Transcript Some Biology that Computer Scientists Need for

Some Biology That Computer
Scientists Need for
Bioinformatics
Lenwood S. Heath
Virginia Tech
Blacksburg, VA 24061
[email protected]
University of Maryland
December 14, 2001
December 14, 2001
Slide 1
Overview
I.
Some Molecular Biology and Genomics
II. Language of the New Biology
III. Existing bioinformatics tools
IV. Bioinformatics challenges
V. Bioinformatics at Virginia Tech
December 14, 2001
Slide 2
I. Some Molecular Biology
• The instruction set for a cell is contained in its
chromosomes.
• Each chromosome is a long molecule called DNA.
• Each DNA molecule contains 100s or 1000s of genes.
• Each gene encodes a protein.
• A gene is transcribed to mRNA in the nucleus.
• An mRNA is translated to a protein on ribosomes.
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Slide 3
Transcription and Translation
Transcription
DNA
December 14, 2001
Translation
mRNA
Protein
Slide 4
Elaborating Cellular Function
Regulation
Degradation
Transcription
DNA
Translation
mRNA
(Genetic Code)
Protein
Reverse
Transcription
Thousands
of Genes!
December 14, 2001
Functions:
• Structure
• Catalyze chemical reactions
• Respond to environment
Slide 5
Chromosomes
• Long molecules of DNA: 10^4 to 10^8 base pairs
• 26 matched pairs in humans
• A gene is a subsequence of a chromosome that
encodes a protein.
• Proteins associated with cell function, structure,
and regulation.
• Only a fraction of the genes are in use at any
time.
• Every gene is present in every cell.
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Slide 6
DNA Strand
2’-deoxyribose (sugar)
5’ End
C
A
C
T
T
T
A
G
A
G
3’ End
C
G
Bases
A (adenine) complements T (thymine)
C (cytosine) complements G (guanine)
December 14, 2001
Slide 7
Complementary DNA Strands
C
A
C
T
T
T
A
G
A
G
C
G
G
T
G
A
A
A
T
C
T
C
G
C
C
A
C
T
T
T
A
G
A
G
C
G
G
T
G
A
A
A
T
C
T
C
G
C
Double-Stranded DNA
December 14, 2001
Slide 8
RNA Strand
Ribose (sugar)
5’ End
C
A
C
U
U
U
A
G
A
3’ End
G
C
G
Bases
U (uracil) replaces T (thymine)
December 14, 2001
Slide 9
Transcription of DNA to mRNA
Coding DNA Strand
C
A
C
T
T
T
A
G
A
G
C
G
G
T
G
A
A
A
T
C
T
C
G
C
Template DNA Strand
mRNA Strand
C
A
C
U
U
U
A
G
A
G
C
G
G
T
G
A
A
A
T
C
T
C
G
C
December 14, 2001
Template DNA Strand
Slide 10
Proteins and Amino Acids
• Protein is a large molecule that is a chain
of amino acids (100 to 5000).
• There are 20 common amino acids
(Alanine, Cysteine, …, Tyrosine)
• Three bases --- a codon --- suffice to
encode an amino acid.
• There are also START and STOP codons.
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Slide 11
Genetic Code
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Slide 12
Translation to a Protein
mRNA Strand
C
A
C
Histidine
U
U
U
Phenylalanine
A
G
A
Arginine
G
C
G
Alanine
Nascent Polypeptide: Amino Acids Bound Together by Peptide Bonds
Unlike DNA, proteins have three-dimensional
structure essential to protein function.
Protein folds to a three-dimensional shape that cannot
yet be predicted from the primary sequence.
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Slide 13
Transcription and Translation
Transcription
DNA
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Translation
mRNA
Protein
Slide 14
Transcription of DNA to mRNA
Coding DNA Strand
C
A
C
T
T
T
A
G
A
G
C
G
G
T
G
A
A
A
T
C
T
C
G
C
Template DNA Strand
mRNA Strand
C
A
C
U
U
U
A
G
A
G
C
G
G
T
G
A
A
A
T
C
T
C
G
C
December 14, 2001
Template DNA Strand
Slide 15
Translation to a Protein
mRNA Strand
C
A
C
Histidine
U
U
U
Phenylalanine
A
G
A
Arginine
G
C
G
Alanine
Nascent Polypeptide: Amino Acids Bound
Together by Peptide Bonds
December 14, 2001
Slide 16
Cell’s Fetch-Execute Cycle
• Stored Program: DNA, chromosomes, genes
• Fetch/Decode: RNA, ribosomes
• Execute Functions: Proteins --- oxygen
transport, cell structures, enzymes
• Inputs: Nutrients, environmental signals,
external proteins
• Outputs: Waste, response proteins, enzymes
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Slide 17
II. The Language of the New Biology
A new language has been created. Words in the
language that are useful for today’s talks.
Genomics
Functional Genomics
Proteomics
cDNA Microarrays
Global Gene Expression Patterns
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Slide 18
Genomics
• Discovery of genetic sequences and the ordering of
those sequences into
• individual genes;
• gene families;
• chromosomes.
• Identification of
• sequences that code for gene products/proteins;
• sequences that act as regulatory elements.
December 14, 2001
Slide 19
Genome Sequencing Projects
•
•
•
•
•
•
•
•
Drosophila
Yeast
Mouse
Rat
Arabidopsis
Human
Microbes
…
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Slide 20
Drosophila Genome
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Slide 21
Functional Genomics
• The biological role of individual genes.
• Mechanisms underlying the regulation of
their expression.
• Regulatory interactions among them .
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Slide 22
Glycolysis, Citric Acid Cycle, and
Related Metabolic Processes
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Slide 23
Gene Expression
• Only certain genes are “turned on” at any
particular time.
• When a gene is transcribed (copied to mRNA), it is
said to be expressed.
• The mRNA in a cell can be isolated. Its contents
give a snapshot of the genes currently being
expressed.
• Correlating gene expressions with conditions gives
hints into the dynamic functioning of the cell.
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Slide 24
Responses to Environmental Signals
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Slide 26
Intracellular Decision Making
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Slide 27
Microarray Technology
• In the past, gene expression and gene
interactions were examined known gene by
known gene, process by process.
• With microarray technology:
– Simultaneous examination of large groups
of genes and associated interactions
– Possible discovery of new cellular
mechanisms involving gene expression
December 14, 2001
Slide 28
Flow of a Microarray Experiment
PCR
Select cDNAs
Replication and
Randomization
Robotic Printing
Hypotheses
Identify Spots
Intensities
Statistics
Hybridization
Test of
Hypotheses
Extract RNA
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Clustering
Reverse
Transcription and
Fluorescent
Labeling
Data Mining, ILP
Slide 29
Relative Abundance
Detection
Detection
Treatment
1
1
1
Control
1
2
2
3
3
3
3
2
2
Mix
Spots: 1
2
(Sequences affixed to slide)
1
3
2
3
Hybridization
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Slide 30
Gene Expression Varies
Cy5 to Cy3 ratios
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Slide 31
III. Existing Computational
Tools in Bioinformatics
•
•
•
•
•
•
Sequence similarity
Multiple sequence alignments
Database searching
Evolutionary (phylogenetic) tree construction
Sequence assemblers
Gene finders
December 14, 2001
Slide 32
Existing Biological Databases
• Molecular Sequences: Genomic DNA,
mRNA, ESTs, proteins
• Protein domains, motifs, or blocks
• Protein families
• Genomes
• Nomenclature and ontologies
• Biological literature
December 14, 2001
Slide 33
IV. Challenges for Bioinformatics
• Analyzing and synthesizing complex
experimental data
• Representing and accessing vast quantities
of information
• Pattern matching
• Data mining --- whole genome analysis
• Gene discovery
• Function discovery
• Modeling the dynamics of cell function
December 14, 2001
Slide 34
V. Bioinformatics at Virginia Tech
Computer science interacts with the life sciences.
• Computer Science in Bioinformatics:
• Joint research with: plant biologists, microbial
biologists, biochemists, cell-cycle biologists, animal
scientists, crop scientists, statisticians.
• Projects: Expresso; Nupotato; MURI; Arabidopsis
Genome; Barista; Cell-Cycle Modeling
• Graduate option in bioinformatics
• Virginia Bioinformatics Institute (VBI)
December 14, 2001
Slide 35
Expresso: A Problem Solving Environment
(PSE) for Microarray Experiment Design
and Analysis
• Integration of design and procedures
• Integration of image analysis tools and statistical
analysis
• Data mining using inductive logic programming
(ILP)
• Closing the loop
• Integrating models
December 14, 2001
Slide 36
Getting Into Bioinformatics
• Learn some biology --- genetics, cell
biology
• Study computational (molecular) biology
• Get involved with bioinformatics
research in interdisciplinary teams
• Work with biologists to solve their
problems
December 14, 2001
Slide 42