8/20/07bcb 444/544 f07 isu dobbs #1 - what is bioinformatics?1 lecture 1 what is bioinformatics?...

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


Introduction to Bioinformatics

Instructors: Drena Dobbs [email protected] Michael Terribilini [email protected] Jae-Hyung Lee [email protected]

TAs: Jeff Sander [email protected] Pete Zaback [email protected]

Lab: MBB 106, 4-4991

BCB 444/544


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!


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


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


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• Mount - good reference for both "biologists" and "computer scientists" - but a bit out of date; Online resources - include lists of applications with URLs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.


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


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


Assignment #1: Tell us about you

Due: Wed, Aug 22

1- Complete HW1_Aug20 for Drena


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


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)


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!


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


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



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*


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.


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"


• Where are the genes?• Which DNA sequences encode RNA?• Which genomic DNA is "junk"? • Which RNA sequences encode proteins?


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)?



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?)


We don't understand the protein folding code yet - but we try to engineer proteins anyway!



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


"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)


1st a complete bacterial genome, then yeast


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.



Modified from Eric Green

More recently? Pyro-sequencing454 sequencing http://www.454.com/$ 1000 genomes?


1st Draft Human Genome: "Finished" in 2001





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)


Public Sequencing:International Consortium





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…


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



• 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




• Rational drug design• RNA structure prediction• Protein structure prediction• Artificial life simulations• Artificial immunology • Computer security

YES




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


8/20/07bcb 444/544 f07 isu dobbs #1 - what is bioinformatics?1 lecture 1 what is bioinformatics?...

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