Transcript Computational Biology - University of Missouri

Computational Biology
June 24, 2004
MUPGRET Workshop
Overview
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Math
Statistics
Computer Models
Bioinformatics
Math and Science
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Mathematics are an integral part of
science.
Used everyday by bench scientists to
perform experiments, interpret data,
and make predictions.
Math Examples
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Making solutions
Plotting graphs
Calculating area
Area calculations
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NIH Image Software
http://rsb.info.nih.gov/nihimage/Default.html
Allows you to measure length, width,
area, density on objects in a picture.
Free
Statistics and Science
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Necessity for analyzing datasets.
Experiment must be well designed to be
meaningful.
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Ex. replications and controls
Should know how you’ll analyze data
before you start the experiment.
Means, standard deviations, and linear
regression are often used.
Probability
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Tests the likelihood that something will
or will not occur.
Used extensively in everyday life.
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Las Vegas type gaming
Lotto
Insurance amortization
Decisions regarding medical treatment
Everyday examples
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Rolling the dice
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1 in 6 chance that you will roll a one with a
single die.
(1/6)2 = 1/36 chance you will roll snake
eyes.
Playing cards
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4 in 52 chance (1/13) of drawing an ace at
random from a deck.
What’s the chance of a full house?
Biology examples
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Punnett square
Nucleotide frequencies along a gene are
used to examine evolutionary forces.
Mutation rates
Testing limits and sample sizes for
transgenics.
DNA forensics
Computers
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Data
Data
Data
Data
Data
quality
storage
analysis
validation
manipulation
Barcode systems
The “ics”
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Genomics
Proteomics
Metabolomics
Bioinformatics
Bioinformatics
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Revolutionized our ability to do biology
in much the same way as PCR and
robotics changed the bench science.
“the computational branch of molecular
biology” (Bioinformatics for Dummies).
a merger of computer science and
biology (Introduction to Bioinformatics)
Before bioinformatics
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In vivo experiments
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In the living organism
In vitro experiments
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In a test tube
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Manhattan Project
Space Program
Human Genome Project
Progress towards the HGP
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1953-DNA structure
1975-Maxim and Gilbert DNA
sequencing
1977- First genome sequenced (x174)
1981-Human mitochondrial genome
sequenced
1984-Epstein Barr virus sequenced
Progress towards the HGP
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1990- Human genome project launched
1992-TIGR formed
1996-High resolution map of the human
genome
1998-C. elegans genome sequenced
1999-Drosophila genome sequenced
2000-Draft sequence of human genome
completed.
Bioinformatics
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Integration of computer science and
biology
Applied field
Inference
Connection
Prediction
The basics
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DNA sequence  protein sequence
protein sequence  protein structure
protein structure  protein function
Bioinformatics
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Computer simulation
Data management and retrieval
Pattern recognition
Artificial intelligence
Data management/retrieval
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Database design and implementation
Data entry tools
Distributed computing
Querying tools
www.mgdb.org
Pattern Recognition
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DNA sequence analysis
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www.ncbi.nlm.nih
Geneology
Disease diagnosis
Artificial intelligence
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Software learns from the data it is given
and modifies its programs to be more
efficient or to be more accurate.
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Proteomics software
Disease diagnostic imaging
Computer Science
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Algorithm-program that specifies how to
solve a problem
Data structure and information retrieval
Software engineering
The human side
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Curation
Annotation
Quality control design
Examples of utility
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Determining phylogenetic relationships
Sequence similarities
Protein structure prediction
Disease diagnosis
Pharmacogenomics
Detailed structure information
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Requires crystallization of the protein.
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Large amount of protein required.
Often time consuming.
Limiting step to high throughput.
Followed by X-ray crystallography or
NMR.
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Determines position of each atom in the
molecule.
A Rational Approach
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Christendat et al. 2000. Nat. Struct.
Biol. 7:903-908.
Determine structure of all proteins in
Methanobacterium
thermoautotrophicum.
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1871 ORFs
The dilemma
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Cell membrane is “semipermeable” and
comprised of phospholipids.
Only hydrophobic molecules can pass
through cell membranes.
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Conversely, no charged (polar) molecules.
Water can pass through membranes.
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Water is a polar molecule.
Aquaporin-1
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First water channel protein cloned.
Water travels through aquaporin rather
than phospholipid bilayer.
Water can pass through but protons
can’t.
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Membrane potential
Hydrogen gradients
Aquaporin
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But protons can move along a column
of water so how does aquaporin
prevent this?
Monomer has 269 aa with 6 membrane
spanning domains.
Heterotetramer is the functional
molecule.
Aquaporin
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Protein has a hourglass shape.
The narrowest place is 3.0 A wide (water is
2.8 A).
Passage is lined with hydrophobic aa that
help exclude other small charged molecules.
Predicts one water molecule passes through
at a time.
Hydrogen bond between molecules is
transferred to two asparagine molecules.
Fig. 6.11
Prions
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Proteins that can change shape.
And make other proteins change their
shape!
As number of changed proteins
increases a phenotype is observed.
Causal agent of mad cow disease,
scrapie in sheep and Creutzfeldt-Jakob
disease in humans.
Prions II
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Previously thought only nucleic acid
encoded changes caused disease.
Stanley Prusiner discovered prion’s
ability to change other protein’s
structure and won the Nobel Prize.
Sup35 is a prion-like protein in yeast.
Sup35
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Translation termination factor
Carboxyl end binds to the ribosomal
complex to terminate translation.
If Sup35 is converted to an alternate
conformation (infectious prion
conformation) the shape change
spreads throughout the cell and is
passed to daughter cells.
Sup35
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In prion conformation causes ribosomes
to read through stop codons altering
shape and function of proteins.
Fig. 6.13
Not adaptively advantageous so why is
it maintained?
Why?
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True et al. 2000. Nature 407: 477-483.
Reduced translation fidelity, extends
proteins.
Some of these are antibiotic resistant.
Could lead to stabilization of new
phenotype under correct environment.
Introduction to Bioinformatics
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www.oup.com/uk/lesk/bioinf