Human developmental-kb-2012


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  • 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
  • TODO: key
  • Human developmental-kb-2012

    1. 1. CJ Mungall, C Torniai, JBL Bard, GV Gkoutos, SEssaid, PN Schofield, PN Robinson, D Smedley, M Westerfield, SE Lewis, MA Haendel
    2. 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. 3. Challenges 1. Databases do not speak a common semantic language OpenBiologicalOntologies (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. 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. 5. ontogenetic and phylogeneticknowledge transfer zebrafish mouse human neural tube embryonicdevelopment 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. 6. Strategy for anatomy ontologies SNOMED (anatomy Uberon subset) NCIt (anatomy subset) EMAPA EHDAA2 ZFA MA FMACJ Mungall, C Torniai, GV Gkoutos, SE Lewis, MA Haendel.Uberon, an integrative multi-species anatomy ontology. (2012) Genome biology 13 (1), R5
    7. 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. 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. 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‟
    10. 10. The developmental logic ofEHDAA2 • 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 crest „has part‟ o „develops from‟  „has developmental contribution from‟neural endoderm crest
    11. 11. equivalence axioms allowintegrative 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 crest bridge/collected-mammal.owl
    12. 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 structuresCJ Mungall, GV Gkoutos, C Smith, MA Haendel, SE Lewis, M AshburnerIntegrating phenotype ontologies across multiple species. (2010) Genome biology 11 (1), R2
    13. 13. OmEO: omics data OmEO : Omics Entities Ontology   Class-based obo-compliant representations of genes, variants, transcripts, proteins, families and their relationships ○ Sources:  ENSEMBL, GO, PANTHER, PRO, MODs Expression data  Functional annotation owl owl owl   biogrid Phenotype data importer  Phenotype-commons ○ OMIM  HPO ○ MGI  MPO ○ ZFIN  ZFA+GO_PATO
    14. 14. Using the knowledge base Current: Access via OWL tool chain  Reasoner: Elk  UI: Protégé 4  Querying and semantic similarity searching ○  Core URL: ○  imports multiple other ontologies via owl:imports chain Future: web access via rdftriplestores  LAMHDI  Many components are available via neurocommons and  Challenge: ○ EL++ reasoning required
    15. 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 ○ srv/mousefinder/mousefinder.phpR Hoehndorf P Schofield, GV Gkoutos. PhenoNET: a whole phenome approach to disease genediscovery. NAR 2011CK Chen, CJ Mungall, GV Gkoutos et al.MouseFinder: candidate disease genes from mouse phenotype data. Human Mutation 2012
    16. 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   
    17. 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