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Gene expression abnormalities in the autistic brain

  • Author(s): Chow, Maggie Lok Mun
  • et al.

Although it is accepted that autism is a highly heritable neurodevelopmental disorder that exhibits brain overgrowth in early years of life, underlying genetic mechanisms of this abnormal development remain unknown. It has been long hypothesized that autism begins prenatally due to abnormal cell proliferation, cell number regulation, and cell migration functions as the cortex is formed. These possibilities have never been systematically examined in the young developing autistic cerebral cortex, in part due to the limitations of tissue preservation quality. We aimed to test these hypotheses through genome-wide expression profiling and RTPCRon mRNA from postmortem brain tissue of young autistic and control cases. To yield the most reliable dataset with the largest sample size possible for this analysis, we first compared in vitro transcription (IVT)- and cDNA-mediated Annealing Selection and Ligation (DASL)-based expression platforms on partially degraded RNA from reference pools, and frozen and formalin fixed postmortem brain tissue. Results suggested that the DASL-based platform produced more reliable expression data than the IVT-based platform with partially degraded RNA. Next, data preprocessing procedures for the DASL-based gene expression results from postmortem frozen brain samples were systematically tested. We developed a data preprocessing pipeline to prepare this dataset for downstream analyses between autistic and control samples. Differential expression and enrichment analyses revealed that genes regulating cell cycle, apoptosis, proliferation, cellular differentiation, and neural patterning functions were dysregulated in young autistic cases. Similar results were found in an expanded analysis of autism at young and adult ages. Our observations suggest that molecular aberrancies in prenatal and early postnatal neurodevelopment may be responsible for brain overgrowth, cortical asymmetry, cortical disconnectivity, aberrant neural function, and ultimately the behavioral phenotype of autism

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