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2IF35: Formal Modelling in Cell Biology
Lambda switch in GINsim
Fall 2007
Mohammed El-Kebir
Koen Schuurmans
Monique Hendriks
Tim Muller
Outline
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Genetic toggle switch
GINsim
Bacteriophage
Lambda phage
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GINsim model
Comparison
Conclusion
Genetic toggle switch
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Two genes: b and c
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Promoters pb and pc
Resulting proteins: B and C
Transcription factors: A, B, C
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A promotes expression of gene b and c
B inhibits expression of gene c
C inhibits expression of gene b
GINsim
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GINsim is made for modeling genetic regulatory
networks
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Building blocks are genes, genes have
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Basal expression level
Maximal expression level
Genes can be connected with each other, for
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Activation
Inhibition
GINsim (ctn.)
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Genetic switch model:
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State space generation (a = 1, b = 0, c = 0):
GINsim (ctn.)
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Internally GINsim is based on petri-nets.
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It is possible to export the regulatory network as a petrinet
(PNML)
Unfortunately, exported PNMLs are incorrect
Every gene corresponds with a place
#Tokens in a place denote the expression level
Transitions are the various modi of the gene (inhibited,
activated, basal, etc.)
Bacteriophage
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Virus that only infects bacteria
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Etymology: eater of bacteria
A phage consists of:
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Head with DNA or RNA
Tail for attachment to cell membrane and penetration
Bacteriophage (ctn.)
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A bacteriophage may have a
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Lytic cycle
Virus keeps on reproducing, ultimately causing lysis of host cell
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Lysogenic cycle
DNA of phage is merged with DNA of host. Peaceful coexistence
with the host.
Lambda phage
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Lambda phage is a bacteriophage
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The choice of the cycle depends on the environment:
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Infects the E. coli bacterium
Has both a lytic and a lysogenic cycle
If the environment is not supporting the growth of more potential
hosts, then there is no reason to reproduce
If the environment is right for potential hosts, then reproduction
will result in more infected cells.
The choice is regulated by the lambda switch
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Extremely stable (transition to lytic growth once every 5000
years)
But upon environmental change: lytic growth
Lambda phage (cnt.)
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CII
Lysogenic cycle
cI
Prm CI2
Or3
CI
Or2
Pr
1.
3.
cIII
CIII
CII
Pre
cII
Or1
2.
CIPl
cro
4.
CII binds to promoter Pre
Gene cI is expressed
CI binds to PI
Gene cIII is expressed
Stabilization
1. CIII prevents destruction of CII
2. Dimerized CI binds to Or1 and Or2
prevents expression of cro and enhances expression of cI
Lambda phage (cnt.)
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Lytic cycle
cI
Cro
CroPr
2
Prm
Or3
Or2
Cro
cro
Pre
cII
Or1
1.
2.
3.
Pl
CII
CII degraded by protease before reaching Pre
In absence of CII Pr is weakly active
Gene cro is expressed
cIII
Stabilization
1. Dimer Cro2 binds to Or2 and Or1
prevents expression of cI and enhances expression of cro
Lambda phage (cnt.)
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Lambda switch
cI
Prm
Or3
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CII
Pr
Or2
cro
Pre
cII
Or1
[CII]  A
As soon as cI or cro is expressed, the switched is locked
(just like with the expression of b or c)
Comparison
Maude
PRISM
GINsim
Qualitative
Yes
Yes
Yes
Quantitative
No
Yes
No
Model checking
LTL
TPCTL
Path finding
Limitations
Purely
qualitative
State
explosion for
realistic
models
Only regulatory
genetic
networks