Bioinformatics

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Bioinformatics
- Science Honors Program - Computer Modeling and
Visualization in Chemistry

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What is Bioinformatics?

• Its at the intersection of biotechnology and
  computer science, to analyze the enormous amount
  of sequence and structural data that we have
  generated over the past decades.
• Computational tools to mine this enormous
  amount of data.

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Bioinformatics is multidisciplinary
Mathematics/computer science
Genomics

Molecular biology Biomedicine
Bioinformatics
Biophysics
Ethical, legal, and social implications
Molecular evolution
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• Biological data
• Huge data sets
• Complexity of biological systems

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What are we trying to Find out?
KEGG Kyoto Encyclopedia of Genes and Genomes.
A grand challenge in the post genomic era is a
complete computer representation of the cell and
the organism, which will enable computational
prediction of higher-level complexity of cellular
processes and organism behaviors from genomic
information. http//www.genome.jp/kegg/
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Where Does the Data Come From?

• Primary Protein Structure Determination a
  variety of chemical techniques
• Nucleic Acid Sequencing
• PCR (polymerase chain reaction)
• 3D Structure
• X-Ray Crystallography
• Nuclear Magnetic Resonance (NMR)

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Biological information From genes to proteins
Gene
DNA
Transcription
genomics molecular biology
RNA
Translation
structural biology biophysics
Protein
Protein folding
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Eukaryotic Genome DNA
Structure
Nucleotides (bases) Adenine (A) Cytosine
(C) Guanine (G) Thymine (T)
Sequence data Strings of letters
triplet codons genetic code
20 amino acids (A, L, V, S etc.)
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Three-dimensional protein structure atomic
coordinates in 3D space
Measured in Angstrom
Conversion into metric measurement Unit Angstrom
x 10-8 cm x 0.1 nm
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Proteins Prediction of biochemical function

• Relationships between
• DNA or amino acid
• sequence 3D structure
  protein function
• Use of this knowledge for prediction of function,
  molecular modelling, and design (e.g., new
  therapies)

CGCCAGCTGGACGGGCACACCATGAGGCTGCTGACCCTCCTGGGCCTTCT
G TDQAAFDTNIVTLTRFVMEQGRKARGTGEMTQLLNSLCTAVKAI
STAVRKAGIAHLYGIAGSTNVTGDQVKKLDVLSNDLVINVLKSSFATCVL
VTEEDKNAIIVEPEKRGKYVVCFDPLDGSSNIDCLVSIGTIFGIYRKNST
DEPSEKDALQPGRNLVAAGYALYGSATML
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DNA Sequence Gene Protein
Sequence Function
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Sequence Databases

• Protein Sequences
• ExPASy Molecular Biology Server (SWISS-PROT)
  http//expasy.ch
• Protein Information Resource (PIR)
  http//pir.georgetown.edu
• Protein Research Foundation (PRF)
  http//www.prf.or.jp/en
• NR from NCBI www.ncbi.nlm.nih.gov
• OMIM Online Mendelian Inheritance in Man.
  Genetic diseases http//www.ncbi.nlm.nih.gov/
  entrez/query.fcgi?dbOMIM

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Other Databases

• GeneBank (Nucleotide) www.ncbi.nlm.nih.gov/Ge
  nbank
• NCBI Entrez, an integrated, text-based search and
  retrieval system used at NCBI for the major
  databases, including PubMed, Nucleotide and
  Protein Sequences, Protein Structures, Complete
  Genomes, Taxonomy, and others.
  http//www.ncbi.nlm.nih.gov/gquery/gquery.fcgi\
• PDB Protein Databank. Protein Structures.
  www.rcsb.org/pdb
• KEGG Kyoto Encyclopedia of Genes and Genomes
  http//www.genome.jp
• PubMed Literature References
  http//www.ncbi.nlm.nih.gov/entrez/query.fcgi?dbP
  ubMed
• NCBI primers bottom of page. This page has
  education resources. http//www.ncbi.nih.gov/
  Education

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Genome sequencing and analysis (genomics)
Genomics generates a vast amount of DNA sequence
data. Sophisticated algorithms are used to
predict gene regions. Only 3 of the vertebrate
genome codes for proteins.

• Genbank hold sequences from over 800 organisms.
  There are currently 113 complete genomes.
• The completion of a "working draft" of the human
  genome was announced in June 2001.
• Estimates of 38 - 120,000 genes (40, 000)

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Explore the following databases

• KEGG Kyoto Encyclopedia of Genes and Genomes
• Main Map http//www.genome.jp/kegg/pathway/map/m
  ap01100.html
• Main Page http//www.genome.jp/kegg/
• Genbank
• What is it? An annotated collection of all
  publicly available DNA sequences
• www.ncbi.nlm.nih.gov/Genbank
• PDB The Protein Databank
• What is it?A database of 3D structures of
  proteins (and some DNA or other molecules)
• www.rcsb.org/pdb

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What is homology?

• Homology common ancestry
• Why homology
• much easier to get a DNA or protein sequence than
  to experimentally determine structure or function
  of a biological molecule
• Rapid expansion of databases of sequences (DNA,
  protein, RNA) far greater than structural or
  functional databases.
• Develop computational methods to infer
  biologically relevant information from sequence
  alone.
• E.g., If know that two protein sequences are
  homologous, then we can infer that the two
  proteins may share the same protein fold, active
  site, and even function.
• In simple terms, much of todays class involves
  Darwinian evolution discussed at the microscopic
  genetic level.

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Stochastic Evolutionary Forces Act on Genomes

• Forces that alter a genetic sequence
• Random Mutation
• Natural Selection
• Genetic Drift
• Comparison of protein sequences can be used to
  infer evolutionary events that happened possibly
  billions of years ago.
• If find a homologous protein sequence to a given
  protein, often from very divergent organisms,
  then a common ancestral protein must have
  existed.
• Homologous protein share similar 3-D structure.
• Homologous proteins can have seemingly very
  different sequences.

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EvolutionaryTree
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Modes of Evolution.
Globin Family Evolution
Orthologous differ because of
speciation Paralogous differ because of gene
duplication
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Orthologous Sequences Cytochrome c Family
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Sequence Alignment
Optimal alignments of human myoglobin and human
hemoglobin (alpha chain) Algorithms
Needleman-Wunsch, Smith-Waterman Heuristic
Algorithms Pairwise Alignment
BLAST (www.ncbi.nlm.nih.gov) Multiple
Sequence Alignment ClustalW
(www.ebi.ac.uk) PSI-BLAST
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Structural Alignment
Comparison of dihydrofolate reductases from
Mycobacterium tuberculosis (1DF7) and Esherichia
coli (1DRE) with 41 sequence identity. After
the sequences of these two proteins were aligned,
the alpha-carbons of the backbone were
structurally aligned.
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Amino Acid Similarity Matrix
A similarity matrix incorporates information
about the likelihood that one amino-acid will be
mutated into another over evolutionary time.
Shown here is the PAM250 matrix. Another common
one is BLOSUM50
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Sequence AlignmentNeedleman-Wunsch
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Global Alignment
Needleman-Wunsch Algorithm
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Global Alignment Example
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Local Alignment
Smith-Waterman Algorithm
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Local Alignment Example
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Multliple Sequence Alignment
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Gene Doping
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Gene Therapy
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Gene Doped Mice
HEAVY WORKOUT. This rat, injected with a
muscle-enhancing gene, boosts its strength by
lugging weights up a ladder. http//www.sciencene
ws.org/articles/20041030/bob9.asp