An update on ongoing projects within Biorange SP3.2.2.1

1. An update on ongoing projects within Biorange SP3.2.2.1 Biorange Project Meeting Leiden, September 15 Tim Hulsen

2. User Knowledge integration ArrayExpress db CoPub Xref db Biorange SP3.2.2 • Gene annotation through applications: PhyloPat, BioVenn, OrthoPath, CoPub

3. Overview • PhyloPat • Published in BMC Bioinformatics (2006) • Update submitted to Nucleic Acids Res. Database issue • BioVenn • Revised version submitted to BMC Genomics • Orthologous networks & OrthoPath • Manuscript in preparation • CoPub (Taverna workflows) • Published in Nucleic Acids Res. Web Server issue (2008)

4. PhyloPat - Introduction • Phylogenetic patterns show the presence or absence of certain genes in a set of full genomes derived from different species • PhyloPat allows the complete Ensembl gene database to be queried using phylogenetic patterns • Published in september 2006, now new version with: • Ensembl v50 • Support of HGNC and EntrezGene IDs • FASTA-format sequences of the members of a phylogenetic lineage • Gene neighborhood view • http://www.cmbi.ru.nl/phylopat

5. PhyloPat: Update to Ensembl v50 • 39 species, under which model organisms such as C. elegans, D. melanogaster, D. rerio, G. gallus, M. musculus, R. norvegicus, C. familiaris, M. mulatta, and human • In total 814,936 genes • In total 244,114 orthologous groups, created by clustering the orthologous gene pairs predicted by Ensembl

6. PhyloPat: Support of HGNC and EntrezGene IDs • HGNC-Ensembl mapping for 29 species • EntrezGene-Ensembl mapping for 18 species Choose form four types of IDs

7. PhyloPat: FASTA-format sequences “L”: Longest peptide sequences from this orthologous group (only the longest peptide per gene) “A”: All peptide sequences from this orthologous group (all peptides per gene)

8. PhyloPat: Gene neighborhood view • The ‘Gene neighborhood view’ shows all genes from all species in a certain phylogenetic lineage, and all genes in their proximity on the genome (10 genes to both sides) • Neighbouring genes are color-coded according to the orthologous groups they belong to • Gene neighborhood gives information about functional relationships (genes involved in similar processes are often clustered together) • Can be used to find the ‘true’ ortholog from a set of genes, by using not only phylogenetic information but also genomic context

9. PhyloPat: Gene neighborhood view ERN1 and ERN2 can be distinguished by looking At gene context Each cell: - Ensembl Gene ID - PhyloPat ID - HGNC Symbol

10. Overview • PhyloPat • Published in BMC Bioinformatics (2006) • Update submitted to Nucleic Acids Res. Database issue • BioVenn • Revised version submitted to BMC Genomics • Orthologous networks & OrthoPath • Manuscript in preparation • CoPub (Taverna workflows) • Published in Nucleic Acids Res. Web Server issue (2008)

11. BioVenn • Web application to see the overlap between different lists of biological identifiers, using area-proportional Venn diagrams • Support of wide range of IDs, which are recognized and linked to the corresponding database: Affymetrix, COG, Ensembl, EntrezGene, Gene Ontology, InterPro, IPI, KEGG Pathway, KOG, PhyloPat and RefSeq • Optional mapping of Affymetrix and EntrezGene to Ensembl • Output in SVG (with drag-and-drop functionality) or PNG • http://www.cmbi.ru.nl/biovenn/

12. Absolute numbers / percentages BioVenn Embedded / standalone, SVG / PNG ID mapping

13. BioVenn • Lists for all 13 sets (X total, X only, XY total overlap, XY only overlap, XYZ overlap, etc.) • If type of ID (e.g. Affymetrix, Ensembl) is recognized, output is linked to the corresponding database

14. Overview • PhyloPat • Published in BMC Bioinformatics (2006) • Update submitted to Nucleic Acids Res. Database issue • BioVenn • Revised version submitted to BMC Genomics • Orthologous networks & OrthoPath • Manuscript in preparation • CoPub (Taverna workflows) • Published in Nucleic Acids Res. Web Server issue (2008)

15. Assessing orthologous biology in groups of genes: Application to GC induced insulin resistance • Biorange meeting 2008-03-11: • Goal: Gain better insight into the conservation of genes • involved in glucocorticoid induced insulin resistance • (GC induced IR) between human, mouse and rat. • Use CoPub to build literature networks, map orthology • Validation needed

16. Network Jak/Stat/IL6 Insulin signaling Dexamethosone & insulin Adipocyte differentiation Fatty acid oxidation/catabolism Lipid transport Misc: amino acid metabolism, MAPK signaling, osteoblast Cytochrome P450s

17. Validation approach Get all genes from a KEGG pathway Select random 10% of these genes Repeat with varying thresholds Create Gene Network using these genes (CoPub) Compare with original KEGG pathway

18. Results Average TP = 0.24 Average FP = 0.01

19. Application to all human genes Non-conserved Create network for each gene with R scaled =30, literature count = 5 6,181 networks with size>2 Calculate average conservation for each network based on conservation for all the genes in the network in 4 species (P.tro.,M.mus.,R.nor.,C.fam.) Conserved Get all genes in 100 least conserved networks Get all genes in 100 most conserved networks 211 genes 309 genes Calculate GO enrichment Calculate GO enrichment Compare

20. OrthoPath • OrthoPath is a gene centric search tool for literature networks and their orthologs • Three input methods: • Single gene search: Get the literature network for a given gene. OrthoPath will create a network of genes that are connected to this single gene. • Keyword Search:Get the literature network based on a certain keyword. OrthoPath looks for genes that are connected to the keyword, and creates a network from all these genes. • Multi Gene Search:Get the literature network for a set of genes. OrthoPath creates a network from only these genes that are entered by the user. • http://ws2.grid.sara.nl/cgi-bin/orthopath/op.pl

21. Search with a single gene OrthoPath Search with a keyword Search with a list of genes Set the minimum number of abstracts in which a co-citation between the 2 genes is found Set the minimum strength of a co-citation between two keywords Output in HTML, SVG, Cytoscape or Ingenuity format

22. OrthoPath Each node in the network: • EntrezGene information: ID, symbol, description • number of neighbours • number of orthologs from human (for all five species)

23. Overview • PhyloPat • Published in BMC Bioinformatics (2006) • Update submitted to Nucleic Acids Res. Database issue • BioVenn • Revised version submitted to BMC Genomics • Orthologous networks & OrthoPath • Manuscript in preparation • CoPub (Taverna workflows) • Published in Nucleic Acids Res. Web Server issue (2008)

24. CoPub Taverna Workflows • Taverna: free software tool for designing and executing workflows • Workflow files for CoPub have been developed: (2) Get literature neighbours (1) Search gene

25. CoPub Taverna Workflows (4) Get the complete network (3) Get a list of categories

26. Acknowledgements • Wynand Alkema • Wilco Fleuren • Raoul Frijters • Peter Groenen