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Autism genes are surprisingly large, study finds

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Virginia Hughes
16 September 2013

Long game: Autism-linked genes are 217 kilobases on average, compared with 59 kilobases for a typical gene expressed in neurons of the cortex.

Enzymes called topoisomerases are crucial for the expression of extremely long genes in neurons, according to a study published 5 September in Nature1. 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.

Transcription targets:

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."

Some studies had shown that, in addition to their role in untangling DNA, topoisomerases are involved in transcribing DNA into RNA sequences2.

Following that lead, the researchers exposed cultured mouse and human neurons to topotecan and then measured changes in expression across the genome.

Topoisomerase inhibitors turn up the expression of 28 genes and dial down the expression of 155 genes, the study found. All of the dampened genes are large, at least 67 kilobases (kb).

"As you get bigger and bigger, the odds are greater that the gene’s expression goes down," Zylka says. "Around 200 kb or longer, the drugs inhibit like 90 percent of those genes."

The results suggest that topoisomerases are important for the expression of extremely long genes.

The paper showcases “some really, really beautiful cell biology," says Brett Abrahams, assistant professor of genetics at the Albert Einstein College of Medicine in New York, who was not involved in the study. "It's less clear to me what to make of the potential autism link."

Autism lists:

The researchers noticed that many of the genes regulated by topoisomerases are involved in the function of synapses, the junctions between neurons, and also in autism. They cross-referenced their list with autism candidate genes catalogued by various sequencing studies and by SFARI Gene, a comprehensive database of genes linked to autism. (SFARI Gene is funded by the Simons Foundation, SFARI.org’s parent organization.)

They found that 49 of the 183 genes affected by topoisomerases — 27 percent — had previously been linked to autism, a proportion much higher than would be seen by chance.

While this work was underway, two other studies appeared showing that a few individuals with autism carry mutations in topisomerase genes3, 4. This month, two studies in Nature Neuroscience linked TOP3B — a topoisomerase that influences RNA — with schizophrenia, cognitive impairment and fragile X syndrome5, 6.

The researchers also found that the autism candidate genes on their list are 217 kb on average, compared with 59 kb for a typical gene expressed in neurons of the cortex.

Abrahams notes, however, that a lot of the genes on the list have been only weakly linked to autism. What's more, he says, it's unclear whether the long-gene effect is specific to autism.

"What about cancer genes? What about diabetes genes? What about genes involved in sleep regulation?" Abrahams asks. "If you were to take any of these other lists, would they also show enrichment for long genes?"

Nobody knows why autism genes might be so long. Zylka speculates that it might be because of mechanisms involved in replicating DNA. In dividing cells, he says, there is a selective pressure against long genes because the enzymes involved in making RNA and copying DNA can crash into each other.

Neurons don't divide, however. "We think that evolutionarily, neurons can express these really big genes because there aren't as many detrimental effects," he says.

In ongoing experiments, Zylka and Philpot are investigating drugs that, like topoisomerase inhibitors, have the ability to disrupt the enzymes and, in turn, upset a host of autism genes.

"That's something we're really, really interested in — environmental influences," Philpot says. So far, he and Zylka have found at least one compound that has effects on long genes similar to those of topoisomerase inhibitors. "We have some exciting data."

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1. King I.F. et al. Nature 501, 58-62 (2013) PubMed

2. Capranico G. et al. Biochim. Biophys. Acta 1806, 240-250 (2010) PubMed

3. Neale B.M. et al. Nature 485, 242-245 (2012) PubMed

4. Iossifov I. et al. Neuron 74, 285-299 (2012) PubMed

5. Stoll G. et al. Nat. Neurosci. 16, 1228-1237 (2013) PubMed

6. Xu D. et al. Nat. Neurosci. 16, 1238-1247 (2013) PubMed

Comments

Name: Achieve Beyond Pediatric Therapy & Autism Services
16 September 2013 - 4:29PM

It is amazing at how many more scientific studies have been reported on Autism since insurance companies have been forced to foot the bill for these treatments in many states. It is good because all of this extra research is allowing scientists to have more time to run many studies on the disorder worldwide and collect information and data like these longer Autism genes. Let's keep the studies going and raising awareness as well

Achieve Beyond Pediatric Therapy
http://www.achievebeyondusa.com

Name: usethebrainsgodgiveyou
16 September 2013 - 9:59PM

"That's something we're really, really interested in — environmental influences," Philpot says. So far, he and Zylka have found at least one compound that has effects on long genes similar to those of topoisomerase inhibitors. "We have some exciting data."

That's an interesting teaser.

Name: usethebrainsgodgiveyou
16 September 2013 - 10:06PM

http://news.unchealthcare.org/news/2013/august/researchers-discover-a-potential-cause-of-autism

Name: usethebrainsgodgiveyou
16 September 2013 - 10:12PM

Anti-biotics?

Name: RA Jensen
17 September 2013 - 1:12PM

'Most scientific studies are wrong, and they are wrong because scientists are interested in funding and careers rather than truth'.

http://blogs.bmj.com/bmj/2013/09/09/richard-smith-time-for-science-to-be-about-truth-rather-than-careers/

Name: Curious
17 September 2013 - 6:01PM

Are these scientist seeing the big picture in this autism gene hunt? Do they even realize what they are part of? Think big!

Name: autismepi
6 October 2013 - 5:49PM

It seems to be news to many involved that acetaminophen's toxic metabolite NAPQI is a topoisomerase poison. This is the most common pharmaceutical used by pregnant women and children. Just doubling the recommended dose of acetaminophen can lead to conversion to NAPQI. If this is thinking big then, Yes, we need to think big!

Name: Yankeegirl
22 September 2013 - 4:10PM

Same study as reported in Science Daily:

source: "A Potential Cause of Autism? Key Enzymes Are Found to Have a 'Profound Effect' Across Dozens of Genes Linked to Autism" August 28, 2013

"Our study shows the magnitude of what can happen if topoisomerases are impaired," said senior study author Mark Zylka, PhD, associate professor in the Neuroscience Center and the Department of Cell Biology and Physiology at UNC. "Inhibiting these enzymes has the potential to profoundly affect neurodevelopment -- perhaps even more so than having a mutation in any one of the genes that have been linked to autism."

The study could have important implications for ASD detection and prevention.

"This could point to an environmental component to autism," said Zylka. "A temporary exposure to a topoisomerase inhibitor in utero has the potential to have a long-lasting effect on the brain, by affecting critical periods of brain development. "

This study could also explain why some people with mutations in topoisomerases develop autism and other neurodevelopmental disorders.

Topiosomerases are enzymes found in all human cells. Their main function is to untangle DNA when it becomes overwound, a common occurrence that can interfere with key biological processes."

So if topoisomerases inhibitors (such as cadmium) in the environment can cause an enzyme dysfunction, how are our kids getting exposed to these toxins?

Name: So what next?
23 September 2013 - 7:23PM

Do we want to enhance the function of topoisomerases then? How do we do that?

Name: Askachemist!
23 September 2013 - 7:27PM

You can use an an enzyme inhibitor to reduce the activity of the enzyme but no easy way of increasing its activity.

Name: epiann
24 September 2013 - 7:13PM

Acetaminophen's metabolite NAPQI is a topoisomerase poison. It is the most common drug taken by pregnant women and children. It has a very low therapeutic index.

http://ejournals.ebsco.com/Direct.asp?AccessToken=7DNLITRBDU8N1-4O-VHLF75RPXKOBTDNDR&Show=Object&ErrorURL=http%3A%2F%2Flinksource.ebsco.com%2Ferror.aspx

Name: rose
26 September 2013 - 12:37PM

http://evolutionarypsychiatry.blogspot.com/2012/01/tylenol-and-autism.html

Name: FloxieHope
5 October 2013 - 4:58AM

Fluoroquinolone antibiotics, Cipro, Levaquin, Avelox, Floxin and a few others, are topoisomerase interrupters.

Name: jasmine
10 December 2013 - 10:11PM

cool

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