a modern introduction to molecular biologychazelle/courses/bib/dnalecture.pdf1 a modern introduction...
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A modern introduction toMolecular biology
Lecture 1, COS/MOL 455/551, Fall 2006
Complexity and scales of organization
~1A0 Time: 10-6 sec. to 109 yrs.
~1 m
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Diversity of forms
Diversity of forms
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Prokaryotes Eukaryotes
Universal phylogenetic tree
Woese et al.
Universal phylogenetic tree
Woese et al.
4
Prokaryote vs. Eukaryote
Brown, Genomes
Epistemology
5
Understanding:
• Morphology• Constituents• Chemical transformations• Physiology• Growth• Evolution• Information processing
E. coli
Darnell, Molecular Cell Biology
Understanding:
• Morphology• Constituents• Chemical transformations• Physiology• Growth• Evolution• Information processing
Nucleic Acids
Proteins
Lipids
Salts &Small molecules
Lehninger, Principles of Biochemistry
6
Understanding:
• Morphology• Constituents• Chemical transformations• Physiology• Growth• Evolution• Information processing
Metabolism
Darnell, Molecular Cell Biology
Understanding:
• Morphology• Constituents• Chemical transformations• Physiology• Growth• Evolution• Information processing
Mitochondrion
Darnell, Molecular Cell Biology
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Understanding:
• Morphology• Constituents• Chemical transformations• Physiology• Growth• Evolution• Information processing
Development
Darnell, Molecular Cell Biology
Understanding:
• Morphology• Constituents• Chemical transformations• Physiology• Growth• Evolution• Information processing
Woese et al.
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Understanding:
• Morphology• Constituents• Chemical transformations• Physiology• Growth• Evolution• Information processing
DNA RNA Protein
Lehninger, Principles of Biochemistry
Structure & dynamics of networks
Protein-protein interactions
Genetic interactionsRegulatory interactions
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Lehninger, Principles of Biochemistry
DNA RNA Protein
Information flow:Central Dogma
Genome:
The entire hereditaryinformation contentof an organism
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Context (DNA)
Lehninger, Principles of Biochemistry
Darnell, Molecular Cell Biology
11
Chromatin fiber (30 nm)
DNA
Nucleosomes
Histones
Chromosome
Lehninger, Principles of Biochemistry
3.4 nm
Minor groove Major groove
The Double Helix
Brown, Genomes
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DNA backbone
Sugar
Phosphate
Base
Brown, Genomes
BASES
A
C
G
T
Brown, Genomes
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Darnell, Molecular Cell Biology
RNA
Lehninger, Principles of Biochemistry
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Proteins
Amino acids
H3N—C—H
COO
R
+
Lehninger, Principles of Biochemistry
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Peptide bond
Polypeptide
Stryer, Biochemistry
Primary TertiarySecondary Quaternary
Amino acids α−helix Polypeptidechain
Assembledsubunits
Protein representations
Lehninger, Principles of Biochemistry
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DNA RNA Protein
Central Dogma
Lehninger, Principles of Biochemistry
DNA RNA
ACTG
ACUG
Transcription
CODE:
Lehninger, Principles of Biochemistry
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Promoter Coding region
Bacterial chromosome (5 x 106 bp)
Promoter
RNA Polymerase
Coding region
Bacterial chromosome (5 x 106 bp)
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Promoter
RNA Polymerase
Coding region
Bacterial chromosome (5 x 106 bp)
Promoter
RNA Polymerase
mRNA
Coding region
ACTG
ACUG
Bacterial chromosome (5 x 106 bp)
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Promoter
RNA Polymerase
mRNA
Coding region
ACTG
ACUG
Bacterial chromosome (5 x 106 bp)
RNA Protein
Translation
CODE:ACUG
A C D EF G H IK L M NP Q R ST V W Y
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AUG = methionine/startUUA = LeucineUUG = Leucine
UAA = StopUAG = StopUGA = Stop...
The Genetic Code
Stryer, Biochemistry
GATCTGGAATATACGTACCCATTGAGTACATACGCACTGCTAGACCTTATATGCATGGGTAACTCATGTATGCGTGAC5’ 3’
GACCUUAUAUGCAUGGGUAACUCAUGUAUGCGUGAC5’
Peptide1: Met—Gly—Asn—Ser—Cys—Met—Arg…..
Peptide2: Met—His—Gly—STOP
The importance ofreading frame (register)
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Brown, Genomes
Initiation of translation
Watson, Recombinant DNA
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mRNA
Promoter
RNA Polymerase
Coding region
polypeptide
Ribosome
Coupled transcription/translation (bacteria)
Translation in Proks. vs. Euks.
Watson, Recombinant DNA
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α−Tropomyosin mRNA splicing
Watson, Recombinant DNA
DNA RNA Protein
Interactions
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DNA RNA Protein
Interactions
DNA RNA
Protein
Prokaryote
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DNA RNA
Protein
Eukaryote
DNA RNA
Protein
Eukaryote
Stimulus
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DNA RNA
Protein
Eukaryote
Stimulus
DNA RNA
Protein
Eukaryote
Stimulus
Stim
ulus
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DNA RNA
Protein
StimulusSt
imul
us
Intracellular networks
DNA RNA
Protein
fn
DNA RNA
Protein
fn
DNA RNA
Protein
fn
DNA RNA
Protein
fn
DNA RNA
Protein
fn
DNA RNA
Protein
fn
Network of cells
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DNA RNA
Protein
Stimulus
Stim
ulus
DNA RNA
Protein
fn
DNA RNA
Protein
fn
DNA RNA
Protein
fn
DNA RNA
Protein
fn
DNA RNA
Protein
fn
DNA RNA
Protein
fn
Higher-level organization
Cells Network of cells Organism
DNA RNA
Protein
fn
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DNA RNA
Protein
fn
DNA RNA
Protein
fn
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DNA RNA
Protein
fn
DNA RNA
Protein
fn
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DNA RNA
Protein
fn
fn
Scale of observations
~1011 sequence comparisons~107 observations
~108 possible interactions
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Technology Analysis
K-means clusteringIteration 1
Iteration 2
0) Randomly seed vectors1) Assign closest points to
each vector.2) Calculate new centers
for each vector.3) Iterate back to (2) until
vectors converge.
0 5 10 15 20 25 30 350
0.05
0.1
0.15
0.2
0.25
K = 20
P = 10-11
Eisen et al. Davidson et al.
Boone et al. O’dell et al.
Models