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Linking Animal Models and Human Diseases
Supported by NIH P41 HG002659, U54 HG004028, & R01 HG004838
Cambridge University & the University of Oregon
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Yvonne Bradford
Melissa Haendel
Barbara Ruef
Kevin Schaper
Erik Segerdell
Amy Singer
Michael Ashburner
Rachel Drysdale
George Gkoutos
Paul Schofield
David Sutherland
Mark Gibson
Suzi Lewis
Chris Mungall
Nicole WashingtonSebastian Bauer
Sandra Dölken
Peter Robinson
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Develop methods to:
• Describe phenotypes• Compare descriptions (annotations)• Search phenotypes within and across species
Linking Animal Models and Human Diseases
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zebrafish fly
human
zebrafish
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Humans Animal models
Mutant Gene
Mutant or missing Protein
Mutant Phenotype (disease)
Mutant Gene
Mutant or missing Protein
Mutant Phenotype (disease model)
Animal disease models
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Humans Animal models
Mutant Gene
Mutant or missing Protein
Mutant Phenotype (disease)
Mutant Gene
Mutant or missing Protein
Mutant Phenotype (disease model)
BLAST
BLAST
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Humans Animal models
Mutant Gene
Mutant or missing Protein
Mutant Phenotype (disease)
Mutant Gene
Mutant or missing Protein
Mutant Phenotype (disease model)
Shared ontologies and syntax can connect mutant phenotypes to
candidate human disease genes
PhenoBLAST
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OMIM is a free-text disease description source
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OMIM Query # of records
“large bone” 785
"enlarged bone" 156
"big bones" 16
"huge bones" 4
"massive bones" 28
"hyperplastic bones" 12
"hyperplastic bone" 40
"bone hyperplasia" 134
"increased bone growth" 612
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eye small+
Entity Quality+Phenotype
EQ1
=
=EQ2 = kidney + hypoplastic
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Entity Quality+Phenotype(clinical sign) =
Anatomical ontology
Cell & tissue ontology
Developmental ontology
Gene ontology
biological process
molecular function
cellular component
+ PATO
Ontologies for Phenotype Annotation
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Develop methods to:
• Describe phenotypes
• Compare descriptions (annotations)
• Search phenotypes within and across species
Linking Animal Models and Human Diseases
![Page 13: Linking Animal Models and Human Diseases Supported by NIH P41 HG002659, U54 HG004028, & R01 HG004838 Cambridge University & the University of Oregon](https://reader036.vdocument.in/reader036/viewer/2022062422/56649f145503460f94c285f0/html5/thumbnails/13.jpg)
OMIMgenes
ZFINmutantgenes
FlyBasemutantgenes
Strategy: use shared genes as proof of principle
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• Annotate phenotypes in human, zebrafish, and fly
• Annotate human phenotypes triple blind
• Compare annotations
+
+
ZFIN
BBOP
FlyBase
OBD
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~10% of the annotations for 1 gene
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Curator 1Curator 1 Curator 2Curator 2 Curator 3Curator 3
Annotations vary among curators
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Curator 1 Curator 2 Curator 3
Ontologies support comparisons
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Subsumption reasoning for similarity scoring
Information content (IC) is calculated based on depth within the ontology and annotation frequency
Similarity is calculated
based on ratio
of IC values
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EYA1 SOX10 SOX9 PAX2
0.78 0.71 0.61 0.72
# A
nn
ota
tio
ns
congruence
total annotationstotal annotations
similar annotationssimilar annotations
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Develop methods to:
• Describe phenotypes• Compare descriptions (annotations)
• Search phenotypes within and across species
Linking Animal Models and Human Diseases
![Page 22: Linking Animal Models and Human Diseases Supported by NIH P41 HG002659, U54 HG004028, & R01 HG004838 Cambridge University & the University of Oregon](https://reader036.vdocument.in/reader036/viewer/2022062422/56649f145503460f94c285f0/html5/thumbnails/22.jpg)
All alleles are significantly more similar to alleles of the same gene than to alleles of other genes p<0.0001
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shha query against zebrafish returns signaling pathway members
Annotations can identify other pathway members
Similarity search for zebrafish shhat4/t4 identifies pathway members
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A search for phenotypes similar to:
Human EYA1 variant OMIM:601653 MP:deafness = E = Sensory perception of sound Q = absent
Human phenotypes identify mutations in orthologous model organism genes
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A search for phenotypes similar to:
Human EYA1 variant OMIM:601653 MP:deafness = E = Sensory perception of sound Q = absent
returns:
Mouse Eya1 bor/bor and Eya1tm1Rilm/tm1Rilm
E = Sensory perception of sound Q = decreased
Human phenotypes identify mutations in orthologous model organism genes
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Zebrafish:ZFIN(EQ)
Zebrafish:ZFIN(EQ)
Human:OMIM(HPO)
Human:OMIM(HPO)
Human:DECIPHER(LDD)
Human:DECIPHER(LDD)
Mouse:MGI(MP)
Mouse:MGI(MP)
Rat:RGD(MP)
Rat:RGD(MP)
HPO<->EQ
EQ<->HPO<->LDD
EQ<->MP
Ontology mappings support cross-species comparisons
(Funded by NIH R01 HG004838)
MP<->EQ OBD
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Develop methods to:
• Describe phenotypes• Compare descriptions (annotations)• Search phenotypes within and across species
Linking Animal Models and Human Diseases
![Page 28: Linking Animal Models and Human Diseases Supported by NIH P41 HG002659, U54 HG004028, & R01 HG004838 Cambridge University & the University of Oregon](https://reader036.vdocument.in/reader036/viewer/2022062422/56649f145503460f94c285f0/html5/thumbnails/28.jpg)
Linking Animal Models and Human Diseases
Supported by NIH P41 HG002659, U54 HG004028, & R01 HG004838
Cambridge University & the University of Oregon
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Vocabulary
Anatomical system
Cornea
Embryo
Eye
Nervous system
Visual system
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Ontology
Embryo
Anatomical system
Nervous system
Visual system
Eye
Cornea