Age-dependent brain gene expression and copy number anomalies in autism suggest distinct pathological processes at young versus mature ages
| Autor: | Tiziano Pramparo, Cynthia Carter Barnes, Jian-Bing Fan, Sarah S. Murray, Nicholas J. Schork, Eric Courchesne, Hai Ri Li, Maggie Chow, Xiang-Dong Fu, Anthony Wynshaw-Boris, Haim Belinson, Craig April, Mary E. Winn, Lauren A. Weiss |
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| Přispěvatelé: | Gibson, Greg |
| Rok vydání: | 2012 |
| Předmět: |
Male
Cancer Research Cellular differentiation Autism Gene regulatory network Cell Cycle Proteins 0302 clinical medicine Neurodevelopmental disorder 2.1 Biological and endogenous factors Gene Regulatory Networks Copy-number variation Aetiology Prefrontal cortex Child Genetics (clinical) Genetics Regulation of gene expression Neurons Pediatric 0303 health sciences Genome Age Factors Cell Differentiation Genomics Middle Aged medicine.anatomical_structure Mental Health Child Preschool Neurological Medicine Female Autopsy Research Article Signal Transduction Human Biotechnology Adult lcsh:QH426-470 Adolescent DNA Copy Number Variations Intellectual and Developmental Disabilities (IDD) 1.1 Normal biological development and functioning Prefrontal Cortex Biology 03 medical and health sciences Clinical Research Underpinning research mental disorders medicine Humans Autistic Disorder Preschool Molecular Biology Ecology Evolution Behavior and Systematics 030304 developmental biology Genome Human Human Genome Neurosciences medicine.disease Brain Disorders lcsh:Genetics Gene Expression Regulation Neuron 030217 neurology & neurosurgery Gene Deletion Neuroscience Developmental Biology |
| Zdroj: | PLoS genetics, vol 8, iss 3 PLoS Genetics PLoS Genetics, Vol 8, Iss 3, p e1002592 (2012) Chow, ML; Pramparo, T; Winn, ME; Barnes, CC; Li, HR; Weiss, L; et al.(2012). Age-dependent brain gene expression and copy number anomalies in autism suggest distinct pathological processes at young versus mature ages. PLoS Genetics, 8(3). doi: 10.1371/journal.pgen.1002592. UC San Francisco: Retrieved from: http://www.escholarship.org/uc/item/172879gx |
| DOI: | 10.1371/journal.pgen.1002592. |
| Popis: | Autism is a highly heritable neurodevelopmental disorder, yet the genetic underpinnings of the disorder are largely unknown. Aberrant brain overgrowth is a well-replicated observation in the autism literature; but association, linkage, and expression studies have not identified genetic factors that explain this trajectory. Few studies have had sufficient statistical power to investigate whole-genome gene expression and genotypic variation in the autistic brain, especially in regions that display the greatest growth abnormality. Previous functional genomic studies have identified possible alterations in transcript levels of genes related to neurodevelopment and immune function. Thus, there is a need for genetic studies involving key brain regions to replicate these findings and solidify the role of particular functional pathways in autism pathogenesis. We therefore sought to identify abnormal brain gene expression patterns via whole-genome analysis of mRNA levels and copy number variations (CNVs) in autistic and control postmortem brain samples. We focused on prefrontal cortex tissue where excess neuron numbers and cortical overgrowth are pronounced in the majority of autism cases. We found evidence for dysregulation in pathways governing cell number, cortical patterning, and differentiation in young autistic prefrontal cortex. In contrast, adult autistic prefrontal cortex showed dysregulation of signaling and repair pathways. Genes regulating cell cycle also exhibited autism-specific CNVs in DNA derived from prefrontal cortex, and these genes were significantly associated with autism in genome-wide association study datasets. Our results suggest that CNVs and age-dependent gene expression changes in autism may reflect distinct pathological processes in the developing versus the mature autistic prefrontal cortex. Our results raise the hypothesis that genetic dysregulation in the developing brain leads to abnormal regional patterning, excess prefrontal neurons, cortical overgrowth, and neural dysfunction in autism. Author Summary Autism is a disorder characterized by aberrant social, communication, and restricted and repetitive behaviors. It develops clinically in the first years of life. Toddlers and children with autism often exhibit early brain enlargement and excess neuron numbers in the prefrontal cortex. Adults with autism generally do not display enlargement but instead may have a smaller brain size. Thus, we investigated DNA and mRNA patterns in prefrontal cortex from young versus adult postmortem individuals with autism to identify age-related gene expression differences as well as possible genetic correlates of abnormal brain enlargement, excess neuron numbers, and abnormal functioning in this disorder. We found abnormalities in genetic pathways governing cell number, neurodevelopment, and cortical lateralization in autism. We also found that the key pathways associated with autism are different between younger and older autistic individuals. These findings suggest that dysregulated gene pathways in the early stages of neurodevelopment could lead to later behavioral and cognitive deficits associated with autism. |
| Databáze: | OpenAIRE |
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