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CISBIC:Sub-project 1:
Stephen MuggletonCISBIC, Flowers Building, Imperial College London.www.imperial.ac.uk/cisbic
Modeling genotype-phenotype Modeling genotype-phenotype relations in Campylobacter: an relations in Campylobacter: an update and future plansupdate and future plans
Overview
•Machine Learning in Systems Biology
•CISBIC sub-project 1
•Hypotheses being tested
•Automated experiment selection
•Conclusions
Systems Biology: The CISBIC Vision
Machine Learning
BLPsPMDPsLogic Programs
SCFGsHMMsGrammars
Bayes’ netsNeural netsDecision trees
MixedProbabilisticLogical
Inductive Logic Programming
Background knowledge. Incomplete biological network.
Examples. Temporal traces of up/down regulation.
Hypothesis. Extra network annotation.
CISBIC subproject 1
Aim. Model effects of changes to pathogen genome of expression of glycosolated surface molecules involved in triggering of innate immune response of host.
Mycobacterium bovis Campylobacter jejuni
Initial focus
• Synthetic pathways for capsule in C. jejuni• 38 genes involved. Full set of knock-outs.• Functions - 1/3 known,1/3 suspected, 1/3 unknown. • Microarray and metabonomic experiments.
Polysaccharide capsule
Pathway database
Prolog database
Machine learning
Visualisation
KEGG BioCyc
ONDEXONDEX
Brendan/papers
Hypotheses for capsule pathway (in red)
cj1432c
cj1416c / cj1417c / cj1418c
Hypotheses predict
• Cj1416, Cj1417, Cj1418 involved in OMePN synthesis. Wren group has verified this by mutagenesis and structural analysis. Fairly obvious from BLAST analysis.
• Cj1432, a protein of unknown function, is central to capsule synthesis. Not predictable from amino acid similarity and BLAST analysis.
Experiments to test cj1432 hypothesis
1.Immunoassay.2.Alcian Blue dye staining of
Campylobacter.3.Electron microscopy – direct visual
inspection.4.Complementation – reintroduce cj1432
to chromosome of mutant5.Structural analysis of capsule glycan.6.Protein purification and enzyme assays.
Hypotheses/experiments
E1: A E2: B E3: C E4: D E5: E E6: AB E7: BC E8: BE E9: AD E10: ABC E11: ABCD E12: ABCEH1: codes(geneX,rA) 0 1 1 1 1 0 1 1 0 0 0 0H2: codes(geneX,rB) 1 0 1 1 1 0 0 0 1 0 0 0H3: codes(geneX,rC) 1 1 0 1 1 1 0 1 1 0 0 0H4: codes(geneX,rD) 1 1 1 0 1 1 1 1 0 1 0 1H5: codes(geneX,rE) 1 1 1 1 0 1 1 0 1 1 1 0
E
C B A
Pre-E
Pre-C
Pre-B
rB
rC
rD E
E10
E9 E11
H4H1
0
00
1
11
H5E8
H2 H3
Conclusions
•Integration of diverse background knowledge
•ILP produces readable rules
•Gap-filling in networks
•Ongoing NMR/MS experimental testing of hypotheses
• Cj1432 – potential C. jejuni vaccine