Bioinformatics

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Bioinformatics

• A short introduction

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What is Bioinformatics?

• Precise definition is a matter of debate.
• Computational Biology
• Computational Molecular Biology
• Development of databases to store manipulate
  genetic information
• Not usually used to describe biology above the
  cellular level

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Molecular Biology Background

• The central concepts are not tricky
• Terminology can be a problem
• Look it up!

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DNA
Deoxyribonucleic Acid 4 letter alphabet A,T,C,G
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Transcription
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Amino Acids
20 Letter Alphabet
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Proteins

• Sequences of amino acids
• Primary, Secondary Tertiary structure
• No easy way to predict 3D structure from
  sequence.
• Compare with known sequences
• Modular nature
• Substitutions

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Protein Functions

• Enzymatic catalysis (helping control molecular
  reaction pathways)
• Structural support
• Generation of motion
• Reception of signals between cells
• Transduction of forces (light, pressure, etc)
  into chemical signals
• Many more their functions combine within a cell
  to create a living apparatus

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What is a Gene?

• For every 2 biologists, you get 3 definitions
• A DNA sequence that encodes a heritable
  trait.
• The unit of heredity
• Is it an abstract concept, or something you can
  isolate in a tube or print on your screen?
• Classic vs.. modern understanding of
  molecular biology

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Clustering (Phylogenetics)
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Molecular Biology Summary

• DNA 4 letter alphabet
• Sequences of 3 letters code for an amino acid.
• 4 cubed is 64 and there are only 20 amino acids,
  so there are multiple codons for each amino acid.
• Amino acid sequences are peptides (short) or
  proteins (long gt50).

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Complications

• Start stop sequences
• Noncoding regions
• Introns exons
• Promoter regulatory regions
• Not always present
• No straightforward method to accurately predict

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What is Bioinformatics?

• The study of two information flows in molecular
  biology
• The central dogma of molecular biology.
• DNA sequences are transcribed into mRNA sequences
  that are translated into proteins.
• Protein sequences fold into 3D structures that
  have functions.
• Bioinformatic applications in this first domain
  address any stage of the central dogma.

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What is Bioinformatics?

• Bioinformatic applications in this first domain
  address any stage of the central dogma.
• Sequence databases (GenBank)
• Structure databases (PDB)
• Sequence alignment
• Database searching
• Predictive Methods

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What is Bioinformatics?

• Assisting the scientific method.
• Hypotheses about biological activity are created.
• Experiments are designed to test hypotheses.
• Results are evaluated and may extend or modify
  the hypotheses.
• Bioinformatic applications in this second domain
  address any stage of the scientific method.

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What is Bioinformatics?

• Bioinformatic applications in this second domain
  address any stage of the scientific method.
• Systems which generate hypotheses
• Design experiments
• Store organize data from experiments in
  databases
• Test compatibility of data with models
• Modify hypotheses

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Why Bioinformatics?

• Explosion of data in Biology
• DNA sequencing
• PCR amplification
• Mass spectrometry
• X-Ray crystallography
• Microarrays

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Large Databases

• Once upon a time, GenBank sent out sequence
  updates on CD-ROM disks a few times per year.
• Now GenBank is over 70 Gigabytes
• (20 billion bases)
• Most biocomputing sites update their copy of
  GenBank every day over the internet.
• Scientists access GenBank directly over the Web

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The Human Genome Project

• Started in early 1990s
• Sequence 3 billion base pairs.
• Was not expected to be complete before 2005
• April 2003, 99 complete

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Raw Genome Data
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Mass spectrometry

• Samples are bombarded with electrons resulting
  in the acquisition of a positive charge.
• The samples are accelerated and subjected to a
  magnetic field. Samples will interact with the
  receptor based on their mass.
• The masses are then interpreted to infer the
  amino acid sequence.

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ProteinIdentification
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Microarrays
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Microarrays
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Bioinformatics Tools

• GenBank - genes, proteins, genomes
• Similarity Search tools BLAST, VAST
• Alignment CLUSTAL
• Protein families Pfam, ProDom
• Protein Structures PDB, RasMol
• Whole Genomes UCSC, Entrez Genomes
• Human Mutations OMIM
• Biochemical Pathways KEGG
• Integrated tools Biology Workbench, BCM
  SearchLauncher

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Sequence Alignments

• Global vs. Local
• Substitutions/Deletions/Insertions
• Dynamic Programming
• Optimal path can be found by incrementing the
  optimal subpaths
• Substitution scoring
• PAM250, BLOSUM62
• Performed tens of thousands of times per day.

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Global vs. Local Alignments
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PAM250 (Point accepted mutation)
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BLAST Algorithm
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Databases for use with Blast

• nr Nonredundant GeneBank
• est Expressed Sequence Tags
• sts Sequence tagged sites
• gss Genome survey sequences
• more

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GenBank Sections

• In addition to DNA sequences of genes GenBank
  has a number of other sections including
• Protein sequences (translated from DNA)
• Short RNA fragments (ESTs)
• Cancer Genome Anatomy Project (CGAP) gene
  expression profiles of normal, pre-cancer, and
  cancer cells from a wide variety of tissue types
• Single Nucleotide Polymorphisms (SNPs) which
  represent genetic variations in the human
  population
• Online Mendelian Inheritance in Man (OMIM) a
  database of human genetic disorders

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Entrez Databases contain more than just DNA
protein sequences
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VAST

• Vector Alignment Search Tool
• Protein structure neighbors are determined by
  direct comparison of 3D protein structures.
• Each of the more than 87,804 domains in MMDB is
  compared to every other one.

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Entrez/GenBank

• National Center for Biological Information (NCBI)
• Visit
• Blast for
• GATGCCATAGAGCTGTAGTCGTACCCT

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Research Ideas

• Sequence search algorithms
• Structure search algorithms
• Predictive algorithms
• Database methodologies
• Structure visualization
• Second Domain Apps

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Bibliography

• Bioinformatics, A Practical Guide to the Analysis
  of Genes Protiens, Baxevanis Ouellette,
  Wiley, 2001.
• Structural Bioinformatics, Bourne Weissig,
  Wiley, 2003.
• BioTeach, http//www.bioteach.ubc.ca/index.htm
• ASM Bioinformatics workshop, http//www.med.nyu.ed
  u/rcr/ASM/
• Bioinformatics in Support of Molecular Medicine,
  http//smi-web.stanford.edu/pubs/SM
  I_Abstracts/SMI-98-0731.html
• More links at http//www.cs.utsa.edu/ebrookes/cs7
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