Longer Than Previously Thought: Researchers have discovered something surprising about autism genes: They're three to four times longer than the average gene expressed in neurons. Image: Alfred Hermida/Flickr
Enzymes called topoisomerases are crucial for the expression of extremely long genes in neurons, according to a study published 5 September in Nature. More than one-quarter of these genes are known autism candidates, the study found.
In the process of doing these analyses, the researchers stumbled on something surprising about autism genes in general: They're three to four times longer than the average gene expressed in neurons.
"It's pretty remarkable that, at least to my knowledge, no one had noticed this before," notes Benjamin Philpot, associate professor of cell biology and physiology at the University of North Carolina, Chapel Hill, and one of the study's leaders. "But the genes are definitely much longer. It's very striking."
The findings suggest that defects in topoisomerases — whether caused by genetic mutations or environmental influences — may contribute to some cases of autism and other developmental disorders, the researchers say.
If it's true that long genes are preferentially affected in autism, "the implications are really quite fascinating," notes James Sutcliffe, associate professor of molecular physiology and biophysics at Vanderbilt University in Nashville, Tennessee, who was not involved in the research.
In genetic sequencing studies, for example, mutations found in long genes tend to be discounted in statistical analyses. That’s because the longer a gene is, the more likely it is to harbor a mutation just by chance. But the new study suggests that mutations in long genes should be considered more carefully.
"This raises a really interesting question of whether we may be correcting away something that’s inherent to disease risk," Sutcliffe says.
Topoisomerases are found in all cells and are known to play a role in unraveling knots in DNA.
"When a cell divides, the DNA gets tangled up, and these enzymes cut the DNA to unwind it," says Mark Zylka, associate professor of cell biology and physiology at the University of North Carolina, Chapel Hill, who led the new study along with Philpot.
Drugs that inhibit these enzymes gum up that process, preventing DNA replication and, as a result, cell division. Because of this, these drugs have been used to treat cancer for four decades.
In late 2011, Zylka and Philpot reported in Nature that in spinal cord neurons, a topoisomerase inhibitor called topotecan activates the normally silent copy of UBE3A, the gene that is damaged in Angelman syndrome, a developmental disorder related to autism. Duplications of UBE3A are also thought to cause some cases of autism.
It was a shock to find out that topotecan had this affect in neurons, Zylka says, because neurons don't divide. "So we wanted to figure out what the heck these enzymes were doing there."