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Mungall keynote-biocurator-2017
Chris Mungall discussed his path in biocuration which led him to focus on ontologies. Ontologies can amplify the impact of data by providing a structured knowledge framework. Early ontologies like GO became too monolithic so the Open Biological Ontologies (OBO) Foundry was created to develop interoperable, modular ontologies through collaboration. Mungall described work developing ontologies like Uberon, developing tools like ROBOT for quality control, and a vision for more sophisticated ontology annotation to encode biological knowledge.
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Mungall keynote-biocurator-2017
- 1. Chris Mungall Biocuration, Stanford,2017 2017: AN ONTOLOGY BIOCURATION ODYSSEY chrismungall
- 2. Outline My pathtowards biocuration Ontologies past and future Some final thoughts on biocuration
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- 7. Which path toAI? (circa 1990s) Knowledge- Based Knowledge- Free statisti cs logic learnin g encodin g Artificial Intelligence Narrow AI Broad AI ‘knowin g that’ ‘knowin g how’ Biologicall y inspired Cognitivel y inspired
- 8. - All catsare mammals - All dogs are mammals
- 9. - All catsare mammals - All dogs are mammals - Mammals have fur - Dogs like balls - Fido is a dog
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- 14. • Analysis pipeline •Curation tools • Annotation databa From sequence to genome annotation
- 15. • Analysis pipeline •Curation tools • Annotation databa Chado Mungall, C. J., Emmert, D. B., & FlyBase Consortium, (2007). A Chado case study: an ontology-based modular schema for representing genome-associated biological information. Bioinformatics, 23(13), i337-346. http://doi.org/10.1093/bioinformatics/btm189 Generalized community tools
- 16. • Analysis pipeline •Curation tools • Annotation database • Functional annotation Genomes to function annotation? What does it do?
- 17. Gene Ontology: toolfor the unification of biology (2000) Organize generalized biological knowledge as a graph Attach genes to nodes Propagate across species Create gene lists Interpret high throughput data Ashburner, M., Ball, C. A., Blake, J. A., Botstein, D., Butler, H., Cherry, J. M., … Sherlock, G. (2000). Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet, 25(1), 25–29. http://doi.org/10.1038/75556
- 18. Ontologies as forceamplifiers for data domain knowledgedata biocurationexperimen
- 19. Don’t worship themonolith PROBLEM: GO and other ontologies were becoming monolithic - lots of implicit overlap with other ontologies, latent structure
- 20. Open Biological Ontologies (OBO) http://obofoundry.org 1.Well-integrated Modular ontologies 2. Provide technical and sociotechnological framework for cooperation 4. Allow us to curate all of the things 3. Provide tools, best practices and infrastructure for forging new ontologies @obofoundry
- 21. OBO Library PURLs PURL: Persistent URL Consistent, predictable, stable and versioned URLs for ontology objects Can be shortened as compact URIs (CURIEs), e.g. GO:0008150 Can be registered and viewed on OBO site http://obofoundry.org Ontology purls Main ontology, subsets versionIRIs Ontology term purls
- 22. compound eye ommatidium sense organ eye disc is_a part_of develops from detection oflight stimulus involved in visual perception (GO) One ontology to bind them: the Relation Ontology (RO) capable of outer photoreceptor cell part_of http://obofoundry.org/ontology/ro.html lamina monopolar neuron L3 synapsed by
- 23. Contributions to anduses of RO virtualflybrain.org globalbioticinteractions.org Osumi-Sutherland, D. (2012). doi:10.1093/bioinformatics/bts113 Has soma location Has synaptic terminal in Upstream in neural circuit with … Eats Epiphyte of Parasite of Kleptoparasitizes hyperparasitizes Neurocellular Bioitic interaction Is model of Has phenotype Molecularly controls Allosteric inhibitor of causes or contributes to condition ... David Osumi-Sutherland Anne ThessenMatt Brush Greg Stupp Gene, drug, phenotype >500 relations
- 25. What happens whenthe pieces don’t fit together?
- 26. Making the piecesfit together: GO and CHEBI Hill, D. P., Adams, N., Bada, M., Batchelor, C., Berardini, T. Z., Dietze, H., … Lomax, J. (2013). Dovetailing biology and chemistry: integrating the Gene Ontology with the ChEBI chemical ontology. BMC Genomics, 14(1), 513. http://doi.org/10.1186/1471-2164-14-513 GO CHEBI • Some relationships didn’t make sense • E.g. nucleotide isa carbohydrate • Acids conjugate bases Harold Drabkin David Hill Jane Lomax Tanya Berardini Janna Hastings
- 27. Making the piecesfit together: GO and CHEBI Hill, D. P., Adams, N., Bada, M., Batchelor, C., Berardini, T. Z., Dietze, H., … Lomax, J. (2013). Dovetailing biology and chemistry: integrating the Gene Ontology with the ChEBI chemical ontology. BMC Genomics, 14(1), 513. http://doi.org/10.1186/1471-2164-14-513 GO CHEBI • Fixed many is-as • E.g. nucleotide isa carbohydrate • Acids conjugate bases + OWL reasoning Harold Drabkin David Hill Jane Lomax Tanya Berardini Janna Hastings GO CHEBI + Design Patterns
- 28. lung lung lobular organ parenchymatous organ solid organ pleuralsac thoracic cavity organ thoracic cavity abnormal lung morphology abnormal respiratory system morphology Mammalian Phenotype Mouse Anatomy FMA abnormal pulmonary acinus morphology abnormal pulmonary alveolus morphology lung alveolus organ system respiratory system Lower respiratory tract alveolar sac pulmonary acinus organ system respiratory system Human development lung lung bud respiratory primordium pharyngeal region Challenges of multi-species anatomy and phenotypes develops_from part_of is_a (SubClassOf) surrounded_by
- 29. The perils ofmappings Class A Class B Mapped ? Useful ? FMA: extensor retinaculum of wrist MouseAnatomy: retina Yes No Plant Ontology: Pith Fly Anat: femur MouseAnatomy: medulla MouseAnatomy: femur Yes Yes No No* ZfishAnat: hypophysis MouseAnatomy: pituitary No Yes TAO:fossa AdverseReactions: depression Yes No FMA: colon GAZ: Colón, Panama Yes No Quality: male Chebi: maleate 2(-) Yes No
- 30. http://uberon.org • Initial Phase •Bottom-up • Create groupings of terms • Light curation • Next Phase • Top down • 14k classes • Design Patterns • Periodic alignment and feeding back to curators Uberon
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- 32. Uberon for geneexpression curation http://bgee.org/
- 33. Uberon for geneexpression curation http://bgee.org/
- 34. dinosaurs, sponges, combjellies and cephalopods, oh my Thacker, R. W., (2014). The Porifera Ontology (PORO): enhancing sponge systematics with an anatomy ontology. Journal of Biomedical Semantics, 5(1), 39. http://doi.org/10.1186/2041-1480-5-39 Graphic courtesy Nizar Ibrahim, Paul Sereno, et al. Phenotype RCN Wasila Dahdul Bob Thacker obofoundry.org/ ontology/ceph.html obofoundry.org/ ontology/cteno.html
- 35. Phenotype and Disease Ontologies Problem: Many ontologies, vocabularies and condition/phenotype lists: HP, MP, WBPhenotype, FBcv, TO, VT, FYPO, APO, SNOMED OMIM, Orphanet, DO, NCIT, MESH, ICD, UMLS, MEDGEN … ZFIN, Phenoscape: EQ Köhler, S.. (2013).. F1000Research, 1– 12. http://doi.org/10.3410/f1000research.2- Standardized Design Patterns + OWL Reasoning Bayesian OWL Ontology Merging (BOOM) Mungall, C.J et al (2016) kBOOM. bioRxiv 10.1101/048843 Monarch merged ‘upheno’ ontology MonDO Elvira Mitraka Sue Bello Nicole Vasileksky
- 36. Combined score Remove off-targetand common variants Whole exome Variant Score based on allele frequency and pathological impact Mendelian filters Whole or partial phenome (HPO) Owl Sim Gene phenotype scores Curated Phenotype Data Monarch Integrated KB upheno Curated Orthology, Interaction, .. Data +GENOMISER
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- 38. animal- associated soil marine plant- associated sediment aquatic hot spring food cultured freshwater hydrothermal vent terrestrialsludge wastewater extremeorganism- associated air microbial mat lite http://obofoundry.org/ontology/envo.html Ramona Walls Pier Luigi Buttigieg
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- 40. Biological knowledge andcuration QC Deegan, J., Dimmer, E., & Mungall, C. J. (2010). Formalization of taxon-based constraints to detect inconsistencies in annotation and ontology development. BMC Bioinformatics, 11(1), 530. http://doi.org/10.1186/1471-2105-11-530 Annotation errors can arise for different reasons - machine error (inappropriate propagation) - human error Previous versions of the GO had various unusual annotations: • Genes in chicken responsible for lactation
- 41. Biological knowledge andcuration QC Deegan, J., Dimmer, E., & Mungall, C. J. (2010). Formalization of taxon-based constraints to detect inconsistencies in annotation and ontology development. BMC Bioinformatics, 11(1), 530. http://doi.org/10.1186/1471-2105-11-530 Annotation errors can arise for different reasons - machine error (inappropriate propagation) - human error Previous versions of the GO had various unusual annotations: • Genes in chicken responsible for lactation • Genes in slime mold responsible for dorsal fin development
- 42. Solution: Taxon constraints Deegan,J., Dimmer, E., & Mungall, C. J. (2010). Formalization of taxon-based constraints to detect inconsistencies in annotation and ontology development. BMC Bioinformatics, 11(1), 530. http://doi.org/10.1186/1471-2105-11-530 Encode taxon constraints as OWL rules in the ontology only in taxon never in taxon Can be propagated across ontologies E.g. dorsal fin only in vertebrata (uberon) dorsal fin never in tetrapod (uberon) lactation only in mammals (go)
- 43. Hi, ROBOT Howcan we package things up and make them easier to use in ontology/curation QC pipelines? Enter ROBOT Design Patterns Continuous Integration
- 44. Next steps forontology annotation Existing ontology annotation model: Bag of terms gene ter m ter m ter m ter m ter m ter m ter m ter m
- 45. All GO annotations for (human)beta- catenin:(Molec ular Function branch)
- 50. Next generation ontology annotationin Noctua http://noctua.berkeleybop.org/
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- 53. Take homes Knowledgeis a force multiplier Applies to all biocuration work But pinpoints need for QC Design for generality But acknowledge difficulties Better support required Biological knowledge is multifaceted and nuanced Computer scientists have a tendency towards hubris Biology is our nemesis Collaborative approach is vital
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- 59. Acknowledgments Monarch Initiative:Jeremy Nguyen-Xuan, Kent Shefcheck, Matt Brush, Tom Conlin, Lilly Winfree, Eric Douglass, Jules Jacobsen, Craig McLachan, Suzanna Lewis, Julie McMurry, Dan Keith, Nicole Washington, Nicole Vasilevsky, Nathan Dunn, Harry Hochheiser, William Bone, Neal Boerkel, Damian Smedley, Tudor Groza, Sebastian Koehler, Melissa Haendel, Peter Robinson GO: Michael Ashburner, David Hill, Paola Roncaglia, David Osumi-Sutherland, Tanya Berardini, Jen Deegan, Jane Lomax, Karen Christie, Pascale Gaudet, Monica Munoz-Torres, Seth Carbon, Eric Douglass, Heiko Dietze, Ruth Loverin, Rachael Huntley, Midori Harris, Harold Drabkin, Kimberley Van Auken, Marc Feuermann, Petra Fey, Jim Hu, Debbie Siegel, Helen Parkinson, Tony Sawford, Stacia Engel, Sylav Poux, Melanie Courtot, Becky Foulger, Emily Dimmer, Rachael Huntley, Huaiyu Mi, Judy Blake, Paul Sternberg, Mike Cherry, Suzi Lewis, Paul Thomas OBO: Michael Ashburner, Suzanna Lewis, Barry Smith, Richard Scheuermann, Chris Stockert, Jie Zheng, Melanie Courtot, Simon Jupp, Ramona Wall,s Darren Natale, Melissa Haendel, Lynn Schriml, Alan Ruttenberg, Seth Carbon, James Overton, Bjoern Peters, + all contributors Planteome: Pankaj Jaiswal, Dennis Stevenson, Laurel Cooper, Austin Meier, Marie Angelique Laporte, Elizabeth Arnaud Uberon: David Osumi-Sutherland, Paula Mabee, Jim Balhoff, Wasila Dahdul, Alex Dececci, Nizar Ibrahim, Paul Sereno, Frederic Bastian, Ann Niknejad, Marc Robinson-Rechavi, David Blackburn, Terry Hayamizu, Yvonne Bradford, Ceri Van Slyke, Alex Diehl, Terry Meehab, Robert Druzinsky, Melissa Haendel ALL OF THE BIOCURATORSNIH ORIP R24OD011883 NHGRI U41HG 002273 NSF DEB-0956049 DOE DE-AC02-05CH11231 NSF IOS 1340112 NSF DBI 1062404
- 62. Give me aplace to stand and with a lever I will move the whole world
- 63. Uncovering latent meaningin ontologies Mungall, C. J. (2004). Obol: Integrating Language and Meaning in Bio-Ontologies. Comparative and Functional Genomics, 5(7), 509–520. regulation of Notch signaling pathway involved in heart induction relation relation anatomicpathway OWL EXPRESSION HERE ≡ ∃regulates (NSP ⊓ ∃ part-of HI)
- 64. Open Biological Ontologies (OBO) To provide modular building blocks Not just functional annotation of genes and gene products Framework, tools and infrastructure for cooperation and harmonization Smith, B., Ashburner, M., Rosse, C., Bard, J., Bug, W., Ceusters, W., … Lewis, S. (2007). The OBO Foundry: coordinated evolution of ontologies to support biomedical data integration. Nat Biotechnol, 25(11), 1251–1255. Functio n (GO) Anatomy Environ ment Chemical s (CHEBI) Phenotyp e and Disease Genes (SO, GENO) Occurs in … http://obofoundry.org
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- 66. Relations: the gluethat holds it together RO 2005 paper 10 relations Current RO >500 relations Molecular biology Neurobiology Biotic interactions … Many rules on how relations compose together Working with wikidata http://obofoundry.org/ontology/ro.html
- 67. Beyond the GO Functional Genomics:Gene function Transcriptomics: Gene expression Phenomics: Effects of gene mutations Gene Ontology Anatomy and Stage Ontology Phenotype and Trait Ontology Links genes to What they do Links genes to where they are expressed Links genes to what happens when they are disrupted or when they varyDisease Ontology Environment Ontology
- 68. anatomical structure endoderm of forgut lung bud lung respirationorgan organ foregut alveolus alveolus of lung organ part FMA:lung MA:lung endoderm GO: respiratory gaseous exchange MA:lung alveolus FMA: pulmonary alveolus is_a (taxon equivalent) develops_from part_of is_a (SubClassOf) capable_of NCBITaxon: Mammalia EHDAA: lung bud only_in_taxon pulmonary acinus alveolar sac lung primordium swim bladder respiratory primordium NCBITaxon: Actinopterygii http://uberon.org Mungall, C. J., Torniai, C., Gkoutos, G. V, Lewis, S. E., & Haendel, M. A. (2012). Uberon, an integrative multi-species anatomy ontology. Genome Biology, 13(1), R5. doi:10.1186/gb-2012-13-1-r5 Uberon bridges anatomy ontologies
- 69. Uberon for comparativeGene Expression http://bgee.org/
- 70. Uberon Core Extensions toother animals… Thacker, R. W., Díaz, M. C., Kerner, A., Vignes-Lebbe, R., Segerdell, E., Haendel, M. a, & Mungall, C. J. (2014). The Porifera Ontology (PORO): enhancing sponge systematics with an anatomy ontology. Journal of Biomedical Semantics, 5(1), 39 Non-model/human extension Porifera Ontology Ctenophore Ontology Cephalopod Ontology http://phenotypercn.org https://github.com/obophenotype/cephalopod-ontology https://github.com/obophenotype/ctenophore-ontology https://github.com/obophenotype/porifera-ontology https://github.com/obophenotype/uberon Arthropod Ontology
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- 72. The Undiagnosed DiseasePatient (UDP) Use Case Clinical Phenotyping (HPO/phenot ips) Exome Sequencing Causative Variant?
- 73. https://www.sanger.ac.uk/resources/databases/exomiser/query/exomiser2 Robinson, P., etal . (2013). Improved exome prioritization of disease genes through cross species phenotype comparison. Genome Research. doi:10.1101/gr.160325.113
- 74. TODO DEPRECATED Theneed for modularization Growing pains of GO Terms were added as-needed for curation Hard to maintain Scope: Encompassing all of biology is hard Biochemistry, cell biology, plants, animal development and physiology, … We needed to modularize Meanwhile Other ontologies in the ‘style’ of GO were popping up, for annotating other kinds of data Challenge: how were we going to coordinate this?
- 75. Biological knowledge andcuration QC Taxon constraints CONCRETE EXAMPLE HERE Intersection rules (see Seth’s talk) Deegan, J., Dimmer, E., & Mungall, C. J. (2010). Formalization of taxon-based constraints to detect inconsistencies in annotation and ontology development. BMC Bioinformatics, 11(1), 530. http://doi.org/10.1186/1471-2105-11-530
- 76. Knowledge-Based • ice creamderived-from dairy • Ice cream is yummy
- 82. Uberon/CL applications and users Ontology Modularization GO CLO Pheno Ontologies (EQ definitions) ENVO Transcriptomics and genome annotation ENCODE FANTOM5 LINCS BgeeDb Phenomics Human and Mammalia Phenotype Ontology Phenotype comparison algorithms Evolutionary Phenotypes: Phenoscape http://uberon.github.io/about/adopters.html
- 83. The path toAI, 1990s Two goals Broad AI Narrow AI What path to get there? Knowledge-Based Explicit Encoding of knowledge about the world Analytic or deductive reasoning Mathematical Logic vs Cognitively inspired (neats vs scruffs) ‘Knowing that’ Knowledge-Free Machine Learning, Neural Networks Statistics Pattern Recognition Biological Inspired ‘Knowing how’
- 84. Opposites Koehler et al,bioRxiv https://doi.org/10.1101/108977
- 85. compound eye ommatidium sense organ eye disc is_a part_of develops from detection oflight stimulus involved in visual perception One ontology to bind them: the Relation Ontology (RO) capable of outer photoreceptor cell part_of http://obofoundry.org/ontology/ro.html lamina monopolar neuron L3 synapsed by