In many cases, a single mutated gene can alter an entire network of genes linked to autism. One of those genes, ZFX, may also help explain why females are relatively protected from severe autism symptoms.
The finding could also explain why different mutations in one or several of the hundreds of genes linked to autism can lead to a similar condition.
The study, published in Nature, examined a number of genes linked to autism in a human cell model, where 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 lead author Rebecca 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.”
Anderson and team also looked for a possible connection to the female protective effect, the observation that autism is 4 to 5x 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 60 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.
According to the study results, 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 transcriptomic 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.
Data from Boston Children’s Hospital