CS 598SS Probabilistic Methods in Biological Sequence Analysis

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CS 598SSProbabilistic Methods in Biological
Sequence Analysis

• Saurabh Sinha

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What is the course about?

• Bioinformatics / Computational Biology
• Algorithms for analyzing genomes
• Probabilistic methods

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What is the course format?

• Research course
• Lectures by instructor
• Student presentations of research papers
• 1 students per paper
• 2 papers in a session, typically
• Research project presentation
• 1-3 students per project
• 20 - 30 mins presentation at end of course.

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Grading

• Project 60
• Paper presentation 20
• Participation (including assignments or quizzes,
  if any) 20

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Expectations

• Programming skills (for the project)
• Basic exposure to probability theory
• Basic exposure to algorithm

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What you can do at the end of the course

• Start working on research projects in
  bioinformatics biological sequence analysis
• Use principled approaches, supported by
  probability theory, instead of ad hoc methods
• If project succeeds, publish a paper in
  bioinformatics
• Join me as a graduate advisee ?

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Administrative Details

• Instructor
• Saurabh Sinha
• Room 2122, Siebel Center
• Email sinhas_at_cs.uiuc.edu
• Class hrs Wed Fri, 1230pm-145pm, 1111SC
• Office hrs Thursdays, 2pm - 3pm, 2122SC
• CRN 46042
• Credits 4 graduate hrs
• Welcome to sit in, if not taking for credit

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Recommended books

• Not required, but recommended
• Biological Sequence Analysis Probabilistic
  Models of Proteins and Nucleic Acids
• -- Durbin, Eddy, Krogh, Mitchison
• Bioinformatics The Machine Learning Approach
• -- Baldi, Brunak

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Companion Course

• CS498-CXZ Algorithms in Bioinformatics (Fall
  2005)
• T/Th 1230pm 145pm
• http//sifaka.cs.uiuc.edu/course/498cxz05f/info.ht
  ml

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Why study bioinformatics?

• Molecular biology is the new frontier of 21st
  century science
• Computer science is the crown prince of 20th
  century engineering
• Bioinformatics is the application and development
  of computer science with the goal of supporting
  molecular biology

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Why study bioinformatics?

• Flood of data several Gigabytes of sequence, and
  gene expression data.
• Noise in the data
• Biological
• Experimental
• Algorithms needed to make discoveries
• Probabilistic methods
• Need for efficiency

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Why study bioinformatics?

• The big picture
• Human health and quality of life
• Fundamental science
• Billions of dollars being spent
• Health research gets the major chunk of the US
  Govts funds
• Fundamental health research is at the molecular
  level
• Molecular biology research increasingly a
  quantitative science

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Fundamental Science

• Recent issue of Science top 25 questions
• gtWhat Is the Universe Made Of?gtWhat is the
  Biological Basis of Consciousness?gtWhy Do Humans
  Have So Few Genes?gtTo What Extent Are Genetic
  Variation and Personal Health Linked?gtCan the
  Laws of Physics Be Unified?gtHow Much Can Human
  Life Span Be Extended?gtWhat Controls Organ
  Regeneration?gtHow Can a Skin Cell Become a Nerve
  Cell?gtHow Does a Single Somatic Cell Become a
  Whole Plant?gtHow Does Earth's Interior Work?gtAre
  We Alone in the Universe?gtHow and Where Did Life
  on Earth Arise?gtWhat Determines Species
  Diversity?gtWhat Genetic Changes Made Us Uniquely
  Human?gtHow Are Memories Stored and Retrieved?gtHow
  Did Cooperative Behavior Evolve?gtHow Will Big
  Pictures Emerge from a Sea of Biological
  Data?gtHow Far Can We Push Chemical
  Self-Assembly?gtWhat Are the Limits of
  Conventional Computing?gtCan We Selectively Shut
  Off Immune Responses?gtDo Deeper Principles
  Underlie Quantum Uncertainty and Nonlocality?gtIs
  an Effective HIV Vaccine Feasible?gtHow Hot Will
  the Greenhouse World Be?gtWhat Can Replace Cheap
  Oil -- and When?gtWill Malthus Continue to Be
  Wrong?

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• Let the fun begin

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Heredity and DNA

• Heredity children resemble parents
• Easy to see
• Hard to explain
• DNA discovered as the physical (molecular)
  carrier of hereditary information
• Watson Crick explain DNA structure in 1953.

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Life, Cells, Proteins

• The study of life ? the study of cells
• Cells are born, do their job, duplicate, die
• All these processes controlled by proteins

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Protein functions

• Enzymes (catalysts)
• Control chemical reactions in cell
• E.g., Aspirin inhibits an enzyme that produces
  the inflammation messenger
• Transfer of signals/molecules between and inside
  cells
• E.g., sensing of environment
• Regulate activity of genes

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DNA

• DNA is a molecule deoxyribonucleic acid
• Double helical structure (discovered by Watson,
  Crick Franklin)
• Chromosomes are densely coiled and packed DNA

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Chromosome
DNA
SOURCE http//www.microbe.org/espanol/news/human_
genome.asp
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The DNA Molecule
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G -- C A -- T T -- A G -- C C -- G G -- C T -- A
G -- C T -- A T -- A A -- T A -- T C -- G T -- A
?
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Base Nucleotide
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Protein

• Protein is a sequence or chain of amino-acids
• 20 possible amino acids
• The amino-acid sequence folds into a 3-D
  structure called protein

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Protein Structure
Protein
PNAS cover, courtesy Amie Boal
DNA
The DNA repair protein MutY (blue) bound to DNA
(purple).
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From DNA to Amino-acid sequence
Cell
SRChttp//www.biologycorner.com/resources/DNA-RNA
.gif
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From DNA to Protein In words

• DNA nucleotide sequence
• Alphabet size 4 (A,C,G,T)
• DNA ? mRNA (single stranded)
• Alphabet size 4 (A,C,G,U)
• mRNA ? amino acid sequence
• Alphabet size 20
• Amino acid sequence folds into 3-dimensional
  molecule called protein

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What about RNA ?

• RNA ribonucleic acid
• U instead of T
• Usually single stranded
• Has base-pairing capability
• Can form simple non-linear structures
• Life may have started with RNA

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Central Dogma

• Information flows from DNA to RNA to Protein
• Once information it has passed on to protein, it
  cannot come back to DNA

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DNA and genes

• DNA is a very long molecule
• If kept straight, will cover 5cm (!!) in human
  cell
• DNA in human has 3 billion base-pairs
• String of 3 billion characters !
• DNA harbors genes
• A gene is a substring of the DNA string
• A gene codes for a protein

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Genes code for proteins

• DNA ? mRNA ? protein can actually be written as
  Gene ? mRNA ? protein
• A gene is typically few hundred base-pairs (bp)
  long

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Transcription

• Process of making a single stranded mRNA using
  double stranded DNA as template
• Only genes are transcribed, not all DNA
• Gene has a transcription start site and a
  transcription stop site

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Step 1 From DNA to mRNA
Transcription
SOURCE http//academy.d20.co.edu/kadets/lundberg/
DNA_animations/rna.dcr
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Translation

• Process of making an amino acid sequence from
  (single stranded) mRNA
• Each triplet of bases translates into one amino
  acid
• Each such triplet is called codon
• The translation is basically a table lookup

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(No Transcript)
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The Genetic Code
SOURCE http//www.bioscience.org/atlases/genecode
/genecode.htm
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Step 2 mRNA to Amino acid sequence
Translation
SOURCE http//bioweb.uwlax.edu/GenWeb/Molecular/T
heory/Translation/translation.htm
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Gene structure
SOURCE http//www.wellcome.ac.uk/en/genome/thegen
ome/hg02b001.html
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Gene structure

• Exons and Introns
• Introns are spliced out, and are not part of
  mRNA
• Promoter (upstream) of gene

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Gene expression

• Process of making a protein from a gene as
  template
• Transcription, then translation
• Can be regulated

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Gene Regulation

• Chromosomal activation/deactivation
• Transcriptional regulation
• Splicing regulation
• mRNA degradation
• mRNA transport regulation
• Control of translation initiation
• Post-translational modification

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Transcriptional regulation
TRANSCRIPTION FACTOR

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Transcriptional regulation
TRANSCRIPTION FACTOR
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The importance of gene regulation
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Genetic regulatory network controlling the
development of the body plan of the sea urchin
embryo Davidson et al., Science,
295(5560)1669-1678.
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• That was the circuit responsible for
  development of the sea urchin embryo
• Nodes genes
• Switches gene regulation
• Change the switches and the circuit changes
• Gene regulation significance
• Development of an organism
• Functioning of the organism
• Evolution of organisms

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Genome

• The entire sequence of DNA in a cell
• All cells have the same genome
• All cells came from repeated duplications
  starting from initial cell (zygote)
• Human genome is 99.9 identical among individuals
• Human genome is 3 billion base-pairs (bp) long

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Genome features

• Genes
• Regulatory sequences
• The above two make up 5of human genome
• Whats the rest doing?
• We dont know for sure
• Annotating the genome
• Task of bioinformatics

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Some genome sizes
Organism Genome size (base pairs) Virus, Phage
F-X174 5387 - First sequenced genome Virus,
Phage ? 5104 Bacterium, Escherichia
coli 4106 Plant, Fritillary assyrica 131010
Largest known genome Fungus,Saccharomyces
cerevisiae 2107 Nematode, Caenorhabditis
elegans 8107 Insect, Drosophila
melanogaster 2108 Mammal, Homo
sapiens 3109 Note The DNA from a single human
cell has a length of 1.8m.
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Evolution

• A model/theory to explain the diversity of life
  forms
• Some aspects known, some not
• An active field of research in itself
• Bioinformatics deals with genomes, which are
  end-products of evolution. Hence bioinformatics
  cannot ignore the study of evolution

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endless forms most beautiful and most
wonderful - Charled Darwin
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Evolution

• All organisms share the genetic code
• Similar genes across species
• Probably had a common ancestor
• Genomes are a wonderful resource to trace back
  the history of life
• Got to be careful though -- the inferences may
  require clever techniques

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Evolution

• Lamarck, Darwin, Weissmann, Mendel

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Some mechanisms of evolution

• New or different genes
• Gene duplication new gene
• Gene mutation different gene
• New or different regulation of genes
• Switches change, therefore circuit changes, even
  though genes are same
• A difference of time scales