pathway finding by reverse engineering based on simulation
DESCRIPTION
Pathway Finding by Reverse Engineering Based on Simulation. C.Y. Tang Department of Computer Science NTHU. Reverse Engineering (Computer Aided Engineering). VLSI CAD Communication Protocol Bio-X ?. Protocol Implementation. Key Issues. Formal Specification Relationship Exploring. - PowerPoint PPT PresentationTRANSCRIPT
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Pathway Finding by Reverse Engineering Based on
Simulation
C.Y. TangDepartment of Computer
ScienceNTHU
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Reverse Engineering (Computer Aided
Engineering)
VLSI CADCommunication ProtocolBio-X ?
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Protocol ImplementationCorret Spec. & Documentation
coding & debugging
test generation
code generation
pass?
Diagnostics
Error Reports
Product
Interoperability Testing
Program code test suite
Conformance Testing
test env. Yes
No
YesNo
Standard
Error Reports
Validation Model
SDLFormal Spec.
Read & Formal Specify
add assertions
Validate
pass?
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Key IssuesFormal SpecificationRelationship Exploring
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Bolouri, H., and Davidson, E. H. (2002). Modeling DNA sequence-based cis-regulatory gene networks. Dev. Biol. 246, 2–13. Brown, C. T., Rust, A. G., Clarke, P. J. C., Pan, Z., Schilstra, M. J., De Buysscher, T., Griffin, G., Wold, B. J., Cameron, R. A., Davidson, E. H., and Bolouri, H. (2002). New computational approaches for analysis of cis-regulatory networks. Dev. Biol. 246, 86–102.
Davidson, E. H., Rast, J. P., Oliveri, P., Ransick A., Calestani, C., Yuh, C.-H., Minokawa, T., Amore, G., Hinman, V., Arenas-Mena, C., Otim, O., Brown, C. T., Livi, C. B., Lee, P. Y., Revilla, R., Schilstra, M. J., Clarkes, P. J. C., Rust, A. G., Pan, Z., Arnone, M. I., Rowen, L., Cameron, R. A., McClay, D. R., Hood, L., and Bolouri, H. (2002). A provisional regulatory gene network for specification of endomesoderm in the sea urchin embryo. Dev. Biol. 246, 162–190. Yuh, C.-H., Brown, C. T., Livi, C. B., Rowen, L., Clarke, P. J. C., and Davidson, E. H. (2002). Patchy interspecific sequence similarities efficiently identify positive cis-regulatory elements in the sea urchin. Dev. Biol. 246, 148–161.
Construction of cis-regulatory gene networks (update continuously at http://www.its.caltech.edu/~mirsky/endomes.htm)
Purpose:
To understand how various genes are expressed under the regulation of cis-regulatory elements during the developmental period of sea urchin embryos
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Purple sea urchin (Strongylocentrotus purpuratus)
and white sea urchin (Lytechinus variegatus)
http://www.divebums.com/FishID/Pages/sea_urchin_purple.html
http://digimorph.org/specimens/Strongylocentrotus_purpuratus/
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Cells at different location have different fates in embryogenesis
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cis-Regulation
trans-Regulation
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A network exists in the cis-regulatory elements
with some logical rules
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Constructing Relationshipsof Networks from
Expression and Perturbation Data
Developing a computational platform which can inference networks automatically by e
xperiment data
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What is network ?Network is commonly in organism. e.g. gene regulatory network, pathway, neuron network…etc.Abstractly, network can defined as combinations of a group nodes and edges.
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Our approachMining the relationship between nodes from expression curve and perturbation matrix.Inference networks by the relationships we found.
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Expression curvenode A
node B Alignment
Bioinformatics 2003 19: 905-912
Scoring
Score
Relationship of A & B
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Perturbation matrix
0
1
1
1
D
1
0
1
1
C
0
1
0
1
B
0
0
0
0
A
1
1
1
1
WT
D
C
B
A A BCD
AAB D
A
B
C
D
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Integrated Genomic and Proteomic Analyses of a Systematically Perturbed Met
abolic Network
SCIENCE VOL 292:929-934, MAY 4, 2001
Trey Ideker, Vesteinn Thorsson, Jeffrey A. Ranish, Rowan Christmas, Jeremy Buhler, Jimmy K. Eng, Roger Bumgarner,
David R. Goodlett, Ruedi Aebersold, Leroy Hood
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Perturbation Matrix(mRNA Level)
mR
NA
加 Galactose 不加 Galactose
WT
A
B
C
A
B
A
C
B
C
A
BC
WT
A
B
C
A
B
A
C
B
C
A
BC
A
B
C
數量變化
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Reverse Engineering Strategy
Hypothesis
Simulation Models
Candidate Set
Match
實際 Microarray 輸出結果
Believe it or not是否唯一吻合
重新假設
再作 Distinguishable 實驗
是
否
否
是
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A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
BC
A
BC
A
BC
A
BC
a b c d e
A
B
C
g
s t u v
Possible ModelsA
B
C
f
A
BC
A
BCp
A
BCq r
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A(GAL4)
B(GAL80)
C(GAL3)
D(Galactose)
Gala
ctose
調控機制核心
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A System of Cellular Pathway
化學連鎖反應
調控機制核心 Regulation Gene
Metabolic Flow
Structure Gene
化學物質
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化學連鎖反應( Metabolic Flow )
Mutate structure genes and then we will find a Acyclic Directed Graph(ADG).
Mutate structure genes and then we will find a Acyclic Directed Graph(ADG).
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A Pathway with Cycle(1/2)
1 2 3 4 5
On/Off Switch
A B C
E
D
?
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A Pathway with Cycle(2/2)
1 2 3 4 5
On/Off Switch
B C
E
D
Observed
A
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Raw Data
Mining information
HypothesisModeling
Experimental Simulator
Simulation Result
Match
Verification by other biologists
New Biological study
New Biological Experiments
Experiment results
Revise hypothesis by biologists
Error Report
Significant Information
Confirm
Error Report
Biological Study
N
Y
N
Y