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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
A translational medicine approach to orphandiseases
Robert Hoehndorf and George Gkoutos
University of CambridgeAberystwyth University
20 September 2012
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Translational research
National Cancer Institute:
Translational research transforms scientific discoveries arising fromlaboratory, clinical, or population studies into clinical applicationsto reduce [disease] incidence, morbidity, and mortality.
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseasesAlmost 4,000 genetic diseases in OMIM have an unknown molecular basis.
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseasesOrphaNet
5,917 orphan diseases
2,543 genes linked to 2,544 diseases
2,700 diseases indexed with clinical signs
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseasesAnimal models have been shown to be highly successful in studying human disease
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Approach
1 make animal and human phenotypes comparable
2 systematically analyze the phenome for possible causativemutations
3 evaluate using real biomedical data
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseasesPATO and the EQ method enable the integration of phenotype ontologies across species.
use of Entity-Quality definitions
integration based on species-independent ontologies
GOChEBI, Protein ontology, Celltype ontologyanatomy ontologies + homology
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseasesIntegration of phenotypes enables direct comparison between species
Proximal fibular overgrowth(HPO):
E: Proximal epiphysis offibula
Q: hypertrophic
Abnormal fibula morphology(MP):
E: fibula
Q: morphology (abnormal)
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
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseasesSemantic similarity over phenotype ontologies measures phenotypic similarity.
semantic similarity: metric based on information contained inthe axioms of an ontology
pairwise comparison of disease and animal phenotypes
sim(P,D) =
∑x∈Cl(P)∩Cl(D)
IC (x)
∑y∈Cl(P)∪Cl(D)
IC (y)
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseases
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseasesOMIM phenotypes
AUC (OMIM): 0.78
AUC (MGI): 0.87
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseasesOrphaNet phenotypes
AUC (OrphaNet):0.73
AUC (OMIM): 0.76
AUC (MGI): 0.80
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Bassoe 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, hypoplastictestis, reduced fertility
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Bassoe Syndromehttp://phenomebrowser.net
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Bassoe SyndromeHIP1 knockout mice
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Bassoe SyndromeHIP1 mouse phenotypes
Bassoe Syndrome:
kyphosis, hypertensiblejoints, cubitus valgus
amyotrophy, hypotonia,muscle hypotrophy
abnormal gait, amimia
cataract, strabismus
testicular atrophy,hypogonadism,hypogenitalism,abnormal ovaries,reduced fertility
Mouse phenotypes:
kyphosis, abnormal spine curvature,lordosis
abnormal muscle morphology
, musclehypotrophy, muscle wasting
abnormal gait, hypoactivity, tremors
,failure to thrive, ataxia
nuclear cataracts, microphthalmia
testicular atrophy, male infertility
,ovarian abnormalities, testiculardegeneration, increased apoptosis ofpostmeiotic spermatids, oligospermia
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Bassoe SyndromeHIP1 mouse phenotypes
Bassoe Syndrome:
kyphosis, hypertensiblejoints, cubitus valgus
amyotrophy, hypotonia,muscle hypotrophy
abnormal gait, amimia
cataract, strabismus
testicular atrophy,hypogonadism,hypogenitalism,abnormal ovaries,reduced fertility
Mouse phenotypes:
kyphosis, abnormal spine curvature,lordosis
abnormal muscle morphology, musclehypotrophy, muscle wasting
abnormal gait, hypoactivity, tremors,failure to thrive, ataxia
nuclear cataracts, microphthalmia
testicular atrophy, male infertility,ovarian abnormalities, testiculardegeneration, increased apoptosis ofpostmeiotic spermatids, oligospermia
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Bassoe Syndrome
Computational analysis of mouse phenotypes provides a strongindication that HIP1 may be involved in Bassoe syndrome.
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Summary and future work
phenotype-based analysis can suggest candidate genes
requires no prior information about molecular basis of disease
future: integration with literature mining, pathwayrepositories, gene expression, etc.
future: experimental validation
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Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Thank you!
http://phenomebrowser.net