bioinformatics? (cont.)

Xiong: Chp 1

1 Introduction What Is Bioinformatics? Goal Scope Applications Limitations New Themes Further Reading


1st Draft Human Genome: "Finished" in 2001

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

Modified from Eric Green


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

How many genes? ~ 20,000 (Science, May 2007)


Public Sequencing:International Consortium







Comparison of Sequenced Genome Sizes

Plants? Many have much larger genomes than human!



"Complete" Human Genome Sequence: What next?



from Eric Green


Next Step after the Complete Sequence?

• Expression Analysis• Structural Genomics• Protein Interactions• Network Analysis• Systems Biology

Understanding Gene Function on a Genomic Scale

Evolutionary Implications of: • Intergenic Regions as "Gene Graveyard"• Introns & Exons

Modified from Mark Gerstein


How can we begin to understand the complete Human Genome Sequence?



from Eric Green


Comparative Genomics: Compare entire genomes



from Eric Green


Comparing Genomes: Identifying functional elements



from Eric Green


Gene Expression Data: the Transcriptome

MicroArray Data

Yeast Expression Data:

• Levels for all 6,000 genes!

•Investigate how all genes respond to changes in environment or, in humans, e.g., how patterns of RNA expression change in normal vs cancerous tissue


ISU's Biotechnology Facilities include state-of-the-art Microarray Instrumentation


Other "Omes" Proteome, Metabolome, Glycome, etc.

ISU has state-of-the-art Proteomics Instrumentation

ISU's has state-of-the-art Metabolomics Instrumentation


Systems Biology seeks to integrate all of these to explain the complex behaviors of whole systems (cells, organisms, ecosystems)

How are "Omes" related?


Molecular Biology Information:Integrating Data

Understanding the function of genomes requires integration of many diverse and complex types of information:

• Metabolic pathways • Regulatory networks• Whole organism physiology• Evolution, phylogeny• Environment, ecology• Literature (MEDLINE)



Other Genome-Scale Experiments

Systematic Knockouts:

Make "knockout" (null) mutations in every gene - one at a time - and analyze the resulting phenotypes!

For yeast: 6,000 KO mutants!

2-hybrid Experiments:

For each (and every) protein, identify every other protein with which it interacts!

For yeast: 6000 x 6000 / 2

~ 18M interactions!!Modified from Mark Gerstein


Storing & Analyzing Geonomic Information:

Exponential Growth of Data Coupled with Development of Fast Computer Technology

• Increases in computer speed & starage capacity have been dramatic

• Improved computing resources & more efficient algorithms have been driving forces in Bioinformatics & Computational Biology


ISU's supercomputer "CyBlue" is among 100 most powerful computers in the world!


Bioinformatics is born!& more Bioinformaticists are

needed!

(Internet picture adaptedfrom D Brutlag, Stanford)



“Informatics” techniques used in Bioinformatics

• DatabasesBuilding & querying object-

oriented & relational DBs

• String Comparison• Text search• Alignment• Significance statistics

• Patterns Finding• Machine Learning• Data Mining• Statistics• Linguistics

• Computational Geometry• Robotics• Graphics (surfaces, volumes)• Comparison & 3D matching

• Simulation & Modeling• Newtonian mechanics• Electrostatics• Numerical algorithms• Simulation• Network modeling• Population modeling


Challenges in Organizing Information:

Redundancy and Multiplicity

• Different protein sequences can assume the same 3-D structure

• Organisms have many similar genes with redundant functions

• A single gene may have several different functions

• Genes & proteins function in complex genetic & regulatory pathways

• How do we organize all this information so that we can make sense of it?

Functional Genomics & Systems Biology:sequences <> motifs <> genes <> RNAs <> proteins <> structures <> functions <> expression levels <> pathways <> regulatory networks <> functional systems



One Strategy:Molecular Parts = Conserved Domains



"Parts List" approach to bike maintenance:

Which are the common parts (bolt, nut,washer, spring, bearing)?Which are unique parts (cogs, levers)?

How flexible and adaptable are parts mechanically?

Where are the parts

located?



~ 2,000 folds

~ 20,000 genes

~ 2,000 genes1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 …

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 …H. sapiens

World of macromolecular structures is also finite, providing a valuable simplification

Global surveys of a finite set of parts from different perspectives

Same logic for pathways, functions, sequence families, blocks, motifs....

T. pallidum



BUT, what actually happens inside cells or within whole organisms is very complex - providing a challenging complication !

Exploring the Virtual Cell at ISU

Virtual Cell projects elsewhere...

NCBI's Bookshelf - a great resource!


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…


So, this is Bioinformatics

What is it good for?

Just a few examples…


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).



Finding homologs of "new" human genes



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



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



Molecular Recognition:Analyzing & Predicting Macromolecular

Interfaces (in DNA, RNA & protein complexes)

Drena Dobbs, GDCBJae-Hyung LeeMichael TerribiliniJeff SanderPete Zaback

Vasant Honavar, Com SFeihong WuCornelia CarageaFadi TowficJivo Sinapov

Robert Jernigan, BBMBTaner SenAndrzej Kloczkowski

Kai-Ming Ho, Physics


Designing Zinc Finger DNA-binding Proteins to Recognize Specific Sites in Genomic DNA

Drena Dobbs, GDCBJeff SanderPete Zaback

Dan Voytas, GDCBFengli Fu

Les Miller, ComSVasant Honavar, ComS

Keith Joung, Harvard


Structure & Function of Human Telomerase:

Predicting structure & functional sites in a clinically important but "recalcitrant" RNP

www.intl-pag.org/

Cell Biologist: Biochemist: Imagined structure:

Lingner et al (1997) Science 276: 561-567.www.chemicon.com

How would a systems biologist study telomerase?


SUMMARY:#1- What is

Bioinformatics?


#2- Biological Databases

Xiong: Chp 2

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


What is a Database?

Duh!!

OK: skip we'll skip that!


Types of Databases

3 Major types of electronic databases:

1- Flat files - simple text files• no organization to facilitate retrieval

2- Relational - data organized as tables ("relations")

• shared features among tables allows rapid search

3- Object-oriented - data organized as "objects"• objects associated hierarchically


Biological Databases

Currently - all 3 types, but MANY flat files

What are goals of biological databases?

1- Information retrieval

2- Knowledge discovery

Important issue: Interconnectivity


Types of Biological Databases

1- Primary• "simple" archives of sequences, structures, images,

etc.

• raw data, minimal annotations, not always well

curated!

2- Secondary• enhanced with more complete annotation of

sequences, structures, images, etc.

• usually curated!

3- Specialized• focused on a particular research interest or organism

• usually - not always - highly curated


Examples of Biological Databases

1- Primary

• DNA sequences

• GenBank - US

• European Molecular Biology Lab - EMBL

• DNA Data Bank of Japan - DDBI

• Structures (Protein, DNA, RNA)

• PDB - Protein Data Bank

• NDB - Nucleic Acid Databank


Examples of Biological Databases

2- Secondary

• Protein sequences

• Swiss-Prot, TreEMBL, PIR

• these recently combined into UniProt

3- Specialized

• Species-specific (or "taxonomic"

specific)

• Flybase, WormBase, AceDB, PlantDB

• Molecule-specific,disease-specific


Pitfalls of Biological Databases

• Errors! &• Lack of documentation re: quality or reliability of data• Limited mechanisms for "data checking" or preventing propagation of errors (esp. annotation errors!!)• Redundancy• Inconsistency• Incompatibility (format, terminology, data types, etc.)


Information Retrieval from Biological Databases

2 most popular retrieval systems:

• ENTREZ - NCBI

• will use a LOT - Introduced in Lab 1

• SRS - Sequence Retrieval Systems - EBI

• will use less, similar to ENTREZ

Both:

• Provide access to multiple databases

• Allow complex queries


Web Resources: Bioinformatics & Computational Biology

• Wikipedia: Bioinformatics

• NCBI - National Center for Biotechnology Information• ISCB - International Society for Computational Biology• JCB - Jena Center for Bioinformatics• UBC - Bioinformatics Links Directory• UWa - BioMolecules• Pitt - OBRC Online Bioinformatics Resources Collection

• ISU - Bioinformatics Resources - Andrea Dinkelman• ISU - YABI = "Yet Another Bioinformatics Index"

(from BCB Lab at ISU)


ISU Resources & Experts

ISU Research Centers & Graduate Training Programs:

• BCB Lab - (Student-Led Consulting & Resources)• BCB - Bioinformatics & Computational Biology• LH Baker Center - Bioinformatics & Biological Statistics• CIAG - Center for Integrated Animal Genomics• CILD - Computational Intelligence, Learning & Discovery• NSF IGERT Training Grant - Computational Molecular

Biology

ISU Facilities:

• Biotechnology - Instrumentation Facilities• PSI - Plant Sciences Institute • PSI Centers


SUMMARY:#2- Biological Databases

BEWARE!

8/22/07bcb 444/544 f07 isu dobbs #2 - biological databases1 finish: lecture 1- what is...

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