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Human developmental-kb-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
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
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
Editor's Notes
Many disorders arise through some kind of failure of a developmental process. An understanding of these developmental processes at the level of molecular biology and gross anatomy can inform our understanding of these disorders.Connecting datasets via development.Development: the process of one structure changing into another.
obo foundrychasm of semantic despair
Select orthogonal ontologies covering domainCreate bridging ontologiesCurate high quality developmental graph * aim: have full lineage for every structure, genes and pathways active at each stageEnhance with OWL2 axioms for advanced reasoningTranslate omics resources to OWLBuild knowledge base in modular fashion using small ontologies and import chains Query using fast EL++ reasonersDevelop data mining tools on top of the OWL API
Basic schema. Both ontogeny and phylogeny can inform our approach.Our understanding of disorders exhibited in the post-natal and adult human can be informed both by looking at equivalent structures in experimentally tractable model systems, and by looking at the lineage of that structure. E.gspina bifida and neural tube closure. These can be combined – our understanding of human development is informed by model systems, although there can be important differences – these inform us too.
We created a bridging
We apply expert knowledge to the task of completing developmental relationships. In collaborations with the NSF phenoscape RCN we held a workshop at the National Evolutionary Synthesis Center dedicated to completing neural crest relationships in existing ontologies
We apply expert knowledge to the task of completing developmental relationships. In collaborations with the NSF phenoscape RCN we held a workshop at the National Evolutionary Synthesis Center dedicated to completing neural crest relationships in existing ontologies