摘要： 尽管自闭症有高度遗传性，但在遗传上却有明显的异质性。这便提出一个问题：“自闭症系列障碍” (ASD)是具有不同的病理模型，还是大多数病例反映的生理通道障碍（遗传因素引起的）？转录组和“基因共表达网络分析”技术分析得出，事实属于后一种，即“融合模型”是正确的。额叶皮层和颞叶皮层的基因在ASD患者脑中表达不明显，而与自闭症有关的“共表达基因”在基因信号关联方面表现出较多的拼接异常，这说明基因信号拼接异常和转录比例失衡是这类神经疾病的病理机制。
”共表达基因“协调不一致引起自闭症
生物探索推荐英文摘要
Nature doi:10.1038/nature10110
Transcriptomic analysis of autistic brain reveals convergent molecular pathology
Abstract: Autism spectrum disorder (ASD) is a common, highly heritable neurodevelopmental condition characterized by marked genetic heterogeneity1, 2, 3. Thus, a fundamental question is whether autism represents an aetiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain4. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co-expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1 (also known as FOX1), and a module enriched for immune genes and glial markers. Using high-throughput RNA sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in the ASD brain. Moreover, using a published autism genome-wide association study (GWAS) data set, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic aetiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder.
