Introduction to Bioinformatics

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Introduction to Bioinformatics

• Lecture 1 part 1

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Reading (all on reserve in library)

• Hagen, J. The origins of bioinformatics .
  Nature Reviews. 1 231-236.
• Ardeshir, Bayat. 2002. Bioinformatics
  Science, medicine and the future. BMJ. 324
  1018-1022.

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Bioinformatics

• Combination of computer science, mathematics,
  physics, chemistry and biology
• Used to answer fundamental questions in the life
  sciences
• What are the evolutionary origins of this
  protein?
• What gene does this DNA sequence code for?
• What does this gene do?
• How does this enzyme/ribozyme work and what does
  it look like?
• When is this gene expressed?
• What genes are expressed before the onset of
  cancer?
• What drugs can be used to treat this disease?
• What mutations are responsible for this genetic
  disorder?

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Applications Human Insulin
Recombinant Insulin
Improvements
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Sequence and Structure Analysis

• Questions
• What are the evolutionary origins of this
  protein?
• What gene does this DNA sequence code for?
• What does this gene do?
• How does this enzyme/ribozyme work and what does
  it look like?
• Who was the responsible for publishing this
  information and how can I find out more?

• Types of Analyses
• Determine phylogeny (MSA and construction of
  phylogenetic trees)
• Predict gene locations (ORF Finder or other gene
  prediction software)
• Predict gene product function (Blast or FastA
  searches)
• Predict protein/nucleic acid structure and
  function (Protein Explorer)
• Literature Searches (PubMed and Galileo)

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Sequence and Structure Analysis

• Questions
• When is this gene expressed?
• What genes are expressed before the onset of
  cancer?
• What drugs can be used to treat this disease?
• What mutations are responsible for this genetic
  disorder?

• Types of Analyses
• Traditional Bioinformatics analyses
• Sequencing of genomes
• Microarray analysis
• Pharmacogenomics applications

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Significance to the World

• Locate mutations responsible for genetic
  diseases.
• Aids in the treatment and diagnosis of those
  diseases
• Pharmacogenomics
• Designer drugs and therapies
• Discover and exploit new enzymes
• Environmental clean-up
• Antibiotics and other chemotherapeutic agents
• Useful products

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http//www.d2ol.com/
Volunteer your computer to fight disease?
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Major Events in Molecular Biology History

• 1869 DNA discovered
• Johann Friedrich Mieschers nuclein
• 1941 Central Dogma revealed
• Beadle and Tatum
• 1950 Complementary Bases discovered
• Edwin Chargaff
• 1953 DNA is a double helix
• Watson, Crick and Franklin
• 1956Role of ribosomes
• George Emil Palade

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Major Events in the History of Molecular Biology

• 1950s
• The first protein sequenced
• Frederick Sanger
• Edman degradation
• Simplified Sangers method
• 1960s
• Ion exchange columns, chromatography and
  electrophoresis
• Sped up the process
• Pehr Edman
• Sequenatorautomated sequencing
• 1975 (Sanger)
• Dideoxy termination sequencing for DNA

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History of Bioinformatics

• From Computational Biology (early 60s) to
  Bioinformatics (80s)
• Discovery that macromolecules carry information
• Availability of computers that could crunch
  numbers
• Bioinformatics is information driven
• Large amounts of molecular data and computers to
  analyze the data became available in the 60s
• How can we use this data to address our many
  biological questions?
• Margaret Dayhoff (Bioinformatics Founder)
• Protein Information Resource database in 1980
• Algorithms to study protein sequences
• Tools to design and utilize sequence databases

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Dayhoffs Contributions
Dayhoff wrote FORTRAN programs to solve a
puzzle sequence assembly from weeks to minutes!
AVTALWGKVNVDEVG
VHLTPEEKS
AVTALWGKVNV
LVVYPWTQRF
GEALGRLLVVYP
PEEKSAVTA
KVNVDEVGGEALGR
These represent short segments of amino acid
sequences that make up hemoglobin.
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Dayhoffs Contributions
Dayhoff wrote FORTRAN programs to solve a
puzzle sequence assembly from weeks to minutes!
AVTALWGKVNVDEVG
VHLTPEEKS
LVVYPWTQRF
PEEKSAVTA
AVTALWGKVNV
GEALGRLLVVYP
KVNVDEVGGEALGR
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Dayhoffs Contributions
Dayhoff wrote FORTRAN programs to solve a
puzzle sequence assembly from weeks to minutes!
VHLTPEEKS
PEEKSAVTA
AVTALWGKVNV
AVTALWGKVNVDEVG
KVNVDEVGGEALGR
GEALGRLLVVYP
LVVYPWTQRF
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Dayhoffs Contributions
Dayhoff wrote FORTRAN programs to solve a
puzzle sequence assembly from weeks to minutes!
VHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRF

• Her programs were later added to automated
  sequencers.
• She also established the Atlas of Protein
  Sequence (65) and Structure (a book), which later
  became the PIR (80)
• The PIR allowed sequence comparison, which lead
  to molecular evolutionary biology (molecular
  phylogeny)

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Macromolecular Information

• Three concepts gain much attention in late 60s
  and 70s
• The genetic code
• How do genes code for proteins
• DNA and RNA sequencing became popular in the
  1970s
• Protein structure
• How do proteins fold into functional products?
• Christian Anfinsen discovered that denatured
  proteins often refold into their original
  structure?Protein structure CAN be Predicted!
• X-ray diffraction leads to X-ray crystallography
• Protein structures are predicted and more
  information is gathered on their exact function
  in a cell.
• Protein Evolution
• Zuckerkandl and Pauling?semantides
• Information carrying sequences can be used to
  measure change
• Amino acid substitutions occur at a constant
  rate?molecular clocks

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Development of Algorithms

• Phylogenetic Algorithm
• Complex mathematical formula used to determine
  sequence homology
• All possible ways a large number of sequences can
  be compared to one another.
• Fitch and Margoliash
• 1000 comparisonscomputer calculates the min.
  number of mutations to convert one sequence to
  another
• Needleman and Wunsch
• Elaborated on the original
• Dayhoff and Eck
• Took each possible amino acid change during
  protein evolution into account
• PAM and MDM matrices

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Summary of Bioinformatics Applications to Learn

• What can you do with a sequence?
• Determine Gene function
• BLAST queries (Chapter 2)
• Determine protein sequence and predict protein
  structure (Chapters 7 and 8)
• Plan site directed mutagenesis experiments to
  determine function
• Bioinformatics techniques required Designing
  Primers, mapping restriction sites, building
  contiguous sequences from sequence products
  (Chapter 1)
• Locate Genes
• ORF finder and pattern searching (Chapter 6)
• Determine Gene Evolutionary Origins
• Multiple Sequence Alignments, phylogenetic trees
  (Chapter 3, 4 and 5)
• Learn something about an organisms gene
  expression
• Gene expression (Microarray data) analysis
  (Chapter 6)

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Bioinformatics

• What can you tell from a sequence?

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Bioinformatics

• Genomics
• DNA Sequence
• Homology locations of genes and functional
  sites phylogeny mapping
• Infer function
• Transcriptomics
• mRNA sequence and structure
• Determine expression mechanisms via identifying
  alternative splicing regions
• Proteomics
• Amino acid Sequence and protein structure
• Predict structure
• Solve structure
• Infer function from structure