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Autism, Long Genes and DNA Detanglers

Discovery links autism to disruptions in very long genes and the enzymes that untangle them, implications for prevention and treatment
December 01, 2013


A “Top Ten Advances in Autism Research 2013” Selection
See all the year’s “Top Ten” here.


Enzymes called topoisomerases help detangle DNA when the molecule unwinds during gene expression. This year, researchers discovered that when these enzymes are prevented from doing their job, it’s bad news for very long genes – including a great many whose malfunction predisposes to autism.

Their report, in the journal Nature, stirred excitement in the autism research community for good reason.

"We've been talking for a long time about the interaction between genes and environment in autism," explains Andy Shih, Autism Speaks senior vice president for scientific affairs. “This study suggests that topoisomerases may offer a way to zero in on the biological pathways that connect many of the genes and environmental factors that intersect to produce ASD.”

Autism genes surprisingly long
The University of North Carolina researchers were studying topoisomerases to understand their role controlling a gene connected to Angelman syndrome. Many individuals with this syndrome also have autism spectrum disorder (ASD).

In the process, the researchers discovered that topoisomerases were crucial for the expression of genes more than 200 kilobases long. “That’s four times longer than the average gene,” says study co-author Mark Zylka, of the University of North Carolina. They also found that a cancer drug (topotecan) that inhibits these enzymes blocked the activity of virtually all genes above this length.

What does this have to do with autism?

The UNC researchers found that these super-long genes were extremely active in neurons, or brain nerve cells. Even more surprising, they found that more than a quarter of these mega genes – nearly 50 in all – were among the 300 genes that previous research had associated with autism. In other words, disruptions in these genes increased the risk that an individual would develop the disorder.

Blocking the detangler
“That was the eureka moment,” says Dr. Zylka. The researchers realized that prenatal exposure to any chemical that inhibited topoisomerases could disrupt the action of scores of genes vital to brain development – including dozens of genes implicated in autism.

“There could be many other compounds in the environment that inhibit these vital enzymes as well,” Dr. Zylka says. “It’s vital that we identify them because it may be important for pregnant women to avoid them during certain periods of prenatal brain development.”

Since their report was published, the researchers have been actively scanning environmental pollutants as well as medicines for topoisomerase-blocking activity. “We’ve found something of great interest,” Dr. Zylka hints. “And we anticipate that our research will lead to the identification of other compounds that pregnant women, in particular, may want to avoid.”

Length matters
In addition, the UNC scientists are urging their colleagues in autism research to consider the implications of their discovery that so many autism genes are extremely long.

“Over the course of a lifetime, our genes are regularly subject to mutations,” Dr. Zylka notes. “These mutations may be more likely to hit longer genes, simply because longer genes are bigger targets.”

Research has found, for example, that a man’s sperm-producing germ cells accrue about two spontaneous, or de novo, mutations per year. A similar process occurs in women’s egg-producing germ cells. These mutations can be passed from parents to offspring at conception.

Could these findings help explain why multiple studies have found higher rates of autism among the children of older parents?

Could medicines that enhance topoisomerases function prevent autism or ease its symptoms in some individuals?

“Some of the most interesting research poses more questions than it answers,” Dr. Shih concludes.