Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers
Open accessAbstract
Genetic mechanisms underlying abnormal early neural development in toddlers with Autism Spectrum Disorder (ASD) remain uncertain due to the impossibility of direct brain gene expression measurement during critical periods of early development. Recent findings from a multi‐tissue study demonstrated high expression of many of the same gene networks between blood and brain tissues, in particular with cell cycle functions. We explored relationships between blood gene expression and total brain volume (TBV) in 142 ASD and control male toddlers. In control toddlers, TBV variation significantly correlated with cell cycle and protein folding gene networks, potentially impacting neuron number and synapse development. In ASD toddlers, their correlations with brain size were lost as a result of considerable changes in network organization, while cell adhesion gene networks significantly correlated with TBV variation. Cell cycle networks detected in blood are highly preserved in the human brain and are upregulated during prenatal states of development. Overall, alterations were more pronounced in bigger brains. We identified 23 candidate genes for brain maldevelopment linked to 32 genes frequently mutated in ASD. The integrated network includes genes that are dysregulated in leukocyte and/or postmortem brain tissue of ASD subjects and belong to signaling pathways regulating cell cycle G1/S and G2/M phase transition. Finally, analyses of the CHD8 subnetwork and altered transcript levels from an independent study of CHD8 suppression further confirmed the central role of genes regulating neurogenesis and cell adhesion processes in ASD brain maldevelopment.
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Functional genomic analyses identified 23 candidate genes for brain maldevelopment linked to 32 upstream high-confidence ASD genes.
“Functional genomic analyses identified 23 candidate genes for brain maldevelopment linked to 32 upstream high-confidence ASD genes [56].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [56]
In analyses of gene expression and MRI measures of brain size at young ages, ASD toddlers with the most abnormal expression of cell cycle hub genes had the most brain overgrowth, while those with milder cell cycle disruption had smaller than normal brain size.
“In analyses of gene expression and MRI measures of brain size at young ages, ASD toddlers with the most abnormal expression of cell cycle hub genes had the most brain overgrowth, while those with milder cell cycle disruption had smaller than normal brain size [56].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [56]
Genes frequently found mutated in ASD may regulate the downstream expression of genes directly relevant to brain size as well as other regulatory genes with cell cycle functions, particularly those involved in the regulation of the G1-S phase transition.
“We recently demonstrated that genes frequently found mutated in ASD1 may regulate the downstream expression of genes directly relevant to brain size as well as other regulatory genes with cell cycle functions, particularly those involved in the regulation of the G1–S phase transition.67”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [67]
A potential major defect underlying early ASD development in dysregulated cell proliferation and differentiation processes likely cannot be adequately examined via study of the ASD brain in later development.
“Thus, a potential major defect underlying early ASD development14, 36, 37, 67 in dysregulated cell proliferation and differentiation processes likely cannot be adequately examined via study of the ASD brain in later development.”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [67]
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References 85 · Cited by 88
- Authors
- Pramparo, T., Lombardo, M. V., Campbell, K., Barnes, C. C., Marinero, S., Solso, S., Young, J., Mayo, M., Dale, A., Ahrens‐Barbeau, C., Murray, S. S., Lopez, L., Lewis, N., Pierce, K., & Courchesne, E.
- Affiliations
- University of California San Diego (US)
- University of Cambridge (GB)
- Scripps Research Institute (US)
- Corresponding author
- Courchesne, Eric
- ORCID
- Venue
- Molecular Systems Biology
- Published
- 2015-12-01
- Volume
- 11
- Issue
- 12
- Pages
- 841-841
- ISSN
- 1744-4292 (ISSN-L)
- PMC
- PMC4704485
- OpenAlex
- W2215644351
- Cited by
- 88
- References
- 85
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 10 · 2023: 5 · 2022: 6 · 2021: 13 · 2020: 15 · 2019: 9 · 2018: 7 · 2017: 9 · 2016: 6
- FWCI
- 4.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Systems Biology (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- CentAUR (University of Reading) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- UCSD CTRI (P50‐MH081755, R01‐MH080134, R01‐MH036840, KL2TR00099, 1KL2TR001444)
- NIH (1U54RR025204‐01)
- Novo Nordisk Foundation
- Center for Biosustainability at the Technical University of Denmark
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Child Nutrition and Feeding Issues
- Keywords
- autism spectrum disorder, toddlers, blood gene expression, brain maldevelopment, total brain volume, CHD8, neurogenesis, cell adhesion, candidate genes, brain size, gene expression dysregulation
- MeSH terms
- Autism Spectrum Disorder, Brain, Cell Adhesion, Child, Preschool, Gene Expression Regulation, Humans, Infant, Male, Mutation, Cell Cycle Proteins, Computational Biology, Gene Expression Profiling, Gene Regulatory Networks
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