Terrence Meehan - Autism Candidate Genes via Mouse Phenomics
Transcript of Terrence Meehan - Autism Candidate Genes via Mouse Phenomics
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Terrence F. Meehana,, Christopher J. Carra,1, Jeremy J. Jaya, Carol J.
Bulta
, Elissa J. Cheslera
, Judith A. Blakea
aThe Jackson Laboratory, 600 Main St. Bar Harbor, ME 04609 USA1 Present address: North Carolina State University, Raleigh, NC
USA
Autism Candidate Genes via MouseAutism Candidate Genes via Mouse
PhenomicsPhenomics
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y Autism Spectrum Disorders (ASD)
y ASD has a strong genetic component
y Mouse models of ASD have given valuable insights
y Mouse Genome Informatics (MGI) is the repository for
mouse genomic data
y phenotypic data represented by the Mammalian Phenotype
ontology (MP)
y 7961 MP terms annotated to >13,000 genes
y Autism mouse models underrepresented in database
ASD & Mouse Phenomics
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Phenolog
s
ODE
Phenome
Map
Literature
Review
ODE
ABBAMouseNET
Expanded
Gene List
Search Autism
Enriched MP Terms
Highly associated mouse genes
Mouse Genes
8 genes fromASD mouse models
MGI
Curation
Identified Mouse Models
Comparison
(MP, CNV)
Mouse Genes
ASD-Candidate
Genes by Mouse
Phenomics
Orthologous Genes
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MET
MECP2
NLGN3
NLGN4X
SHANK3
Mecp2
Met
Nlgn3
GLO1 Glo1
EN2 En2
Small
Cerebellum
Abnormal
Cerebellar
Foliation
Abnormal
Behavior
Impaired
Coordination
Abnormal
Social
Investigation13
151
19
25
39
Human AutisticGenes (OMIM)
MouseOrthologs
MP Terms
Associated
Mouse Genes(Phenologs)
Abnormal Motor
Capabilities66
Phenologs
Systematic discovery of non-obvious human disease models through orthologous phenotypesKriston L, et. al. (Edward M. Marcotte), Proc NatlAcad Sci U S A, 2010 Apr 6;107(14):6544
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En2
Rora Gabrb3
Legend (MP Term IDs)
MP:0002066 Abnormal motor capabilitiesMP:0000852 Small cerebellumMP:0000857 Abnormal cerebellar foliationMP:0001405 Impaired coordinationMP:0001360 Abnormal social investigationMP:0004924 Abnormal behavior
Phenome Map- Finding common connectivity to
ASD-related phenotypes
Ontological Discovery Environment: a system for integrating gene-phenotype associations.Baker EJ, Jay JJ, Philip VM, Zhang Y, Li Z, Kirova R, Langston MA, Chesler EJ. Genomics. 2009 Dec;94(6):377-87.
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USER QUERY:
genes of interest -Cadps2 En2 Gabrb3 Gstm1
Nlgn3 Pten Ehmt1 Nrcam
Common gene-sets
associated to at least N (2)
genes of interest
Functional partner genes
associated to at least M gene-setsM : genes
22: En1, Grin1, L1cam18: En1, Grin1, L1cam, Shh, Itgb1, Htt , Numb
16: 22 genes
9: 329 genes
Anchored Best Biomolecular Associates (ABBA)
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y Rare CNVs enriched in
ASD patients
y CNVs are small, impacting
only 1 or 2 genesy Over 300 genes implicated
y A warning of what is to
come
D. Pinto, A.T. Pagnamenta, L. Klei, R. Anney, D. Merico, R. Regan, et al., Functional impact of global rare copy number variation in autism
spectrum disorders, Nature. 466 (2010) 368-372.
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Intersection of datasets prioritizes
genes
Camk4 CaskChrna3 Chrnb4
Fgfr3 Ghr
Plcb4 Thrb
Unc5c
Anks1b Dsc3
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Lets add Autworks!
Cask
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Conclusionsy MP and other MGI annotations are a rich resource for integrated
analysis for gene identification
y Mouse strains with phenotypes similar to ASD models can find
new ASD gene candidates or prioritize existing candidate genes
y Approach is generalizable for sparsely characterized complex
human genetic diseases
y MGI lists 1,071 Human diseases with one or more mouse models
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Acknowledgements
y The Jackson Laboratory
y Judith Blake
y Carol Bult (MouseNET)
y
Christopher Carr (JAX Summer student)y Elissa Chesler
y Jeremy Waselovich
y Phenologs resource
y
Edward Marcotte
This work was supported by the National Human Genome Research Institute grant HG00330 (CB, CC, JB, TFM), the National Institute on
Alcohol Abuse and Alcoholism grant AA18776 (EC, JJ), and the Jackson Laboratory Summer Student Program funded in party by the
Horace W. Goldsmith Foundation (CC).
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ABBA- Anchored Bicliques of
Biomolecular Associates ABBA takes input genes
finds gene-sets with>2 inputs genes
output list of enrichedgenes ranked bynumber of genesets
they appear on
Performed a precision,recall analysis using a listof human ASD 137genes as true positives
Compared results to1000 randomly drawnranked gene lists andplotted the precision andrecall at a 95%confidence level
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Discovering new ASD gene candidates
Integrate tools that use the MP ontology
Find ASD gene candidates through guilt by association
Compare candidate list to known and putative ASD genes
(CNV study of ASD patients)
D. Pinto, A.T. Pagnamenta, L. Klei, R. Anney, D. Merico, R. Regan, et al., Functional impact of global rare copy number variation in autism spectrum disorders, Nature. 466(2010) 368-372.
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ASD candidate
genes Analyzed candidate
genes for:
Prior association with
ASD
Association withneurological or
behavioral MP terms
Overlap with genes
implicated in CNV
study of ASD patients
D. Pinto, A.T. Pagnamenta, L. Klei, R. Anney, D. Merico, R. Regan, et al., Functional impact of global rare copy number variation in autism spectrum disorders, Nature. 466(2010) 368-372.