Although autism is highly heritable, its heterogeneity has challenged gene-finding efforts. Daniel Geschwind and his colleagues at the University of California, Los Angeles, propose to identify the gene networks frequently dysregulated in people with autism, regardless of the underlying mutations.
The relationships among genes — the gene network — resemble a web, regulating and executing a common goal. Geschwind and his colleagues untangle the gene networks involved in complex diseases, including autism spectrum disorders, using modern genetics, genome analysis and bioinformatics to see the whole network simultaneously. In 2011, they reported in Nature that more than half of people with autism have changes in one of two gene networks: a network featuring the RNA splicing factor A2BP1/FOX1 that regulates neuronal cell development and function, or a network of immune and inflammatory genes, many of which are expressed in glial cells.
Based on their findings, the researchers further hypothesized that the failure of the A2BP1/FOX1 network to splice RNA may cause autism, while the increased expression of the immune and inflammatory gene network may be a response to the disruption of neuronal development.
The researchers also observed that the normal pattern of gene expression differentiating the temporal and frontal cerebral cortex is absent in people with autism spectrum disorders, suggesting that brain patterning is altered during development. Altogether, these findings suggest that the heterogeneous genetics of autism may converge on a few fundamental pathways, providing new insights on the disorder’s molecular pathology.
Geschwind and his colleagues propose to extend these studies using RNA sequencing to perform a comprehensive genome-wide analysis of many brain regions. The researchers plan to study how epigenetic modifications affect the gene expression changes that they observed. The data will be available on the web for use by the autism research community.