Researchers identify specific gene linked to female protection from autism

In many cases all it takes is one mutated gene to orchestrate changes across a whole network of genes linked to autism, according to new results published today in Nature by researchers at Boston Children's Hospital. The finding could explain why different mutations in one or several of the hundreds of genes linked to autism can lead to a similar condition. And further building on this discovery, the investigators also found that one gene in particular, ZFX, is central to a well-known effect whereby females are relatively protected from severe autism symptoms even when they carry autism-associated mutations.

Senior study author Christopher Walsh, MD, PhD, chief of the Division of Genetics and Genomics and Investigator of the Howard Hughes Medical Institute, and lead authors Rebecca Andersen, PhD and Maya Talukdar, PhD, along with colleagues studied a number of genes linked to autism in a human cell model. They observed similar genetic patterns in most cases regardless of which gene was disrupted.

"The point is, if you down-regulate one autism gene, you down-regulate a whole bunch of them," said Andersen. "This 'transcriptomic convergence,' as we call it, gives us a way to understand how hundreds of different genes can cause similar phenotypes, a similar condition."

The new research suggests that many of the diverse genes that can cause autism when disrupted by rare mutations, actually may act in concert. Down-regulation of one may down-regulate many.

The investigators also looked for a possible connection to the female protective effect, the observation that autism is four to five times more common in males than females. It has been proposed that the X chromosome plays a role, but it is more nuanced than the fact that females carry two copies and males carry one. Since females carry two X chromosomes, every individual cell in the human body turns off most of the genes on one of them to avoid toxicity and cell death. There are exceptions, however: more than sixty genes on the X chromosome escape this "X chromosome inactivation," including the transcriptional activator ZFX. As a result, females have higher expression of ZFX since it is expressed from both of their X chromosomes. The researchers found that ZFX regulates the expression of many autism-related genes, so the higher expression of ZFX in females could potentially drive the protection against mutations in autism-related genes.

"The most important take-home messages are the idea of this transcriptomic convergence in autism and our identification of the ZFX gene as a potential driver of autism's male bias," said Walsh.

This convergence also suggests that it may be possible to envision therapies that might upregulate many autism-associated genes, rather than needing to develop a separate therapy for each of the hundreds of genetic mutations one at a time. Because one gene can regulate many, targeting fewer genes could be effective. For example, upregulating ZFX in males might bring them partial protection against autism closer to what females experience. Determining a way to boost ZFX levels could benefit girls as well, added Walsh. It could be a case of "a rising tide lifts all boats."

This work was supported by the Autism Speaks Postdoctoral Fellowship 13008 and NIGMS T32 GM007748 (R.E.A.); NIH T32 GM007753 and T32 GM144273 (M.T.); the Simons Foundation Autism Research Initiative, the Howard Hughes Medical Institute, Autism BrainNet (953759), the Yang Tan Collective at Harvard University, the Hock E. Tan and K. Lisa Yang Center for Autism Research at Harvard University. D.C.P. and C.A.W. are Investigators of the Howard Hughes Medical Institute.