from AMIA/TBI 2012

1. CJ Mungall, C Torniai, JBL Bard, GV Gkoutos, S
Essaid, PN Schofield, PN Robinson, D Smedley, M
Westerfield, SE Lewis, MA Haendel

2. From development to disorders
genes
 Development informs our understanding
of diseases and disorders neural
crest
 Congenital anomalies, cancer, etc
 Can we build an informatics resource
that encodes developmental neural
knowledge? crest
derived
○ Find all disorders that affect structures meckel‟s
structures
derived from the neural crest cartilage
○ Dynamically classify diseases based on
developmental origin ossicle
○ What disease phenotypes are similar in
terms of their developmental origins
○ What genes are implicated in disorders
affecting X, and are differentially expressed disorders
in precursors of X?

3. Challenges
1. Databases do not speak a common semantic language
Open
Biological
Ontologies
(OBO
?? SNOMED
Library)
clinical resources
bioinformatics
databases ICD9
e.g. EHRs
“chasm of
semantic
despair”
2. Developmental relationships in mammalian ontologies are incomplete
spina
neural
l
tube
cord
adult
embryo ??

4. Creating a developmental KB:
Approach
 Ontologies
 Select open orthogonal ontologies covering domain
 Create bridging ontologies to cross chasm of despair
 Curate high quality developmental graph using OWL
axiom
 Infrastructure
 Translate omics resources to OWL
 Build knowledge base on linked data cloud in modular
fashion using small ontologies and import chains
 Discovery
 Query using fast EL++ reasonersand semantic similarity
engines

5. ontogenetic and phylogenetic
knowledge transfer
zebrafish mouse human
neural
tube
embryonic
development
anatomy
post-natal to adult
anatomy
spinal
cord
NL Washington, MA Haendel, CJ Mungallet
al.Linking Human Diseases to Animal Models
homology using Ontology-based Phenotype Annotation.
PLoS Biology 2009

6. Strategy for anatomy ontologies
SNOMED
(anatomy
Uberon subset)
NCIt
(anatomy
subset)
EMAPA EHDAA2
ZFA
MA FMA
CJ Mungall, C Torniai, GV Gkoutos, SE Lewis, MA Haendel.
Uberon, an integrative multi-species anatomy ontology. (2012) Genome biology 13 (1), R5

7. filling holes in developmental
graphs SNOMED
EMAPA •taxon: human-centric
•taxon: mouse •adult and embryonic
•use: gene expression (MGI) •no develops from relationships
•embryonic only
•no develops from relationships
MA
•taxon: mouse FMA
•taxon: human
•use: gene expression (MGI)
•adult only
•adult only
•no develops from relationships
•no develops from relationships
ZFA
•taxon: zebrafish
•use: gene expression and phenotypes
(ZFIN)
•adult and embryonic
•463 develops from relationships

8. filling holes in developmental
graphs
EMAPA EHDAA2
•taxon: mouse •taxon: human
•use: gene expression (MGI) •embryonic only (CS1-20)
•embryonic only •2108 develops from relationships
•no develops from relationships •high precision
MA FMA
•taxon: human
•taxon: mouse •adult only
•use: gene expression (MGI) •no develops from relationships
•adult only
•no develops from relationships
Uberon
ZFA
•taxon: metazoa
•taxon: zebrafish •adult and embryonic
•use: gene expression and phenotypes •783 develops from relationships
(ZFIN) •75 developmental contribution relationships
•adult and embryonic •20 developmental induction relationships
•463 develops from relationships

9. developmental relationships in
uberon
 uberon includes ~900 developmental relationships
 curated from literature, expert input
 classes in uberon are applicable across multiple species
 parathyroid : tetrapods
 meninges: vertebrates
 Challenge:
 developmental relationships vary throughout evolution
 Solution:
 use OWL2 General Class Inclusion (GCI) axioms to encode
phylogenetically variable relationships
 Example:
○ (parathyroid and „part of some Aves) SubClassOf „has
developmental contribution from‟ some „ventral pouch of arch
3+4‟
○ (parathyroid and „part of some Mammal) SubClassOf „has
developmental contribution from‟ some „dorsal pouch of arch 3+4‟
http://uberon.org

10. The developmental logic of
EHDAA2
• precise assignment of develops
from relationships
• subdivide organs by tissue type
inferior parathyroid
• e.g.
mesenchyme epithelium •mesenchyme/epithelium
• leaf nodes in partonomy have full
developmental lineage
3rd arch
3rd arch dorsal 3rd
mesenchyme arch pouch
from neural endoderm RO http://purl.obolibrary.org/obo/ro.owl
crest „has part‟ o „develops from‟ 
„has developmental contribution from‟
neural endoderm
crest
http://www.obofoundry.org/wiki/index.php/EHDAA2:Main_Page

11. equivalence axioms allow
integrative DL queries
inferior parathyroid (Uberon) [mammal]
inferior parathyroid
inferior inferior
mesenchyme epithelium parathyroid parathyroid gland
gland (SNOMED)
(FMA)
equivalent to:
3rd arch „inferior parathyroid[mammal]‟
and „part of‟ some „Homo sapiens‟
3rd arch dorsal 3rd
mesenchyme arch pouch
from neural endoderm OWL-DL Query
crest „has developmental contribution from‟ some
„neural crest‟
neural endoderm http://purl.obolibrary.org/obo/uberon/
crest bridge/collected-mammal.owl

12. integrating disorders and
phenotypes
 Different disorder and phenotype resources
use different ontologies
 MPO (mouse - MGD)
 HPO (human – OMIM, Orphanet)
 PATO+ZFA (zebrafish)
 SNOMED disorders, findings (human – EHRs)
 Provide integrative definitional axioms
 E.g. „neural tube defect‟ EquivalentTo some
morphological abnormalitypatoand „inheres in‟ some
„neural tube‟uberon
 Current work:
 Extending with axioms connecting GO
developmental processes to anatomical structures
CJ Mungall, GV Gkoutos, C Smith, MA Haendel, SE Lewis, M Ashburner
Integrating phenotype ontologies across multiple species. (2010) Genome biology 11 (1), R2

13. OmEO: omics data
 OmEO : Omics Entities Ontology
 http://purl.obolibrary.org/obo/omeo
 Class-based obo-compliant representations of
genes, variants, transcripts, proteins, families and
their relationships
○ Sources:
 ENSEMBL, GO, PANTHER, PRO, MODs
 Expression data
 http://bgee.unil.ch/bgee/bgee
 Functional annotation owl owl owl
 http://geneontology.org
 biogrid
 Phenotype data importer
 Phenotype-commons
○ OMIM  HPO
○ MGI  MPO
○ ZFIN  ZFA+GO_PATO

14. Using the knowledge base
 Current: Access via OWL tool chain
 Reasoner: Elk
 UI: Protégé 4
 Querying and semantic similarity searching
○ http://owltools.googlecode.com
 Core URL:
○ http://purl.obolibrary.org/obo/omeo/devkb.owl
 imports multiple other ontologies via owl:imports chain
 Future: web access via rdftriplestores
 LAMHDI
 Many components are available via neurocommons and
http://ontobee.org
 Challenge:
○ EL++ reasoning required

15. Current applications: enhancing
semantic similarity queries
 Computing semantic similarity between phenotypes
 find candidate disease genes, drugs
 find contributions of individual genes to multi-gene
phenotypes
 find commonalities between diseases
 Adding developmental knowledge enhances
similarity matching
 results available soon in mousefinder
○ http://wwwdev.ebi.ac.uk/panda-
srv/mousefinder/mousefinder.php
R Hoehndorf P Schofield, GV Gkoutos. PhenoNET: a whole phenome approach to disease gene
discovery. NAR 2011
CK Chen, CJ Mungall, GV Gkoutos et al.
MouseFinder: candidate disease genes from mouse phenotype data. Human Mutation 2012

16. Conclusions
 Using uberon and ontology bridging axioms we can start
crossing the „chasm of semantic despair‟
 EHDAA2 and Uberon provide developmental graphs for
humans and a variety of other species
 Can be used to enhance existing ontologies (e.g. FMA,
SNOMED)
 OMEO DevKB integrates multiple ontologies and omics
resources
 Allows for queries and analyses that were not previously
possible
 Availability
 http://uberon.org
 http://www.obofoundry.org/wiki/index.php/EHDAA2:Main_Page
 http://purl.obolibrary.org/obo/omeo/devkb

17. Acknowledgments
 Anatomy Ontologies  EHDAA2
 Melissa Haendel  Jonathan Bard
 Terry Hayamizu  Phenotype Ontologies
 Terry Meehan  George Gkoutos
 Alexander Diehl  Paul Schofield
 David Hill  Sandra Doelken
 Brian Hall  Peter Robinson
 Analysis  OBO Foundry
 Damian Smedley  Barry Smith
 Rob Hoehndorf  Richard Scheuermann
 OWL Infrastructure  Michael Ashburner
 Carlo Torniai  Suzanna Lewis
 Davis Soumi-Sutherland
 HeikoDietze
 Seth Carbon
 Allen Xiang
 Oliver He
 Alan Ruttenberg