Some Biology That Computer Scientists Need for Bioinformatics

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Some Biology That Computer Scientists Need for
Bioinformatics
Lenwood S. Heath Virginia Tech Blacksburg, VA
24061 heath_at_cs.vt.edu
University of Maryland December 14, 2001
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Overview

• Some Molecular Biology and Genomics
• Language of the New Biology
• Existing bioinformatics tools
• Bioinformatics challenges
• Bioinformatics at Virginia Tech

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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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Transcription and Translation
Transcription
Translation
DNA
mRNA
Protein
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Elaborating Cellular Function
Regulation
Degradation
Transcription
Translation
DNA
mRNA
Protein
(Genetic Code)
Reverse Transcription

• Functions
• Structure
• Catalyze chemical reactions
• Respond to environment

Thousands of Genes!
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Chromosomes

• Long molecules of DNA 104 to 108 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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DNA Strand
2-deoxyribose (sugar)
5 End
3 End
C
T
C
A
A
T
T
G
A
G
C
G
Bases
A (adenine) complements T (thymine)
C (cytosine) complements G (guanine)
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Complementary DNA Strands
C
T
C
A
A
T
T
G
A
G
C
G
T
G
A
G
C
C
T
T
A
A
C
G
C
C
C
A
T
T
T
A
A
G
G
G
T
T
T
G
G
G
A
A
A
C
C
C
Double-Stranded DNA
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RNA Strand
Ribose (sugar)
5 End
3 End
C
U
C
A
A
U
U
G
A
G
C
G
Bases
U (uracil) replaces T (thymine)
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Transcription of DNA to mRNA
Coding DNA Strand
C
C
C
A
T
T
T
A
A
T
T
T
G
G
G
A
A
A
C
C
C
Template DNA Strand
mRNA Strand
C
U
C
A
A
U
U
G
A
G
C
G
T
G
A
G
C
C
T
T
A
A
C
G
Template DNA Strand
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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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Genetic Code
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Translation to a Protein
mRNA Strand
C
U
C
A
A
U
U
G
A
G
C
G
Arginine
Histidine
Alanine
Phenylalanine
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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Transcription and Translation
Transcription
Translation
DNA
mRNA
Protein
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Transcription of DNA to mRNA
Coding DNA Strand
C
C
C
A
T
T
T
A
A
T
T
T
G
G
G
A
A
A
C
C
C
Template DNA Strand
mRNA Strand
C
U
C
A
A
U
U
G
A
G
C
G
T
G
A
G
C
C
T
T
A
A
C
G
Template DNA Strand
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Translation to a Protein
mRNA Strand
C
U
C
A
A
U
U
G
A
G
C
G
Arginine
Histidine
Alanine
Phenylalanine
Nascent Polypeptide Amino Acids Bound Together
by Peptide Bonds
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Cells 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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II. The Language of the New Biology
A new language has been created. Words in the
language that are useful for todays talks.
Genomics
Functional Genomics Proteomics
cDNA Microarrays
Global Gene Expression Patterns
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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.

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Genome Sequencing Projects

• Drosophila
• Yeast
• Mouse
• Rat
• Arabidopsis
• Human
• Microbes

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Drosophila Genome
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Functional Genomics

• The biological role of individual genes.
• Mechanisms underlying the regulation of their
  expression.
• Regulatory interactions among them .

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Glycolysis, Citric Acid Cycle, and Related
Metabolic Processes
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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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Gene ExpressionControl Points
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Responses to Environmental Signals
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Intracellular Decision Making
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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

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Flow of a Microarray Experiment
Replication and Randomization
PCR
Select cDNAs
Robotic Printing
Test of Hypotheses
Reverse Transcription and Fluorescent Labeling
Extract RNA
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Relative Abundance Detection
Detection
Treatment
Control
1
2
1
2
1
2
2
3
1
3
3
3
Emission
Excitation
Mix
1
2
3
1
2
3
Spots (Sequences affixed to slide)
Hybridization
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Gene Expression Varies
Cy5 to Cy3 ratios
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III. Existing Computational Tools in
Bioinformatics

• Sequence similarity
• Multiple sequence alignments
• Database searching
• Evolutionary (phylogenetic) tree construction
• Sequence assemblers
• Gene finders

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Existing Biological Databases

• Molecular Sequences Genomic DNA, mRNA, ESTs,
  proteins
• Protein domains, motifs, or blocks
• Protein families
• Genomes
• Nomenclature and ontologies
• Biological literature

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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

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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)

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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

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Nupotato

• Potatoes originated in the Andes, where there are
  many varieties.
• Many varieties survive at high altitude in cold,
  dry conditions.
• Microarray technology can be used to investigate
  genes that are responsible for stress resistance
  and that are responsible for the production of
  nutrients.

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MURI

• Some microorganisms have the ability to survive
  drying out or intense radiation.
• Their genomes are just being sequenced.
• Using microarrays and proteomics, we will try to
  correlate computationally the genes in the
  genomes with the special traits of the
  microorganisms.
• We are currently using multiple genome analysis.

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Arabidopsis Genome Project

• Arabidopsis is a model higher plant.
• It is the first higher plant whose genome has
  been fully sequenced.
• Gene finder software has been used to identify
  putative genes.
• We are computationally mining the regulatory
  regions of these genes for promoter patterns.

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Barista

• Barista serves Expresso!
• Software development team across projects to
  minimize duplication of effort.
• Work with Linux, Perl, C, Python, cvs, Apache,
  PHP,

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Virginia Bioinformatics Institute (VBI)

• Research institute based at Virginia Tech
• Established July 1, 2000, with 3 million
• Will occupy 2 building and have 100 employees
  in 4 years

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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