title: Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers.
abstract: 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.
authors.affiliation: Department of Neurosciences, UC San Diego Autism Center, School of Medicine University of California San Diego, La Jolla, CA, USA.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Pramparo
authors.affiliation: Department of Psychology, University of Cyprus, Nicosia, Cyprus Center for Applied Neuroscience, University of Cyprus, Nicosia, Cyprus Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Lombardo
authors.affiliation: Department of Neurosciences, UC San Diego Autism Center, School of Medicine University of California San Diego, La Jolla, CA, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Campbell
authors.affiliation: Department of Neurosciences, UC San Diego Autism Center, School of Medicine University of California San Diego, La Jolla, CA, USA.
authors.forename: Cynthia Carter
authors.initials: CC
authors.lastname: Barnes
authors.affiliation: Department of Neurosciences, UC San Diego Autism Center, School of Medicine University of California San Diego, La Jolla, CA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Marinero
authors.affiliation: Department of Neurosciences, UC San Diego Autism Center, School of Medicine University of California San Diego, La Jolla, CA, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Solso
authors.affiliation: Department of Neurosciences, UC San Diego Autism Center, School of Medicine University of California San Diego, La Jolla, CA, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Young
authors.affiliation: Department of Neurosciences, UC San Diego Autism Center, School of Medicine University of California San Diego, La Jolla, CA, USA.
authors.forename: Maisi
authors.initials: M
authors.lastname: Mayo
authors.affiliation: Department of Neurosciences, UC San Diego Autism Center, School of Medicine University of California San Diego, La Jolla, CA, USA.
authors.forename: Anders
authors.initials: A
authors.lastname: Dale
authors.affiliation: Department of Neurosciences, UC San Diego Autism Center, School of Medicine University of California San Diego, La Jolla, CA, USA.
authors.forename: Clelia
authors.initials: C
authors.lastname: Ahrens-Barbeau
authors.affiliation: Scripps Genomic Medicine & The Scripps Translational Sciences Institute (STSI), La Jolla, CA, USA Department of Pathology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Murray
authors.affiliation: Department of Neurosciences, UC San Diego Autism Center, School of Medicine University of California San Diego, La Jolla, CA, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Lopez
authors.affiliation: Novo Nordisk Foundation Center for Biosustainability at the UCSD School of Medicine, and Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Lewis
authors.affiliation: Department of Neurosciences, UC San Diego Autism Center, School of Medicine University of California San Diego, La Jolla, CA, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Pierce
authors.affiliation: Department of Neurosciences, UC San Diego Autism Center, School of Medicine University of California San Diego, La Jolla, CA, USA ecourchesne@ucsd.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Courchesne
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000254:growth & development / Q000473:pathology*; D002448:Cell Adhesion; D018797:Cell Cycle Proteins / Q000097:blood / Q000235:genetics*; D002675:Child, Preschool; D019295:Computational Biology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation
chemical_list: D018797:Cell Cycle Proteins
keywords: Autism Spectrum Disorder; brain development; co‐expression; gene networks