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Computational Biology
May 8, 2004MUPGRET Workshop
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Overview Math Statistics Computer Models Bioinformatics
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Math and Science Mathematics are an integral part of
science. Used everyday by bench scientists
to perform experiments, interpret data, and make predictions.
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Math Examples Making solutions Plotting graphs Calculating area
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Area calculations NIH Image Software http://rsb.info.nih.gov/nih-image/D
efault.html Allows you to measure length,
width, area, density on objects in a picture.
Free
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Statistics and Science Necessity for analyzing datasets. Experiment must be well designed
to be meaningful. 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.
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Probability Tests the likelihood that something
will or will not occur. Used extensively in everyday life.
Las Vegas type gaming Lotto Insurance amortization Decisions regarding medical
treatment
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Everyday examples Rolling the dice
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 4 in 52 chance (1/13) of drawing an
ace at random from a deck. What’s the chance of a full house?
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Biology examples Punnett square Nucleotide frequencies along a gene
are used to examine evolutionary forces.
Mutation rates Testing limits and sample sizes for
transgenics. DNA forensics
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Computers Data quality Data storage Data analysis Data validation Data manipulation
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Barcode systems
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The “ics” Genomics Proteomics Metabolomics Bioinformatics
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Bioinformatics 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)
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Before bioinformatics In vivo experiments
In the living organism In vitro experiments
In a test tube
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Manhattan Project Space Program Human Genome Project
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Progress towards the HGP 1953-DNA structure 1975-Maxim and Gilbert DNA
sequencing 1977- First genome sequenced
(x174) 1981-Human mitochondrial genome
sequenced 1984-Epstein Barr virus sequenced
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Progress towards the HGP 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.
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Bioinformatics Integration of computer science
and biology Applied field Inference Connection Prediction
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The basics DNA sequence protein sequence protein sequence protein
structure protein structure protein
function
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Bioinformatics Computer simulation Data management and retrieval Pattern recognition Artificial intelligence
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Data management/retrieval Database design and
implementation Data entry tools Distributed computing Querying tools
www.mgdb.org
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Pattern Recognition DNA sequence analysis
www.ncbi.nlm.nih Geneology Disease diagnosis
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Artificial intelligence Software learns from the data it is
given and modifies its programs to be more efficient or to be more accurate. Proteomics software Disease diagnostic imaging
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Computer Science Algorithm-program that specifies
how to solve a problem Data structure and information
retrieval Software engineering
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The human side Curation Annotation Quality control design
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Examples of utility Determining phylogenetic
relationships Sequence similarities Protein structure prediction Disease diagnosis Pharmacogenomics
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Detailed structure information Requires crystallization of the
protein. Large amount of protein required. Often time consuming. Limiting step to high throughput.
Followed by X-ray crystallography or NMR. Determines position of each atom in
the molecule.
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A Rational Approach Christendat et al. 2000. Nat.
Struct. Biol. 7:903-908. Determine structure of all proteins
in Methanobacterium thermoautotrophicum. 1871 ORFs
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The dilemma Cell membrane is “semipermeable”
and comprised of phospholipids. Only hydrophobic molecules can
pass through cell membranes. Conversely, no charged (polar)
molecules. Water can pass through membranes.
Water is a polar molecule.
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Aquaporin-1 First water channel protein cloned. Water travels through aquaporin
rather than phospholipid bilayer. Water can pass through but
protons can’t. Membrane potential Hydrogen gradients
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Aquaporin 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.
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Aquaporin 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
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Prions 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.
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Prions II 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.
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Sup35 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.
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Sup35 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?
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Why? 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.
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Introduction to Bioinformatics www.oup.com/uk/lesk/bioinf