Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers

• DOI: 10.15252/msb.20156108
• Publication Date: 2015-12-15T03:03:18Z
• Authors: Tiziano Pramparo; Michael V Lombardo; Kathleen Campbell; Cynthia Carter Ba...; Steven Marinero; Stephanie Solso; Julia Young; Maisi Mayo; Anders Dale; Clelia Ahrens‐Bar...; Sarah S Murray; Linda Lopez; Nathan Lewis; Karen Pierce; Eric Courchesne
• Keywords: Male; Medicine (General); Bioinformatics; QH301-705.5; Autism Spectrum Disorder; Autism; Intellectual and Developmental Disabilities (IDD); 1.1 Normal biological development and functioning; Bioinformatics and Computational Biology; 610; brain development; Cell Cycle Proteins; 03 medical and health sciences; R5-920; Genetics; Cell Adhesion; 2.1 Biological and endogenous factors; Humans; Gene Regulatory Networks; Autism spectrum disorder; Biology (General); Child; Preschool; co‐expression; Pediatric; 0303 health sciences; gene networks; Gene Expression Profiling; Gene networks; Neurosciences; Brain; Computational Biology; Infant; Articles; Biological Sciences; Brain development; Co-expression; Brain Disorders; co-expression; Mental Health; Gene Expression Regulation; Biochemistry and cell biology; Child, Preschool; Mutation; Mental health; Biochemistry and Cell Biology; Other Biological Sciences

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.