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Phenotyping produces partslists
Keith Haring, Untitled, 1986 Urs Wehrli, Tidying Up Art, 2003
Functional annotation and pathway integration of hits in genome-wide - - PowerPoint PPT Presentation
Functional annotation and pathway integration of hits in genome-wide - - PowerPoint PPT Presentation
Functional annotation and pathway integration of hits in genome-wide RNAi screens Pathways, enrichment and all that Florian Markowetz markowetzlab.org Phenotyping produces partslists Keith Haring, Untitled , 1986 Urs Wehrli, Tidying Up Art , 2003
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A challenge for computation and statistics
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HTSanalyzeR
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Over-representation analysis
Weak Strong Phenotype
All genes All Hits Hits in GO term Genes in GO term
Hyper-geometric test Collection of gene sets
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Gene Set Enrichment Analysis (GSEA)
Weak Strong Phenotype Weak Strong Phenotype
No signifcant trend Signifcant trend Subramanian et al. (2005)
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Diferential GSEA
Weak Strong Phenotype Weak Strong Phenotype
Phenotype 1 Phenotype 2
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High-scoring subnetworks
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HTSanalyzeR
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From phenotypes to clusters
A B C A B
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From clusters to mechanisms ??
A B A B B A A B A B A B
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Nested Efgects Models
TF1 TF2 Kinase TF1 TF2 TF3 Kinase 1 Kinase 2 TF TF1 TF2
Markowetz et al 2005, 2007 Tresch and Markowetz 2008
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Nested Efgects Models
Inferred pathway Phenotypic profiles
A B C D E F G H
A B C F D H E G
Gene perturbations Efgects
- 1. Set of candidate pathway genes
- 2. High-dimensional phenotypic profjle, e.g. microarray
INPUT OUTPUT Graph representation of information fow explaining the phenotypes
Markowetz et al (’05, ‘07), Fröhlich et al (’07,’08,’09), Zeller et al (‘08), Markowetz and Tresch (‘07), Vaske et al (‘09)
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Anatomy of the NFB pathway
Weak Strong Phenotype
Step 1 Step 2
Hits
Knock-down Known pathway members New RNAi Hits Compare expression phenotypes by NEMs NFB
Roland Schwarz + MPI IB Berlin
?
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Roland Schwarz
Nested Efgect Models for NFB
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Software
NEM
- Froehlich et al (2008)
- Learning nested efgects
models from data
HTSanalyzeR
- Terfve, Rose et al (in
preparation)
- geneset and network
analysis of gene perturbation screens.
http://www.markowetzlab.org/software/
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Acknowledgements
- NFkB: Meyer lab at MPI for Infection Biology
Berlin, esp. Andrè Mäurer and Cindy Rechner
- The NEM community: Rainer Spang, Achim
Tresch, Holger Fröhlich, Tim Beißbarth, …
- and my group
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