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

3. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Translational 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.

5. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseases
Almost 4,000 genetic diseases in OMIM have an unknown molecular basis.

6. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseases
OrphaNet
5,917 orphan diseases
2,543 genes linked to 2,544 diseases
2,700 diseases indexed with clinical signs

7. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseases
Animal models have been shown to be highly successful in studying human disease

8. 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 causative
mutations
3 evaluate using real biomedical data

9. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseases
PATO 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

10. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseases
Integration 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

11. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseases
Semantic 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)

12. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseases

13. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseases
OMIM phenotypes
AUC (OMIM): 0.78
AUC (MGI): 0.87

14. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Genetic diseases
OrphaNet phenotypes
AUC (OrphaNet):
0.73
AUC (OMIM): 0.76
AUC (MGI): 0.80

15. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Bassoe Syndrome
Signs 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

16. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Bassoe Syndrome
http://phenomebrowser.net

17. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Bassoe Syndrome
HIP1 knockout mice

18. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Bassoe Syndrome
HIP1 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

19. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Bassoe Syndrome
HIP1 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

20. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Bassoe Syndrome
Computational analysis of mouse phenotypes provides a strong
indication that HIP1 may be involved in Bassoe syndrome.

21. 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, pathway
repositories, gene expression, etc.
future: experimental validation

22. Introduction Animal and disease phenotypes Analysis of the phenome Bassoe Syndrome Conclusions
Thank you!
http://phenomebrowser.net