Walking the Interactome For Prioritization of Candidate Disease Genes

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Walking the Interactome For Prioritization of
Candidate Disease Genes

• Sebastian Köhler
• Sebastian Bauer
• Denise Horn
• Peter N. Robinson
• Institute for Medical Genetics

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Starting point
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Previous Approaches

• Interaction data between proteins/genes
• Relationship of candidates to known disease genes
• Direct interactions (DI)
• Oti et al. (J Med Genet. 2006)
• Aerts et al. (Nat Biotechnol. 2006)
• Lage et al. (Nat Biotechnol. 2007)

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Previous Approaches

• Interaction data between proteins/genes
• Relationship of candidates to known disease genes
• Shortest path (SP)
• George et al. (Nucleic Acids Res. 2006 )

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Drawbacks

• Most genes have a SP-distance of 1,2 or 3
• Measures based on distance to ONE known disease
  gene
• ? Both approaches are very sensitive to
  false-positive and false-negative interactions!

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Ideas

• Hypothesis Disease Genes of a particular disease
  are located in same modules
• Measure distance to all known disease genes
• Use GLOBAL distance measure in networks
• Random Walk
• Calculation
• r restart probability
• W col. norm. adjacency matrix
• px vector (i-th element holds the probability
  of being at node i at
• time step x)

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Ideas

• Hypothesis Disease Genes of a particular disease
  are located in same modules
• Measure distance to all known disease genes
• Use GLOBAL distance measure in networks
• Random Walk
• Calculation

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Improvement

• DI fails
• SP answer is always "2
• Random Walk

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Results - Interactome

• Physical interactions
• HPRD, BioGrid, BIND, DIP, IntAct
• Interlog mapping (Inparanoid)
• Functional interactions STRING
• Genomic Context
• High-throughput Experiments
• (Conserved) Coexpression
• Previous Knowledge (Textmining)
• Largest network contains
• 13,726 Genes and 258,314 Interactions

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Results - GeneWanderer
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Results - Performance

• Test on 110 diseases
• 12 Polygenic, 12 Cancer
• In 43 disease-gene families all causative genes
  were ranked first.

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Results - Example
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GeneWanderer on the Web

• http//compbio.charite.de/genewanderer

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Thanks to

• Peter N. Robinson (group leader)
• Sebastian Bauer
• Denise Horn
• Köhler S, Bauer S, Horn D, Robinson PNWalking
  the Interactome for Prioritization of Candidate
  Disease Genes.The American Journal of Human
  Genetics (2008), in press. contributed equally

Reference
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Comparison Recently discovered disease genes
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Results subject to Interactome