Co-expression Profiling of Autism Genes in the Mouse Brain

Abstract

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.

The Cerebellum, Sensitive Periods, and Autism

“…Three recent computational studies have used aggregated gene expression patterns to ask when and where ASD genes are expressed (Figure 1a; Menashe et al, 2013; Parikshak et al, 2013; Willsey et al, 2013). Some ASD susceptibility genes show a high degree of co-expression with one another in mouse and human brain, allowing the identification of specific gene networks or “cliques” (Menashe et al, 2013).…”

“…Some ASD susceptibility genes show a high degree of co-expression with one another in mouse and human brain, allowing the identification of specific gene networks or “cliques” (Menashe et al, 2013). ASD-related co-expression networks have been found during two distinct periods of development.…”

“…First, during human gestational weeks 10–24 and mouse P0–10, expression occurs in a broadly defined somato-motor-frontal region (Willsey et al, 2013) especially in layer 5/6 cortical projection neurons (Parikshak et al, 2013; Willsey et al, 2013) and other layers (Parikshak et al, 2013). Second, in humans from neonatal to age 6, cerebellar network expression is strong (Willsey et al, 2013), particularly in the cerebellar granule cell layer (Menashe et al, 2013). Unfortunately, the third recent study examining aggregated gene co-expression patterns did not examine cerebellum (Parikshak et al, 2013).…”

Autism and cerebellar dysfunction: Evidence from animal models

“…However, functions of these genes appear to cluster around several important biologic themes consistent with ASD phenotypes, including synaptic function, homeostasis, growth, and signaling. Many of these susceptibility genes demonstrate high expression in the cerebellum [28], and many demonstrate critical roles in cerebellar function and development in animal models (detailed further below).…”

Cell-type–based model explaining coexpression patterns of genes in the brain

“…To study the genes collectively we use a voxel-by-gene data matrix E, corresponding to V = 49;742 cubic voxels, and 3,041 genes, as in refs. [24][25][26]. The entry Eðv; gÞ is the expression energy of the gene labeled g in the voxel labeled v [a measure representing the level of mRNA in situ hybridization (1,10)].…”