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