This document discusses Uberon, a multi-species anatomy ontology for phenomics and evolutionary developmental biology analyses. It provides an overview of Uberon, including that it integrates species anatomy ontologies, interoperates with other ontologies, uses reasoning and validation, handles taxonomic variation, and has applications in phenotype analysis. It also discusses how Uberon uses logical definitions and general axioms to manage anatomical variation between species and how its development involves iterative curation, alignment with other ontologies, and use of reasoners to detect errors.

1. Uberon – a multi-species ontology for phenomics and
evo-devo analyses
Chris Mungall, LBNL
Melissa Haendel, OHSU
Lausanne Feb 2012

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. 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. 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. 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. 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. 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. 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. 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
lung
abnormal pulmonary
acinus morphology pulmonary
acinus
abnormal pulmonary lung
alveolus morphology
alveolar sac
alveolus

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. Ontologies built for one species will
not work for others
http://ccm.ucdavis.edu/bcancercd/22/mouse_figure.html
http://fme.biostr.washington.edu:8080/FME/index.html

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 erythrocyte
zebrafish human
erythrocyte erythrocyte

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. Sept 2011

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. The problem with mappings
Class A Class B In Bioportal? Useful?
FMA extensor MA retina Yes No
retinaculum of wrist
FMA portion of blood MA blood No Yes
ZFA Macula MA macula Yes No
ZFA aortic arch MA arch of aorta Yes Dubious
ZFA hypophysis MA pitiuitary No Yes
FMA tibia FBbt tibia Yes No
FMA colon GAZColón, Panama Yes No

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. 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. 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 primordium
NCBITaxon: Mammalia alveolus of lung alveolar sac lung bud
FMA:
pulmonary FMA:lung
MA:lung alveolus EHDAA:
MA:lung
alveolus lung bud
Uberon classes generalize species-specific ones, and connect to other ontologies via a
variety of relations

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. Import
closure of
Uberon
‘collector’
ontologies

22. Different ontology modules
ontology contents
basic simple relationships
uberon main ontology
merged main ontology + links to GO, CL, NCBITaxon, NBO
taxon collected merged basic
metazoan ✔ ✔
vertebrate ✔ ✔
amniote ✔
aves ✔
euarchontoglires ✔

23. Collected vs Merged
somite somite
(Ubr) (Ubr)
[includes ZFA axioms
as GCIs]
somite
(ZFA)
somite 1 somite 1
(ZFA) (ZFA)

24. Logical definitions in GO using Uberon
GO:notochord formation: The formation of the notochord from the chordamesoderm. The notochord is composed
of large cells packed within a firm connective tissue sheath and is found in all chordates at the ventral surface of
the 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 Bada
and Tanya Z. Berardini and Jennifer Deegan and Amelia Ireland and Midori A. Harris and David P. Hill and Jane Lomax

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. 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. 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. 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. Axioms encoded
in OWL provide
explicit semantics

30. Uberon iterative development cycle
Text matching
Stem and synonym
matching
Reasoning
Curation • Keep axioms that are
manual adding of new classes consistent across AOs
obsoletion, merging, splitting • automated
consistency checks for
disjointeness violations

31. Using reasoners to detect errors
only_in_taxon
UBERON: bone Vertebrata
disjoint with is_a is_a
Drosophila 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. 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. Ontology
alignment
Differences in bone and bone tissue representation

34. Ontology alignment
Using Uberon for alignment facilitates identification of missing classes

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. 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 most
basal fish and tetrapods the adenohypophyseal anlagen invaginates to form Rathke’s pouch, in
teleost fish the adenohypophysealplacode does not invaginate but rather maintains its initial
organization forming a solid structure in the head

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. 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_from
Credit: Osumi-Sutherland, Haendel and Bard

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 2
OWL:
(‘thymus primordium’ and part_of some NCBITaxon_7778)
SubClassOfhas_developmental_contribution_from ‘dorsal part of pharyngeal pouch
2’
Annotations: source "ISBN10:0073040584-table13.1"

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. Use of Uberon as building block for
other ontologies
• Basic science
– CL
– GO
– NBO (behavior)
– Phenotype (MP, HP)
• Applications
– OBI
– eagle i

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. 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. 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. 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. Using Uberon and vHOG together
• UberHOG?

47. Using Uberon and vHOG together
• vHUG?

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. Conclusions
Anatomy ontologies have been developed independently and do not
integrate 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. 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)