Autism has strong genetic origins, but neither common nor rare gene variants explain the majority of cases. This suggests that less-studied portions of the genome may contribute significantly to the disorder.

To assess the role in autism of DNA sequences that regulate the expression of genes, Nadav Ahituv and his colleagues at the University of California, San Francisco, studied the autism susceptibility candidate 2 (AUTS2) gene. More than 50 individuals with autism or autism-like syndromes have been found to carry structural mutations in AUTS2¹. All of these mutations appear in a single copy of the gene, and some of them are found exclusively in noncoding regions, suggesting that AUTS2 expression levels may be a key factor in autism susceptibility.

Ahituv’s group lowered the expression of AUTS2 in zebrafish, which led to a smaller head size, less mobility and fewer motor, sensory and midbrain neurons than in controls². The researchers also characterized the AUTS2 regulatory pathway in developing mouse forebrains by identifying sequences throughout the genome that AUTS2 regulates. The group tested these sequences for enhancer activity in zebrafish and mice. Enhancers are regulatory elements that control when, where and at what levels genes are expressed. Their hypothesis was that the disruption of such enhancers may lead to autism in some individuals. They found evidence in favor of the hypothesis, though it is not conclusive.

The characterization of AUTS2 regulatory elements and regulatory pathways may uncover novel autism risk factors. This project may also help researchers understand how altered gene regulation predisposes some individuals to autism and other disorders.