Quantitative trait loci for interhemispheric commissure development and social behaviors in the BTBR T+ tf/J mouse model of autism
Open accessAbstract
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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No genetic variants in ASD risk genes have been identified in the BTBR genome.
“Given that no genetic variants in ASD risk genes have been identified in the BTBR genome (Jones-Davis et al., 2013), this model is considered an idiopathic model of ASD (Meyza and Blanchard, 2017).”
From Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder (2019) · cites this paper as Jones-Davis et al., 2013
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- Authors
- Jones-Davis, D. M., Yang, M., Rider, E., Osbun, N. C., da Gente, G. J., Li, J., Katz, A. M., Weber, M. D., Sen, S., Crawley, J., & Sherr, E. H.
- Affiliations
- National Institutes of Health (US)
- University of California, San Francisco (US)
- Corresponding author
- Sherr, Elliott H.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-04-15
- Volume
- 8
- Issue
- 4
- Pages
- e61829
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3626795
- OpenAlex
- W2045420187
- Cited by
- 61
- References
- 40
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 4 · 2022: 6 · 2021: 5 · 2020: 8 · 2019: 3 · 2018: 5 · 2017: 6 · 2016: 7 · 2015: 5 · 2014: 5 · 2013: 4
- FWCI
- 3.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Pfizer
- National Institutes of Health
- National Institute of Mental Health (MH02179, Z01MH002179)
- National Institute of General Medical Sciences (K12GM081266)
- National Institute of Neurological Disorders and Stroke (R21NS062173, K02NS052192, NS062173)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- autism spectrum disorder, agenesis of the corpus callosum, quantitative trait loci, social behavior, hippocampal commissure, white matter development, axon guidance, synaptic activity, candidate genes, chromosome 4
- MeSH terms
- Animals, Autistic Disorder, Disease Models, Animal, Female, Hippocampus, Male, Phenotype, Social Behavior, Genomics, Chromosomes, Mammalian, Quantitative Trait Loci, Mice, Cerebrum, High-Throughput Nucleotide Sequencing, Agenesis of Corpus Callosum
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