Uberon – a multi-species ontology for phenomics and                 evo-devo analyses  Chris Mungall, LBNL  Melissa Haende...
Outline• Introduction to Bio-Ontologies   – Ontologies for data analysis and data integration   – Anatomy ontology re-usev...
Ontologies abstract over repeated       patterns in nature                                  thoracic                      ...
Logical semantics: the difference between ontologies and graphs                                    thoracic               ...
Logical semantics: the difference between ontologies and graphs                                    thoracic               ...
Formal semantics allows for more          precise queries                                                         thoracic...
Ontology Languages• Web Ontology Language (OWL)  – Standard set of logical constructs for building an ontology  – Many syn...
Many perspectives, many ontologies                                                      clinical disorders                ...
The problem:Data Silos                        is_a (SubClassOf)                        part_of                            ...
The OBO Foundry   • Avoid silo-ization via ontologies that are       –   open       –   documented       –   reusable     ...
Ontologies built for one species will                   not work for others                                               ...
Generalization leads to complexity                  cell                                  Variables:                      ...
Anatomy Ontology Menagerie•   Mouse:                                    Reduced taxonomic scope     –     MA (adult)     –...
Sept 2011
Semantic Similarity of Phenotypes        FMA+PATO                        MP                        ZFA+PATO               ...
The problem with mappingsClass A                Class B            In Bioportal?   Useful?FMA extensor           MA retina...
Our solution (2008-2009)• Create grouping classes for mappings    – Used our own software for entity matching    – Manuall...
Uberon in 2012• Size:    – >6500 classes    – >19000 relationships (50 relations)    – >2000 logical definitions• Scope:  ...
is_a (SubClassOf)                                           anatomical                      part_of                       ...
Inter-ontology bridging axioms• Equivalence axioms:  – lung (FMA) EquivalentTolung (Ubr) and ‘part of’ some    NCBITaxon_9...
Importclosure of  Uberon‘collector’ontologies
Different ontology modulesontology           contentsbasic              simple relationshipsuberon             main ontolo...
Collected vs Mergedsomite                        somite (Ubr)                         (Ubr)                       [include...
Logical definitions in GO using UberonGO:notochord formation: The formation of the notochord from the chordamesoderm. The ...
Uberon and phenotype ontologies               UBERON: retinal blood vessel                             is_a  MA: retina   ...
Logical definitions in CL using Uberon                                                        UBERON: epithelium          ...
Logical definitions in Uberon using external ontologies                  UBERON: respiratory system   capable_of   GO: res...
Uberontaxon constraints                    UBERON: respiratory system                    capable_of           GO: respirat...
Axioms encodedin OWL provideexplicit semantics
Uberon iterative development cycle                        Text matching                          Stem and synonym         ...
Using reasoners to detect errors                                                   only_in_taxon                          ...
Spatial disjointness axioms• Example:  – (part_of some midbrain) DisjointWith (part_of    some hindbrain)     • Note: part...
Ontologyalignment    Differences in bone and bone tissue representation
Ontology alignmentUsing Uberon for alignment facilitates identification of missing classes
Managing variation: named subtypes• ‘mammary gland’ part of some ‘female thoracic region’   – humans ✔   – other mammals ✗...
Managing variation: general axioms       • adenohypophysis develops from some ‘Rathke’s pouch’              – tetrapoda✔  ...
Pharyngeal derivatives• Pharyngeal pouches 1-5   – dorsal and ventral parts• Give rise to different structures in differen...
A logic for developmental relationships • Most AOs use a single generic develops from   relationship     – FBbt distinguis...
Provenance for relations      [Term]      id: UBERON:0005562      name: thymus primordium      …      relationship: has_de...
Use of Uberon enhances species-            specific ontologies• Many ontologies lack develops from relationships   – mouse...
Use of Uberon as building block for           other ontologies• Basic science  – CL  – GO  – NBO (behavior)  – Phenotype (...
Applications of Uberon in         bioinformatics analyses• Crucial lynchpin in a number of phenotype  analyses  – Washingt...
Uberon and homology• Uberon classes do not need to be homologous• We try to state necessary and sufficient conditions for ...
Eyes• Eye: organ and has function in go:visual  perception  – Compound eye: has part ommatidia  – Camera-type eye : equiva...
adrenal gland – interrenal gland• Single class in vHOG• Distinct classes in Uberon  – Score highly on semantic similarity ...
Using Uberon and vHOG together• UberHOG?
Using Uberon and vHOG together• vHUG?
Proposal• Separation of concerns   – essentialist definitions   – homology relationships• Create ‘homology knowledgebase’ ...
ConclusionsAnatomy ontologies have been developed independently and do notintegrate well without additional help•Uberon ge...
Acknowledgments•       Uberon               •   Ontologies                             •   Jonathan Bard (EHDAA2)•       M...
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Uberon lausanne-2012

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  • A graph in itself has no semantics. Ontology languages such as OWL provide this
  • A graph in itself has no semantics. Ontology languages such as OWL provide this
  • A graph in itself has no semantics. Ontology languages such as OWL provide this
  • UBERON uses GO or other external ontologies for logicaldefinitions (e.g. chemosensory organ, respiration organ, reproductivesystem -- GO; smooth muscle tissue - CL)
  • Point here is that Uberon can help ensure correct usage of gross anatomical terms in CL. In this example, this means that the tracheal epithelial cell should be defined only for Vertebrata. [Term]id: CL:0000307 ! tracheal epithelial cellintersection_of: CL:0000066 ! epithelial cellintersection_of: part_of UBERON:0003126 ! trachea
  • UBERON uses GO or other external ontologies for logicaldefinitions (e.g. chemosensory organ, respiration organ, reproductivesystem -- GO; smooth muscle tissue - CL)
  • UBERON uses GO or other external ontologies for logicaldefinitions (e.g. chemosensory organ, respiration organ, reproductivesystem -- GO; smooth muscle tissue - CL)
  • Uberon uses the only_in_taxon method to make relationships such as lactifierous gland only in taxonMammalia and boneonly in taxon Vertebrata. These relations are useful for human users of the ontology, and can be used forconsistency checking within the ontology. For example if the FBbt class “tibia” (representing a segment ofan insect leg) were accidentally placed as a child of UBERON:0000979 tibia, this would be flagged by thereasoner because tibia is a bone, bones are found only in vertebrates, and FBbt is a Drosophila ontology
  • Uberon lausanne-2012

    1. 1. Uberon – a multi-species ontology for phenomics and evo-devo analyses Chris Mungall, LBNL Melissa Haendel, OHSU Lausanne Feb 2012
    2. 2. Outline• Introduction to Bio-Ontologies – Ontologies for data analysis and data integration – Anatomy ontology re-usevsvariation in nature• Uberon – Integration with species anatomy ontologies – Interoperation with non-anatomy ontologies – Reasoning and validation – Handling taxonomic variation – Applications• Homology• Conclusions
    3. 3. Ontologies abstract over repeated patterns in nature thoracic organ system cavity respiratory thoracic respiratory primordium cavity organ system lung bud lung lung alveolus is_a (SubClassOf) part_of develops_from
    4. 4. Logical semantics: the difference between ontologies and graphs thoracic organ system cavity respiratory thoracic respiratory primordium cavity organ system lung bud lung lung xinstance-of lung alveolus  xinstance-of ‘thoracic cavity organ’ is_a (SubClassOf) part_of develops_from
    5. 5. Logical semantics: the difference between ontologies and graphs thoracic organ system cavity respiratory thoracic respiratory primordium cavity organ system lung bud lung lung xinstance-of lung alveolus  exists y: yinstance-of ‘lung bud’ xdevelops-from y is_a (SubClassOf) part_of develops_from
    6. 6. Formal semantics allows for more precise queries thoracic organ system cavity respiratory thoracic respiratory primordium cavity organ system lung bud lung xexpressed in y& ypart of z  ✔ lung alveolus xexpressed in z Plunc is_a (SubClassOf) part_of xexpressed ubiquitously in y& develops_from ypart of z  ✗ expressed in xexpressed ubiquitously in z(inferred)
    7. 7. Ontology Languages• Web Ontology Language (OWL) – Standard set of logical constructs for building an ontology – Many syntaxes • OWL-RDF/XML • OWL-XML • Manchester – Many reasoners• OBO-Format – Current formalized by mapping to a subset of OWL • can be treated as another OWL syntax
    8. 8. Many perspectives, many ontologies clinical disorders phenotypes evolutionary characters nervous system anatomy chemical entities cell anatomy gross tissues proteins cells development reactions processes cellular behavior processes physiological processes
    9. 9. The problem:Data Silos is_a (SubClassOf) part_of GO develops_from surrounded_by FMA multicellularorganism EHDAA2 al process organ system solid organ pharyngeal region respiratory gaseous exchange respiratory primordium respiratory parenchymatous lung bud respiratory system system organ process lung MA Lower thoracic respiratory lobular organ organ system tract cavity MPO abnormal respiratory thoracic respiratory system morphology system cavity organ pleural sac lung abnormal lung morphology lungabnormal pulmonary acinus morphology pulmonary acinus abnormal pulmonary lung alveolus morphology alveolar sac alveolus
    10. 10. The OBO Foundry • Avoid silo-ization via ontologies that are – open – documented – reusable – interoperable – built according to shared principles – reuse core relations and patterns • Problem: – How do we re-use in the presence of variability?http://obofoundry.org
    11. 11. Ontologies built for one species will not work for others http://ccm.ucdavis.edu/bcancercd/22/mouse_figure.htmlhttp://fme.biostr.washington.edu:8080/FME/index.html
    12. 12. Generalization leads to complexity cell Variables: V : Variability of entities in domain P : Logical Precision of queries enucleate TP/(TP+FP*c) nucleate cell cell L : “Latticeyness” of class hierarchy ‘exception hierarchy’ Hypothesis: erythrocyte L = kPV nucleate enucleate erythrocyte erythrocytezebrafish human erythrocyte erythrocyte
    13. 13. Anatomy Ontology Menagerie• Mouse: Reduced taxonomic scope – MA (adult) – EMAP / EMAPA (embryonic) =• Human Reduced complexity – FMA (adult) – EHDAA2 (CS1-CS20)• Amphibian Historically little – AAO coordination – XAO• Fish – ZFA – TAO• Nematode – WBbt Contrast to:• Arthropod – FBbt (Drosophila) Gene Ontology (GO) – HAO (all kingdoms of life) – Arthropod anatomy ontology
    14. 14. Sept 2011
    15. 15. Semantic Similarity of Phenotypes FMA+PATO MP ZFA+PATO FBbt+PATO"Linking Human Diseases to Animal Models Using Ontology-Based Phenotype Annotation." PLoSBiol 7(11): e1000247.doi:10.1371/journal.pbio.1000247 Washington NL, Haendel MA, Mungall CJ, Ashburner M, Westerfield M, Lewis SE
    16. 16. The problem with mappingsClass A Class B In Bioportal? Useful?FMA extensor MA retina Yes Noretinaculum of wristFMA portion of blood MA blood No YesZFA Macula MA macula Yes NoZFA aortic arch MA arch of aorta Yes DubiousZFA hypophysis MA pitiuitary No YesFMA tibia FBbt tibia Yes NoFMA colon GAZColón, Panama Yes No
    17. 17. Our solution (2008-2009)• Create grouping classes for mappings – Used our own software for entity matching – Manually split/merge in OboEdit using curator knowledge – Internal joke name: Uberon• Used in phenotype analysis – Washington et al – http://owlsim.org• We kept on tweaking – Used for GO logical definitions – Used in cell ontology – Used to clarify and align existing AOs – Integrated logic-based methods – We got criticized, we got better• Fast forward to 2012…
    18. 18. Uberon in 2012• Size: – >6500 classes – >19000 relationships (50 relations) – >2000 logical definitions• Scope: – Metazoa • vertebrate bias, in particular mammals• Availability – many versions, in obo and owl • http://uberon.org – Source version is obo, compiled to owl using Oort• What does it look like?
    19. 19. is_a (SubClassOf) anatomical part_of structure develops_from capable_of is_a (taxon equivalent) endoderm only_in_taxon organ part foregut swim bladder organ endoderm of forgut NCBITaxon: respiration organ Actinopterygii respiratory primordium GO: respiratory gaseous exchange pulmonary acinus alveolus lung lung primordiumNCBITaxon: Mammalia alveolus of lung alveolar sac lung bud FMA: pulmonary FMA:lung MA:lung alveolus EHDAA: MA:lung alveolus lung budUberon classes generalize species-specific ones, and connect to other ontologies via a variety of relations
    20. 20. Inter-ontology bridging axioms• Equivalence axioms: – lung (FMA) EquivalentTolung (Ubr) and ‘part of’ some NCBITaxon_9606 – lung (MA) EquivalentTolung (Ubr) and ‘part of’ some NCBITaxon_10090• Subclass axioms: – lung (EMAPA) SubClassOf lung (Ubr)• Axioms are maintained as xrefs – Translated to full axioms in obo2owl translation (header tags)
    21. 21. Importclosure of Uberon‘collector’ontologies
    22. 22. Different ontology modulesontology contentsbasic simple relationshipsuberon main ontologymerged main ontology + links to GO, CL, NCBITaxon, NBOtaxon collected merged basicmetazoan ✔ ✔vertebrate ✔ ✔amniote ✔aves ✔euarchontoglires ✔
    23. 23. Collected vs Mergedsomite somite (Ubr) (Ubr) [includes ZFA axioms as GCIs]somite (ZFA)somite 1 somite 1 (ZFA) (ZFA)
    24. 24. Logical definitions in GO using UberonGO:notochord formation: The formation of the notochord from the chordamesoderm. The notochord is composedof large cells packed within a firm connective tissue sheath and is found in all chordates at the ventral surface ofthe neural tube. In vertebrates, the notochord contributes to the vertebral column.Cross-Product Extensions of the Gene Ontology Journal of Biomedical Informatics 2010. Christopher J. Mungall and Michael Badaand Tanya Z. Berardini and Jennifer Deegan and Amelia Ireland and Midori A. Harris and David P. Hill and Jane Lomax
    25. 25. Uberon and phenotype ontologies UBERON: retinal blood vessel is_a MA: retina MA:blood vessel FMA:central retinal artery inheres in inheres in MP:abnormal retinal blood vessel HP: Central retinal artery vascular morphology tortuosity
    26. 26. Logical definitions in CL using Uberon UBERON: epithelium part_of UBERON: trachea CL: epithelial cell part_of is_a CL: tracheal epithelial cell Uberon trachea: A trachea held open by up to 20 C-shaped rings of cartilage. The trachea is the portion of the airway that attaches to the bronchi as it branches.Terrence Meehan, Anna Maria Masci, Amina Abdulla, Lindsay Cowell, Judith Blake, C J Mungall, Alexander Diehl (2011)Logical Development of the Cell Ontology, 6. In BMC Bioinformatics 12 (1)
    27. 27. Logical definitions in Uberon using external ontologies UBERON: respiratory system capable_of GO: respiratory gaseous exchange part_of UBERON: respiratory airway is_a UBERON: trachea CL: epithelial cell part_of is_a CL: tracheal epithelial cell Uberon logical definitions represent functional, developmental, spatial, etc., axes of classification
    28. 28. Uberontaxon constraints UBERON: respiratory system capable_of GO: respiratory gaseous exchange part_of UBERON: respiratory airway is_a only_in_taxon Vertebrata UBERON: trachea CL: epithelial cell part_of is_a CL: tracheal epithelial cell J Deegan, E Dimmer, C J Mungall (2010) Formalization of taxon-based constraints to detect inconsistencies in annotation and ontology development, 530. In BMC bioinformatics 11 (1).
    29. 29. Axioms encodedin OWL provideexplicit semantics
    30. 30. Uberon iterative development cycle Text matching Stem and synonym matching ReasoningCuration • Keep axioms that aremanual adding of new classes consistent across AOsobsoletion, merging, splitting • automated consistency checks for disjointeness violations
    31. 31. Using reasoners to detect errors only_in_taxon UBERON: bone Vertebrata disjoint with is_a is_aDrosophila melanogaster UBERON: tibia Homo sapiens is_a is_a ✗ part_of part_of Fruit fly FBbt‘tibia’ Human FMA ‘tibia’ Developmental Biology, Scott Gilbert, 6th ed.
    32. 32. Spatial disjointness axioms• Example: – (part_of some midbrain) DisjointWith (part_of some hindbrain) • Note: part_of implies all parts are part of – Brain spatial axioms derived from ABA – Used to find problems in existing mouse ontologies
    33. 33. Ontologyalignment Differences in bone and bone tissue representation
    34. 34. Ontology alignmentUsing Uberon for alignment facilitates identification of missing classes
    35. 35. Managing variation: named subtypes• ‘mammary gland’ part of some ‘female thoracic region’ – humans ✔ – other mammals ✗• Solution: – mammary gland • thoracic mammary gland • abdominal mammary gland • inguinal mammary gland
    36. 36. Managing variation: general axioms • adenohypophysis develops from some ‘Rathke’s pouch’ – tetrapoda✔ – teleost✗ • Named subtypes solution – ‘Rathke’s pouch-derived adenohypophysis’ • ugly! • Alternative: – use anonymous classes / OWL general axioms: • (adenohypohysis and part of some tetrapoda) develops from some ‘Rathke’s pouch’the adenohypophysis has different developmental origins in different species - while in mostbasal fish and tetrapods the adenohypophyseal anlagen invaginates to form Rathke’s pouch, inteleost fish the adenohypophysealplacode does not invaginate but rather maintains its initialorganization forming a solid structure in the head
    37. 37. Pharyngeal derivatives• Pharyngeal pouches 1-5 – dorsal and ventral parts• Give rise to different structures in different clades – E.g. • parathyroid from ventral pouch 3 & 4 in many vertebrates • in humans, from dorsal pouches 3 and 4 – Kardong, Vertebrates• All encoded in Uberon using general axioms
    38. 38. A logic for developmental relationships • Most AOs use a single generic develops from relationship – FBbt distinguishes between direct and transitive development – EHDAA2 includes ‘develops in’ • Different structures give different contributions – E.g. neural crest – Modeled explicitly in EHDAA2 • develops from relationships at very specific leaf nodes • Relation composition – has_partodevelops_from - >has_developmental_contribution_fromCredit: Osumi-Sutherland, Haendel and Bard
    39. 39. Provenance for relations [Term] id: UBERON:0005562 name: thymus primordium … relationship: has_developmental_contribution_from UBERON:0010023 {gci_relation="part_of", gci_filler="NCBITaxon:7778", notes="Elasmobranchii", source="ISBN10:0073040584-table13.1"} ! dorsal part of pharyngeal pouch 2OWL:(‘thymus primordium’ and part_of some NCBITaxon_7778)SubClassOfhas_developmental_contribution_from ‘dorsal part of pharyngeal pouch2’ Annotations: source "ISBN10:0073040584-table13.1"
    40. 40. Use of Uberon enhances species- specific ontologies• Many ontologies lack develops from relationships – mouse • MA ✗ • EMAPA ✗ – human • FMA ✗ • EHDAA2 ✔ • SNOMED-CT ✗• These can be enhanced by the develops from relationships in uberon – E.g find all pharyngeal arch derivatives• Combine with Bgee expression data for powerful queries – E.g compare gene expression patterns for pharyngeal arch derivatives
    41. 41. Use of Uberon as building block for other ontologies• Basic science – CL – GO – NBO (behavior) – Phenotype (MP, HP)• Applications – OBI – eagle i
    42. 42. Applications of Uberon in bioinformatics analyses• Crucial lynchpin in a number of phenotype analyses – Washington, Haendel et al – Mousefinder – Phenomenet• Expression analyses – FANTOM5
    43. 43. Uberon and homology• Uberon classes do not need to be homologous• We try to state necessary and sufficient conditions for all classes – Genus: parent class – Differentia may be any mix of: • Locational • Histological • Structural • Functional • Developmental • Or homology!• This is essentially essentialist – ‘essentialist’ may make evo-devo folks uncomfortable, but it’s how most ontologies work
    44. 44. Eyes• Eye: organ and has function in go:visual perception – Compound eye: has part ommatidia – Camera-type eye : equivalent to vHOG eye • vertebrate-type* • cephalod-type* *Not yet in ontology
    45. 45. adrenal gland – interrenal gland• Single class in vHOG• Distinct classes in Uberon – Score highly on semantic similarity measures do to has_part relationships to cell types• Homology can be handled separately• Open question: – interrenal gland vs bodies? – Homology at the level of gland or cortex?
    46. 46. Using Uberon and vHOG together• UberHOG?
    47. 47. Using Uberon and vHOG together• vHUG?
    48. 48. Proposal• Separation of concerns – essentialist definitions – homology relationships• Create ‘homology knowledgebase’ – Statements anchored to Uberon classes • E.g – lung (Ubr) has property: homologous, has_evidence … – head kidney + bone marrow, has property: homologous, has_evidence… – Use homology ontology – Contributions from vHOG and Phenoscape• Automatically aggregate for powerful queries
    49. 49. ConclusionsAnatomy ontologies have been developed independently and do notintegrate well without additional help•Uberon generalizes over species-specific anatomy classes• Includes detailed anatomical knowledge via a variety of relationships •designed for reasoning• Highly interconnected with other ontologies• Homology is largely separated• Growing number of applications•For more info: •http://uberon.org http://genomebiology.com/2012/13/1/R5
    50. 50. Acknowledgments• Uberon • Ontologies • Jonathan Bard (EHDAA2)• Melissa Haendel • Terry Meehan (CL)• George Gkoutos • Alex Diehl (CL)• Carlo Torniai • Terry Hayamizu (MA/CL) • OnardMejino (FMA)• Suzanna Lewis • David Hill (GO) • David Osumi Sutherland (FBbt/CARO) • Paul Schofield (MPATH) • Wasilla Dahdul (TAO/VAO) • Contributions • Paula Mabee (TAO/VAO) • AlanRuttenberg • Erik Segerdell (XAO) • RobHoehndorf • Monte Westerfield (ZFA) • Cynthia Smith (MP) • WacekKusnierczyk • Maryanne Martone (NIF) • Harry Hochheiser • Frederic Bastian (vHOG) • Marc Robinson-Rechavi (vHOG)

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