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CISBIC Sub-project 1:

CISBIC Sub-project 1:. Modeling genotype-phenotype relations in Campylobacter. Stephen Muggleton, Brendan Wren, Victor Lesk CISBIC, Imperial College London. www.imperial.ac.uk/cisbic. Campylobacter jejuni : Unanswered questions. Are all strains equally pathogenic to humans?

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CISBIC Sub-project 1:

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  1. CISBICSub-project 1: Modeling genotype-phenotype relations in Campylobacter Stephen Muggleton, Brendan Wren, Victor LeskCISBIC, Imperial College London.www.imperial.ac.uk/cisbic

  2. Campylobacter jejuni : Unanswered questions • Are all strains equally pathogenic to humans?  Do strains from different sources share common features?  Why is C. jejuni a commensal in avians, but highly infectious in humans? • How does C. jejuni in some cases perturb the immune system to cause neurological sequelae? • Answers are likely to lie in glyco-surface structures

  3. Kelly J, 2006 C. iejuni NCTC11168from gene sequence to glycostructure Aim.Model variation in pathogen genome sequence of glycosylated surface structures & understand how this variation affects immune response.

  4. PglB Cj1126 Glycostructure questions Basic sugars • How do we get from sequence to full glycostructure? • How does glycan diversity affect disease potential and niche adaptation? Use combination of traditional and systems approaches • Mutagenesis • Natural strain variation • Pathway modelling UDP--D-GlcNAc PglF Cj1120 PseB Cj1293 PglE Cj1121 PseC Cj1294 PglD Cj1123 PseH Cj1313 PglC Cj1124 PseG Cj1312 PglA Cj1125 PseI Cj1317 PglH Cj1129 PseF Cj1311 PseA Cj1316 PglJ Cj1127 PglI Cj1128 PglK Cj1130 C L O N

  5. Phylogenomics pipeline Phylogenetic analysis Statistical analysis Analysis Strain collection gDNA Evolution of virulence & pathogenesis Bayesian analysis Binary data GeneSpring GACK analysis Ratio Values Microarray Gene Calling Quality Control

  6. Natural strain variation and phylogenomics • A livestock and non-livestock clade, but most clinical isolates fall in the non-livestock clade • “Unknown” source of C. jejuni infection • 10 further sub-clades • Water/wildlife sub-clade

  7. Identification of sub-clade/niche specific genes Genes Cj1321-6 present Genes Cj1321-6 absent Identified glyco-specific genes for 1) Flagellin glyco (O) 2) Capsule (C) E.g. Phosphoramidate

  8. Importance of Capsule • Side branch sugars more widely conserved than core sugars? • Phosphoramidate present in 86% of strains (232/270)? Link to subproject 3 ► Capsule prevents excessive cytokine production by dendritic cells ► Presence of phosphoramidate appears to reduce cytokine production

  9. Machine learning approach Biochemical Pathways (KEGG, Biocyc) Mutant data (MAS-NMR) Glycan Structures (MAS-NMR) Prolog Database Hypotheses Background rules Machine learning

  10. Examples of hypotheses C. jejuni glycan synthesis pathway

  11. Integrating multi-strain genetic data with machine learning of gene functions Genetic data for 75 serotyped strains of C. jejuni Working assumption for relating gene function to co-presence “If the product of Gene1 synthesises a sugar precursor which is transformed by the product of Gene2, then Gene1 tends to be present in strains with the same serotype as those expressing Gene2”.

  12. Integrating multi-strain genetic data with machine learning of gene functions Knowledgebase (KEGG, BioCyc) Hypothesized transferase-encoding genes Cj1432 Cj1434 Cj1438 Cj1440 Cj1442 Cj1432 Cj1434 Cj1438 Cj1440 Cj1442 ? ? Cj1432 Cj1434 Cj1438 Cj1440 Cj1442 ? Glycan mutant observations WT Cj1432- Cj1433-

  13. Integrating multi-strain genetic data with machine learning of gene functions Knowledgebase (KEGG, BioCyc) Genetic data for serotyped strains Hypothesized transferase-encoding genes Cj1432 Cj1434 Cj1442 ? ? Cj1438 ? Glycan mutant observations WT Cj1432- Cj1433-

  14. Learning from strain data (work in progress) Learning curves with and without strain data Gene functions identified by learning (%) Gene functions provided to learning (%)

  15. Acknowledgements PI‘s and senior staff: Anne Dell, Stephen Muggleton, Jeremy Nicholson, Chris Rawlings, Mike Sternberg, Brendan Wren Postdocs: Richard Barton, Paul Hitchen, Emily Kay, Victor Lesk, Alireza Tamaddoni- Nezhad

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