A translational medicine approach to orphan diseases

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A translational medicine approach to orphan diseases

  1. 1. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions A translational medicine approach to orphan diseases Robert Hoehndorf and George Gkoutos University of Cambridge Aberystwyth University 20 September 2012
  2. 2. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsTranslational research National Cancer Institute: Translational research transforms scientific discoveries arising from laboratory, clinical, or population studies into clinical applications to reduce [disease] incidence, morbidity, and mortality.
  3. 3. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsGenetic diseasesAlmost 4,000 genetic diseases in OMIM have an unknown molecular basis.
  4. 4. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsGenetic diseasesOrphaNet 5,917 orphan diseases 2,543 genes linked to 2,544 diseases 2,700 diseases indexed with clinical signs
  5. 5. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsGenetic diseasesAnimal models have been shown to be highly successful in studying human disease
  6. 6. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsApproach 1 make animal and human phenotypes comparable 2 systematically analyze the phenome for possible causative mutations 3 evaluate using real biomedical data
  7. 7. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsGenetic diseasesPATO and the EQ method enable the integration of phenotype ontologies across species. use of Entity-Quality definitions integration based on species-independent ontologies GO ChEBI, Protein ontology, Celltype ontology anatomy ontologies + homology
  8. 8. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsGenetic diseasesIntegration of phenotypes enables direct comparison between species Proximal fibular overgrowth Abnormal fibula morphology (HPO): (MP): E: Proximal epiphysis of E: fibula fibula Q: morphology (abnormal) Q: hypertrophic UBERON: fibula (MA) orthologous to Fibula (FMA) FMA: Proximal epiphysis of fibula part-of fibula PATO: hypertrophic is-a morphology Proximal fibular overgrowth is-a Abnormal fibula morphology
  9. 9. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsGenetic diseasesSemantic similarity over phenotype ontologies measures phenotypic similarity. semantic similarity: metric based on information contained in the axioms of an ontology pairwise comparison of disease and animal phenotypes IC (x) x∈Cl(P)∩Cl(D) sim(P, D) = IC (y ) y ∈Cl(P)∪Cl(D)
  10. 10. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsGenetic diseases
  11. 11. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsGenetic diseasesOMIM phenotypes AUC (OMIM): 0.78 AUC (MGI): 0.87
  12. 12. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsGenetic diseasesOrphaNet phenotypes AUC (OrphaNet): 0.73 AUC (OMIM): 0.76 AUC (MGI): 0.80
  13. 13. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsBassoe SyndromeSigns and symptoms skeletal: kyphosis, hypertensible joints, cubitus valgus muscular: hypotonia, muscle hypotrophy, amyotrophy behavior: abnormal gait, amimia visual: cataract, strabismus reproductive: hypogonadism, hypogenitalism, abnormal ovaries, hypoplastic testis, reduced fertility
  14. 14. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsBassoe Syndromehttp://phenomebrowser.net
  15. 15. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsBassoe SyndromeHIP1 knockout mice
  16. 16. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsBassoe SyndromeHIP1 mouse phenotypes Bassoe Syndrome: Mouse phenotypes: kyphosis, hypertensible kyphosis, abnormal spine curvature, joints, cubitus valgus lordosis amyotrophy, hypotonia, abnormal muscle morphology muscle hypotrophy abnormal gait, amimia abnormal gait, hypoactivity, tremors cataract, strabismus nuclear cataracts, microphthalmia testicular atrophy, hypogonadism, testicular atrophy, male infertility hypogenitalism, abnormal ovaries, reduced fertility
  17. 17. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsBassoe SyndromeHIP1 mouse phenotypes Bassoe Syndrome: Mouse phenotypes: kyphosis, hypertensible kyphosis, abnormal spine curvature, joints, cubitus valgus lordosis amyotrophy, hypotonia, abnormal muscle morphology, muscle muscle hypotrophy hypotrophy, muscle wasting abnormal gait, amimia abnormal gait, hypoactivity, tremors, failure to thrive, ataxia cataract, strabismus nuclear cataracts, microphthalmia testicular atrophy, hypogonadism, testicular atrophy, male infertility, hypogenitalism, ovarian abnormalities, testicular abnormal ovaries, degeneration, increased apoptosis of reduced fertility postmeiotic spermatids, oligospermia
  18. 18. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsBassoe Syndrome Computational analysis of mouse phenotypes provides a strong indication that HIP1 may be involved in Bassoe syndrome.
  19. 19. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome ConclusionsSummary and future work phenotype-based analysis can suggest candidate genes requires no prior information about molecular basis of disease future: integration with literature mining, pathway repositories, gene expression, etc. future: experimental validation
  20. 20. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions Thank you! http://phenomebrowser.net

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