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'Jumping Genes' Linked to Schizophrenia

2 January 2014 12:00 pm
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Risk and reward. “Jumping genes” (in green neuron) may help ensure that every brain is unique, but could also contribute to neurological disorders such as schizophrenia.

Carol Marchetto (Salk Institute) and Alysson Muotri (UCSD)

Risk and reward. "Jumping genes" (in green neuron) may help ensure that every brain is unique, but could also contribute to neurological disorders such as schizophrenia.

Roaming bits of DNA that can relocate and proliferate throughout the genome, called "jumping genes," may contribute to schizophrenia, a new study suggests. These rogue genetic elements pepper the brain tissue of deceased people with the disorder and multiply in response to stressful events, such as infection during pregnancy, which increase the risk of the disease. The study could help explain how genes and environment work together to produce the complex disorder and may even point to ways of lowering the risk of the disease, researchers say.

Schizophrenia causes hallucinations, delusions, and a host of other cognitive problems, and afflicts roughly 1% of all people. It runs in families—a person whose twin sibling has the disorder, for example, has a roughly 50-50 chance of developing it. Scientists have struggled to define which genes are most important to developing the disease, however; each individual gene associated with the disorder confers only modest risk. Environmental factors such as viral infections before birth have also been shown to increase risk of developing schizophrenia, but how and whether these exposures work together with genes to skew brain development and produce the disease is still unclear, says Tadafumi Kato, a neuroscientist at the RIKEN Brain Science Institute in Wako City, Japan and co-author of the new study.

Over the past several years, a new mechanism for genetic mutation has attracted considerable interest from researchers studying neurological disorders, Kato says. Informally called jumping genes, these bits of DNA can replicate and insert themselves into other regions of the genome, where they either lie silent, doing nothing; start churning out their own genetic products; or alter the activity of their neighboring genes. If that sounds potentially dangerous, it is: Such genes are often the culprits behind tumor-causing mutations and have been implicated in several neurological diseases. However, jumping genes also make up nearly half the current human genome, suggesting that humans owe much of our identity to their audacious leaps.

Recent research by neuroscientist Fred Gage and colleagues at the University of California (UC), San Diego, has shown that one of the most common types of jumping gene in people, called L1, is particularly abundant in human stem cells in the brain that ultimately differentiate into neurons and plays an important role in regulating neuronal development and proliferation. Although Gage and colleagues have found that increased L1 is associated with mental disorders such as Rett syndrome, a form of autism, and a neurological motor disease called Louis-Bar syndrome, "no one had looked very carefully" to see if the gene might also contribute to schizophrenia, he says. 

To investigate that question, principal investigator Kazuya Iwamoto, a neuroscientist; Kato; and their team at RIKEN extracted brain tissue of deceased people who had been diagnosed with schizophrenia as well as several other mental disorders, extracted DNA from their neurons, and compared it with that of healthy people. Compared with controls, there was a 1.1-fold increase in L1 in the tissue of people with schizophrenia, as well as slightly less elevated levels in people with other mental disorders such as major depression, the team reports today in Neuron

Next, the scientists tested whether environmental factors associated with schizophrenia could trigger a comparable increase in L1. They injected pregnant mice with a chemical that simulates viral infection and found that their offspring did, indeed, show higher levels of the gene in their brain tissue. An additional study in infant macaques, which mimicked exposure to a hormone also associated with increased schizophrenia risk, produced similar results. Finally, the group examined human neural stem cells extracted from people with schizophrenia and found that these, too, showed higher levels of L1.

The fact that it is possible to increase the number of copies of L1 in the mouse and macaque brains using established environmental triggers for schizophrenia shows that such genetic mutations in the brain may be preventable if such exposures can be avoided, Kato says. He says he hopes that the "new view" that environmental factors can trigger or deter genetic changes involved in the disease will help remove some of the disorder's stigma.

Combined with previous studies on other disorders, the new study suggests that L1 genes are indeed more active in the brain of patients with neuropsychiatric diseases, Gage says. He cautions, however, that no one yet knows whether they are actually causing the disease. "Now that we have multiple confirmations of this occurring in humans with different diseases, the next step is to determine if possible what role, if any, they play.”

One tantalizing possibility is that as these restless bits of DNA drift throughout the genomes of human brain cells, they help create the vibrant cognitive diversity that helps humans as a species respond to changing environmental conditions, and produces extraordinary "outliers," including innovators and geniuses such as Picasso, says UC San Diego neuroscientist Alysson Muotri. The price of such rich diversity may be that mutations contributing to mental disorders such as schizophrenia sometimes emerge. Figuring out what these jumping genes truly do in the human brain is the "next frontier" for understanding complex mental disorders, he says. "This is only the tip of the iceberg."

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