Co-expression profiling of autism genes in the mouse brain.
Co-expression profiling of autism genes in the mouse brain.
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DOI：
10.1371/journal.pcbi.1003128
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发表时间：
2013
影响因子：
4.3
通讯作者：
Mitra PP
中科院分区：
文献类型：
--
作者：
Menashe I;Grange P;Larsen EC;Banerjee-Basu S;Mitra PP
自闭症谱系障碍（ASD）是人类最普遍和高度遗传的神经发育障碍之一。有重要的证据表明，ASD的发病和严重程度部分由影响大脑正常发育的复杂遗传机制控制。迄今为止，许多基因与ASD相关。然而，这些基因在大脑中的时间和空间共表达仍不清楚。为了解决这个问题，我们在来自艾伦小鼠脑图谱数据库（http：//www.example.com）的3,041个基因的框架中检查了来自AutDB（http：//mindspec.org/autdb.html）的26个自闭症基因的共表达网络，这些基因的表达能量在冠状和矢状图像之间具有最高的相关性。mouse.brain-map.org这些数据来源于对共登记到艾伦Reference Atlas的雄性56日龄C57 BL/6 J小鼠进行的原位杂交实验，并用于产生归一化的共表达矩阵，其指示该数据库中基因的表达载体之间的余弦相似性。由自闭症相关基因形成的网络显示出比该数据集中其他基因更高程度的共表达连通性（Kolmogorov-Smirnov P = 5×10−28）。 使用Monte Carlo模拟，我们鉴定了两个共表达基因群，其显著富集有自闭症基因（A Bonferroni校正P<0.05）。这两类基因在小脑皮质中显著过表达（P = 1×10−5），表明这一大脑区域可能与自闭症有关。 总之，我们的研究提供了小鼠大脑中自闭症基因共表达模式的详细分析，并提出了可能参与自闭症病因的特定大脑区域和新的候选基因。自闭症谱系障碍（ASD）是一种与许多不同基因相关的复杂神经发育状况。然而，这些基因在大脑中的神经解剖学和功能特性在很大程度上是未知的。在这里，我们研究了与ASD相关的26个基因的共表达网络，使用来自艾伦小鼠脑图谱的数据，该图谱提供了成年小鼠脑中基因表达模式的全基因组高分辨率图谱。我们发现自闭症基因的共表达比预期的要多得多，这表明了共同的神经功能特性。然后，我们研究了高度富集自闭症基因的共表达模块的空间特性。因此，我们发现这些模块中的两个模块中的基因在小脑皮质中显着过度表达，特别是在主要由颗粒细胞填充的部分中。这些发现提供了与ASD相关的基因网络和特定脑区域之间的重要联系，因此为进一步探索ASD病因学中涉及的特定神经元回路奠定了基础。
Autism spectrum disorder (ASD) is one of the most prevalent and highly heritable neurodevelopmental disorders in humans. There is significant evidence that the onset and severity of ASD is governed in part by complex genetic mechanisms affecting the normal development of the brain. To date, a number of genes have been associated with ASD. However, the temporal and spatial co-expression of these genes in the brain remain unclear. To address this issue, we examined the co-expression network of 26 autism genes from AutDB (http://mindspec.org/autdb.html), in the framework of 3,041 genes whose expression energies have the highest correlation between the coronal and sagittal images from the Allen Mouse Brain Atlas database (http://mouse.brain-map.org). These data were derived from in situ hybridization experiments conducted on male, 56-day old C57BL/6J mice co-registered to the Allen Reference Atlas, and were used to generate a normalized co-expression matrix indicating the cosine similarity between expression vectors of genes in this database. The network formed by the autism-associated genes showed a higher degree of co-expression connectivity than seen for the other genes in this dataset (Kolmogorov–Smirnov P = 5×10−28). Using Monte Carlo simulations, we identified two cliques of co-expressed genes that were significantly enriched with autism genes (A Bonferroni corrected P<0.05). Genes in both these cliques were significantly over-expressed in the cerebellar cortex (P = 1×10−5) suggesting possible implication of this brain region in autism. In conclusion, our study provides a detailed profiling of co-expression patterns of autism genes in the mouse brain, and suggests specific brain regions and new candidate genes that could be involved in autism etiology. Autism spectrum disorder (ASD) is a complex neurodevelopmental condition associated with many different genes. However, the neuroanatomical and functional properties of these genes in the brain are largely unknown. Here we examined the co-expression network of 26 genes associated with ASD, using data from the Allen Mouse Brain Atlas, which provides a whole-genome, high-resolution map of gene expression pattern in the adult mouse brain. We discovered that autism genes are significantly more co-expressed than expected by chance, suggesting common neuro-functional properties. We then examined the spatial properties of co-expression modules that are highly enriched with autism genes. Consequently, we found that genes in two of these modules are significantly over-expressed in the cerebellar cortex, and particularly in sections that are predominantly populated by granular cells. These findings provide the essential link between gene networks associated with ASD and specific brain regions, and hence lay out a basis for further exploration of the particular neuronal circuits involved in ASD etiology.
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