Canadian Bioinformatics Workshops

1. Canadian Bioinformatics Workshops www.bioinformatics.ca

2. Module #: Title of Module 2

3. Module 4 Analyzing gene list function and associations Quaid Morris Interpreting gene lists from –omics studies July 15-16, 2010 Place an image representing the talk here http://morrislab.med.utoronto.ca

4. Overview • Extending gene lists using functional associations • Sources of functional association • GeneMANIA

5. Extending Gene Lists • Given a gene list, find other similar genes • Gene list defines the query and the “function” of interest • Query: complex or pathway components • Result: additional members • Query: kinases • Result: other kinases and related genes • Query: genes affected in RNAi screen • Result: other genes that may affect phenotype

6. Network-Based Gene Function Prediction • Genes of similar sequence often have similar function • Unknown gene similar to known gene likely to have similar function (annotation transfer) • Guilt-by-association principle • Many other similarity measures for genes (e.g. co-localization) Fraser AG, Marcotte EM - A probabilistic view of gene function - Nat Genet. 2004 Jun;36(6):559-64

7. Cell cycle CDC3 CLB4 CDC16 UNK1 RPT1 RPN3 RPT6 UNK2 Protein degradation Functional association networks to predict gene function Co-expression network Microarray expression data Eisen et al (PNAS 1998) Fraser AG, Marcotte EM - A probabilistic view of gene function - Nat Genet. 2004 Jun;36(6):559-64

8. Predicting Gene Function Using a Network Is gene X involved in cell cycle regulation? + CDC3 CLB4 + + Discriminant value CDC16 UNK1 0.9 ? UNK1 Labelled examples Classification algorithm UNK2 0.1 UNK3 0.05 - - RPT1 RPN3 Discriminant value: a value you can use to rank the genes according to certainty or threshold to classify genes - ? RPT6 UNK2 e.g. co-expression ? UNK3

9. Predicting Gene Function Using a Network Is gene X involved in cell cycle regulation? + CDC3 CLB4 + + Discriminant value CDC16 UNK1 0.9 ? UNK1 Labelled examples kNN,SVM, LabelProp UNK2 0.1 UNK3 0.05 - - RPT1 RPN3 Discriminant value: a value you can a) use to rank the genes according to certainty and b) threshold to classify genes - ? RPT6 UNK2 e.g. co-expression ? UNK3

10. Label propagation vs guilt-by-association CDC48 MCA1 CPR3 TDH2 Discriminant Value CDC48 CDC48 Label propagation algorithm Guilt-by-association MCA1 MCA1 CPR3 CPR3 TDH2 TDH2 -1 …………....+1

11. Types of functional associations • Molecular Interactions (i.e. physical interactions) • Regulatory Interactions (e.g. ChIP-chip binding) • Genetic Interactions (e.g. synthetic lethality) • Similarity relationships • Co-expression • Protein sequence (e.g. BLAST –log(E-value)) • Domain architecture • Phylogenetic profiles • Gene neighborhood** • Gene fusion** • … ** most useful for bacterial genes

12. Problem: genes are multi-function • Gene function could be a/the: • Biological process, • Biochemical/molecular function, • Subcellular/Cellular localization, • Regulatory targets, • Temporal expression pattern, • Phenotypic effect of deletion. Some networks may be better for some types of gene function than others

13. Query-specific weights for multifaceted functional queries w1x w2x w3x weights CDC27 Cell cycle CDC23 + + APC11 UNK1 Co-complexed Jeong et al 2002 Genetic Tong et al. 2001 RAD54 XRS2 DNA repair = MRE11 UNK2 Co-expression Pavlidis et al, 2002, Lanckriet et al, 2004 Mostafavi et al, 2008 The GeneMANIA project

14. GeneMANIA in the MouseFunc contest “Test” benchmark: Predicting held-out genes One of GeneMANIA’s two entries had the best area under the ROC curve in every category Sara Mostafavi

15. GeneMANIA performance on yeast  More error Slower  GeneMANIA on 15 networks GeneMANIA label propagation on bioPIXIE* Probabilistic graph search* on bioPIXIE* GeneMANIA on 5 networks TSS** on 5 networks * Myers et al, 2005 ** Tsuda et al, 2005 Mostafavi et al, 2008

16. GeneMANIA Prediction Server http://www.genemania.org or http://qa.genemania.org

17. GeneMANIA network data sources

18. GeneMANIA Cytoscape Plugin

19. Other prediction servers • STRING (http://string-db.org/) • Funcoup (http://funcoup.sbc.su.se/) • FunctionalNet (http://www.functionalnet.org) • bioPIXIE (http://pixie.princeton.edu) • MouseNet (http://mousenet.princeton.edu/)

20. Chemogenomics • STITCH: Chemical-Protein Interactions • http://stitch.embl.de/

21. What Have We Learned? • Network-based gene function prediction • Guilt-by-association principle • used to predict gene function using functional association networks • Many types of functional associations exist • Can be combined intelligently to optimize prediction accuracy • Convenient software available: GeneMANIA • Emerging area: chemical genomics gene function prediction

22. Please follow along lab display on the wiki