Autism Candidate Genes via

Mouse Phenomics

Terrence F. Meehana,, Christopher J. Carra,1, Jeremy J. Jaya, Carol J.

Bulta, Elissa J. Cheslera, Judith A. Blakea
a The Jackson Laboratory, 600 Main St. Bar Harbor, ME 04609 USA

1 Present address: North Carolina State University, Raleigh, NC USA

ASD & Mouse Phenomics

Autism Spectrum Disorders (ASD)

ASD has a strong genetic component
Mouse models of ASD have given valuable insights
Mouse Genome Informatics (MGI) is the repository
for mouse genomic data
phenotypic data represented by the Mammalian
Phenotype ontology (MP)
7961 MP terms annotated to >13,000 genes
Autism mouse models underrepresented in database
 Search “Autism”

Phenologs

Enriched MP Terms
ODE
Phenome
Map
Highly associated mouse genes
Literature MGI
Review Curation

Identified Mouse Models

8 genes from
ASD mouse models
ODE
MouseNET
ABBA
Mouse Genes
Expanded
Gene List

Mouse Genes

Comparison
(MP, CNV)

Orthologous Genes

ASD-Candidate
Genes by Mouse
Phenomics
 Phenologs
Associated
Human Autistic Mouse Mouse Genes
MP Terms
Genes (OMIM) Orthologs (Phenologs)
Abnormal
MET Met Social 13
Investigation

MECP2 Mecp2 Impaired

Coordination 151

NLGN3 Nlgn3
Abnormal
Behavior
19
EN2 En2
Abnormal
Cerebellar 25
GLO1 Glo1 Foliation

Small
NLGN4X Cerebellum 39

Abnormal Motor
SHANK3
Capabilities 66

Systematic discovery of non-obvious human disease models through orthologous phenotypes Kriston L, et. al. (Edward M. Marcotte), Proc
Natl Acad Sci U S A, 2010 Apr 6;107(14):6544 
Phenome Map- Finding common connectivity to
ASD-related phenotypes
Legend (MP Term IDs)
MP:0002066 – Abnormal motor capabilities
En2 MP:0000852 – Small cerebellum
MP:0000857 – Abnormal cerebellar foliation
MP:0001405 – Impaired coordination
MP:0001360 – Abnormal social investigation
MP:0004924 – Abnormal behavior

Rora Gabrb3

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.
 Anchored Best Biomolecular Associates (ABBA)
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-sets
M : genes
22: En1, Grin1, L1cam
18: En1, Grin1, L1cam, Shh, Itgb1, Htt , Numb
16: 22 genes
9: 329 genes
 Rare CNVs enriched in
ASD patients
CNVs are small,
impacting only 1 or 2
genes
Over 300 genes
implicated
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.
Intersection of datasets prioritizes genes

Anks1b
Dsc3

Camk4 Cask
Chrna3
Chrnb4
Fgfr3 Ghr
Plcb4 Thrb
Unc5c
Lets add Autworks!

Cas
k
Conclusions
MP and other MGI annotations are a rich resource for
integrated analysis for gene identification

Mouse strains with phenotypes similar to ASD models can

find new ASD gene candidates or prioritize existing candidate
genes

Approach is generalizable for sparsely characterized complex

human genetic diseases
MGI lists 1,071 Human diseases with one or more mouse models
 Acknowledgements
The Jackson Laboratory
Judith Blake
Carol Bult (MouseNET)
Christopher Carr (JAX Summer student)
Elissa Chesler
Jeremy Waselovich
Phenologs resource
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).
ABBA- Anchored Bicliques of Biomolecular Associates
• ABBA takes input genes
• finds gene-sets with >2
inputs genes
• output list of enriched
genes ranked by number
of genesets they appear on

• Performed a precision,
recall analysis using a list
of human ASD 137 genes
as true positives

• Compared results to 1000

randomly drawn ranked
gene lists and plotted the
precision and recall at a
95% confidence level
 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.
 ASD candidate
genes
• Analyzed candidate
genes for:
• Prior association with
ASD
• Association with
neurological 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.