Quantitative Trait Loci for Interhemispheric Commissure Development and Social Behaviors in the BTBR T+ tf/J Mouse Model of Autism

Dorothy M. Jones-Davis, Mu Yang, Eric Rider, Nathan C. Osbun, Gilberto J. da Gente, Jiang Li, Adam M. Katz, Michael D. Weber, Saunak Sen, Jacqueline Crawley, Elliott H. Sherr

Research output: Contribution to journalArticle

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Abstract

Background:Autism and Agenesis of the Corpus Callosum (AgCC) are interrelated behavioral and anatomic phenotypes whose genetic etiologies are incompletely understood. We used the BTBR T+ tf/J (BTBR) strain, exhibiting fully penetrant AgCC, a diminished hippocampal commissure, and abnormal behaviors that may have face validity to autism, to study the genetic basis of these disorders.Methods:We generated 410 progeny from an F2 intercross between the BTBR and C57BL/6J strains. The progeny were phenotyped for social behaviors (as juveniles and adults) and commisural morphology, and genotyped using 458 markers. Quantitative trait loci (QTL) were identified using genome scans; significant loci were fine-mapped, and the BTBR genome was sequenced and analyzed to identify candidate genes.Results:Six QTL meeting genome-wide significance for three autism-relevant behaviors in BTBR were identified on chromosomes 1, 3, 9, 10, 12, and X. Four novel QTL for commissural morphology on chromosomes 4, 6, and 12 were also identified. We identified a highly significant QTL (LOD score = 20.2) for callosal morphology on the distal end of chromosome 4.Conclusions:We identified several QTL and candidate genes for both autism-relevant traits and commissural morphology in the BTBR mouse. Twenty-nine candidate genes were associated with synaptic activity, axon guidance, and neural development. This is consistent with a role for these processes in modulating white matter tract development and aspects of autism-relevant behaviors in the BTBR mouse. Our findings reveal candidate genes in a mouse model that will inform future human and preclinical studies of autism and AgCC.

Original languageEnglish (US)
Article numbere61829
JournalPLoS One
Volume8
Issue number4
DOIs
StatePublished - Apr 15 2013

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Corpus Callosum
Social Behavior
Quantitative Trait Loci
Autistic Disorder
social behavior
quantitative trait loci
Genes
animal models
Agenesis of Corpus Callosum
Chromosomes
Chromosomes, Human, Pair 4
Genome
chromosomes
genome
genes
Brain Fornix
Chromosomes, Human, Pair 12
abnormal behavior
Inborn Genetic Diseases
Chromosomes, Human, Pair 6

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Jones-Davis, D. M., Yang, M., Rider, E., Osbun, N. C., da Gente, G. J., Li, J., ... Sherr, E. H. (2013). Quantitative Trait Loci for Interhemispheric Commissure Development and Social Behaviors in the BTBR T+ tf/J Mouse Model of Autism. PLoS One, 8(4), [e61829]. https://doi.org/10.1371/journal.pone.0061829

Quantitative Trait Loci for Interhemispheric Commissure Development and Social Behaviors in the BTBR T+ tf/J Mouse Model of Autism. / Jones-Davis, Dorothy M.; Yang, Mu; Rider, Eric; Osbun, Nathan C.; da Gente, Gilberto J.; Li, Jiang; Katz, Adam M.; Weber, Michael D.; Sen, Saunak; Crawley, Jacqueline; Sherr, Elliott H.

In: PLoS One, Vol. 8, No. 4, e61829, 15.04.2013.

Research output: Contribution to journalArticle

Jones-Davis, DM, Yang, M, Rider, E, Osbun, NC, da Gente, GJ, Li, J, Katz, AM, Weber, MD, Sen, S, Crawley, J & Sherr, EH 2013, 'Quantitative Trait Loci for Interhemispheric Commissure Development and Social Behaviors in the BTBR T+ tf/J Mouse Model of Autism', PLoS One, vol. 8, no. 4, e61829. https://doi.org/10.1371/journal.pone.0061829
Jones-Davis, Dorothy M. ; Yang, Mu ; Rider, Eric ; Osbun, Nathan C. ; da Gente, Gilberto J. ; Li, Jiang ; Katz, Adam M. ; Weber, Michael D. ; Sen, Saunak ; Crawley, Jacqueline ; Sherr, Elliott H. / Quantitative Trait Loci for Interhemispheric Commissure Development and Social Behaviors in the BTBR T+ tf/J Mouse Model of Autism. In: PLoS One. 2013 ; Vol. 8, No. 4.
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abstract = "Background:Autism and Agenesis of the Corpus Callosum (AgCC) are interrelated behavioral and anatomic phenotypes whose genetic etiologies are incompletely understood. We used the BTBR T+ tf/J (BTBR) strain, exhibiting fully penetrant AgCC, a diminished hippocampal commissure, and abnormal behaviors that may have face validity to autism, to study the genetic basis of these disorders.Methods:We generated 410 progeny from an F2 intercross between the BTBR and C57BL/6J strains. The progeny were phenotyped for social behaviors (as juveniles and adults) and commisural morphology, and genotyped using 458 markers. Quantitative trait loci (QTL) were identified using genome scans; significant loci were fine-mapped, and the BTBR genome was sequenced and analyzed to identify candidate genes.Results:Six QTL meeting genome-wide significance for three autism-relevant behaviors in BTBR were identified on chromosomes 1, 3, 9, 10, 12, and X. Four novel QTL for commissural morphology on chromosomes 4, 6, and 12 were also identified. We identified a highly significant QTL (LOD score = 20.2) for callosal morphology on the distal end of chromosome 4.Conclusions:We identified several QTL and candidate genes for both autism-relevant traits and commissural morphology in the BTBR mouse. Twenty-nine candidate genes were associated with synaptic activity, axon guidance, and neural development. This is consistent with a role for these processes in modulating white matter tract development and aspects of autism-relevant behaviors in the BTBR mouse. Our findings reveal candidate genes in a mouse model that will inform future human and preclinical studies of autism and AgCC.",
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AU - Rider, Eric

AU - Osbun, Nathan C.

AU - da Gente, Gilberto J.

AU - Li, Jiang

AU - Katz, Adam M.

AU - Weber, Michael D.

AU - Sen, Saunak

AU - Crawley, Jacqueline

AU - Sherr, Elliott H.

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N2 - Background:Autism and Agenesis of the Corpus Callosum (AgCC) are interrelated behavioral and anatomic phenotypes whose genetic etiologies are incompletely understood. We used the BTBR T+ tf/J (BTBR) strain, exhibiting fully penetrant AgCC, a diminished hippocampal commissure, and abnormal behaviors that may have face validity to autism, to study the genetic basis of these disorders.Methods:We generated 410 progeny from an F2 intercross between the BTBR and C57BL/6J strains. The progeny were phenotyped for social behaviors (as juveniles and adults) and commisural morphology, and genotyped using 458 markers. Quantitative trait loci (QTL) were identified using genome scans; significant loci were fine-mapped, and the BTBR genome was sequenced and analyzed to identify candidate genes.Results:Six QTL meeting genome-wide significance for three autism-relevant behaviors in BTBR were identified on chromosomes 1, 3, 9, 10, 12, and X. Four novel QTL for commissural morphology on chromosomes 4, 6, and 12 were also identified. We identified a highly significant QTL (LOD score = 20.2) for callosal morphology on the distal end of chromosome 4.Conclusions:We identified several QTL and candidate genes for both autism-relevant traits and commissural morphology in the BTBR mouse. Twenty-nine candidate genes were associated with synaptic activity, axon guidance, and neural development. This is consistent with a role for these processes in modulating white matter tract development and aspects of autism-relevant behaviors in the BTBR mouse. Our findings reveal candidate genes in a mouse model that will inform future human and preclinical studies of autism and AgCC.

AB - Background:Autism and Agenesis of the Corpus Callosum (AgCC) are interrelated behavioral and anatomic phenotypes whose genetic etiologies are incompletely understood. We used the BTBR T+ tf/J (BTBR) strain, exhibiting fully penetrant AgCC, a diminished hippocampal commissure, and abnormal behaviors that may have face validity to autism, to study the genetic basis of these disorders.Methods:We generated 410 progeny from an F2 intercross between the BTBR and C57BL/6J strains. The progeny were phenotyped for social behaviors (as juveniles and adults) and commisural morphology, and genotyped using 458 markers. Quantitative trait loci (QTL) were identified using genome scans; significant loci were fine-mapped, and the BTBR genome was sequenced and analyzed to identify candidate genes.Results:Six QTL meeting genome-wide significance for three autism-relevant behaviors in BTBR were identified on chromosomes 1, 3, 9, 10, 12, and X. Four novel QTL for commissural morphology on chromosomes 4, 6, and 12 were also identified. We identified a highly significant QTL (LOD score = 20.2) for callosal morphology on the distal end of chromosome 4.Conclusions:We identified several QTL and candidate genes for both autism-relevant traits and commissural morphology in the BTBR mouse. Twenty-nine candidate genes were associated with synaptic activity, axon guidance, and neural development. This is consistent with a role for these processes in modulating white matter tract development and aspects of autism-relevant behaviors in the BTBR mouse. Our findings reveal candidate genes in a mouse model that will inform future human and preclinical studies of autism and AgCC.

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