terrence meehan - autism candidate genes via mouse phenomics

8/7/2019 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.

terrence meehan - autism candidate genes via mouse phenomics

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