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DAS for Molecular Interactions

DAS for Molecular Interactions. Hagen Blankenburg. Importance of molecular interactions. Functional associations. Fundamental for understanding of cellular processes Prediction of protein function Importance in certain diseases Essentiality of hub proteins? The next big thing?!

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DAS for Molecular Interactions

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  1. DAS for Molecular Interactions Hagen Blankenburg

  2. Importance of molecular interactions Functional associations • Fundamental for understanding of cellular processes • Prediction of protein function • Importance in certain diseases • Essentiality of hub proteins? • The next big thing?! • „Interactomics“, „network medicine“, … Gene-gene associations Gene-gene coexpression Literature relationships Physical interactions Level of detail Domain-domain interactions Protein complexes Biochemical pathways Binary PPI Physical interactions with structures Domain-domain interactions Protein complexes Protein-ligand interactions Binary PPI

  3. Problem I: Data abundance and distribution Scientific impact (Credit: Tim Hubbard) Too little bioinformatics Too many databases Too diverse interfaces

  4. High qualityLow quality Problem II: Data quality „Small-scale experiments are more reliable than high-throughout screens.“ Curation errors False positives Confidence measures: Small-scale experiments • Replicate experiments • Network topology • Functional similarity • Domain interactions • Evolutionary conservation • Co-localization • Positive and negative standard reference sets • … „The results of Y2H screens are not trustworthy.“ Experimental biases High-throughputexperiments „Y2H screens are the most reliable detection method.“ Prediction errors Computational predictions False negatives „Computational predications are inferior.“

  5. Problem II: Data quality STRING MINT PIPs 3DID APID IntAct

  6. Solution: Distributed System Interaction data servers Interaction confidence scoring servers Problem I: Data abundance and distribution Problem II: Data quality

  7. DAS for Molecular Interactions (DASMI) - Servers • Servers have coordinate / identifier systems UniProtKB: P51587, BRCA2_HUMAN Entrez Gene: 675 GeneInfo: 119395734, 28400649, 1177438, 14424438, 2315186, 27065822, 37675289, 1161384, 16116616, RefSeq: NP_000050.2, NM_000059IPI: IPI00412408Ensembl: ENSG00000139618

  8. DAS for Molecular Interactions (DASMI) - Registry

  9. DAS registry – http://www.dasregistry.org • Maintained at Sanger Institute All DAS servers with interaction capability Domain interactions Protein interactions

  10. DAS for Molecular Interactions (DASMI) - Data exchange DAS 1.53E data exchange specification DAS Request http://www.dasmi.de/das/funsimmat/interaction?interactor=P09497&interactor=O60828 &detail=property:bpscore DASINT XML Response <?xml version="1.0" encoding="UTF-8"?> <DASINT xmlns="http://www.dasmi.de/" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:schemaLocation="http://www.dasmi.de/ http://www.dasmi.de/dasint.xsd"> <INTERACTOR intId="1" shortLabel="CLCB_HUMAN" dbSource="uniprotkb"dbSourceCvId="MI:0486" dbVersion="12.1" dbAccessionId="P09497" dbCoordSys="UniProt,Protein Sequence"/> <INTERACTOR intId="2" shortLabel="PQBP1_HUMAN" dbSource="uniprotkb" dbSourceCvId="MI:0486" dbVersion="12.1" dbAccessionId="O60828" dbCoordSys="UniProt,Protein Sequence"/> <INTERACTION name="P09497-O60828" dbSource="" dbAccessionId=""> <DETAIL property="bpscore" value="0.154429056459711"/> <PARTICIPANT intId="1"/> <PARTICIPANT intId="2"/> </INTERACTION> </DASINT>

  11. DAS for Molecular Interactions (DASMI) - Clients Clients merge interactors / interactions

  12. iPfam graphical domain interaction browser Selected domain interaction servers Interaction reported in both datasets

  13. DASMI Cytoscape Client Interactions reported by multiple datasets

  14. DASMI Cytoscape Client

  15. http://www.dasmi.de/web Predictions Literature curation / experiments Interaction reported by multiple datasets

  16. http://www.dasmi.de/web All confidence scoring methods that returned results for the current interactions

  17. http://www.dasmi.de/web Original confidence score provided by the authors

  18. http://www.dasmi.de/web Protein interactions supported by underlying domain interactions

  19. http://www.dasmi.de/web Details on domain interactions

  20. http://www.dasmi.de/web Functional similarity based on GO annotation of interactors

  21. Conclusions & Outlook • Usage of DASMI servers and clients surprisingly good, but more external DASMI servers are desirable • DAS client and server libraries (Dazzle, ProServer, (MyDAS), Dasobert, Bio-DAS-lite) support DASMI • Considerable overlap with HUPO-PSI initiatives for distributed interaction data retrieval (PSICQUIC) and confidence scoring (PSISCORE) • Develop methods for combining different interaction confidence scoring schemas in DASMI clients

  22. Acknowledgements • Joachim Büch • Fidel Ramírez • Dorothea Emig • Sven-Eric Schelhorn • Andreas Schlicker • Thomas Lengauer • Mario Albrecht • Robert Finn • Andreas Prlić • Jonathan Warren • Andrew Jenkinson • Henning Hermjakob

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