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
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.
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.
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
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
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
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
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
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)
Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseases
Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseasesOMIM phenotypes
AUC (OMIM): 0.78
AUC (MGI): 0.87
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
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
Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Bassoe Syndromehttp://phenomebrowser.net
Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Bassoe SyndromeHIP1 knockout mice
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
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
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.
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
Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Thank you!
http://phenomebrowser.net