Edited RNA + invasive DNA add individuality

November 8, 2013
Fly eye color varies based on the level of RNA editing. Red eyes, left, suggest a lot of editing, while white eyes suggest little. Credit: Reenan lab/Brown University

The story of why we are all so different goes well beyond the endless mixing and matching of DNA through breeding. A new study in the journal Nature Communications, for instance, reports a new molecular mechanism of individual variation found in fruit flies that uses components operating in a wide variety of species, including humans.

The new mechanism is based in a surprising genetic oddity. Nearly all genomes—those of humans, fruit flies, and even corn and rice—are constantly grappling with parasitic snippets of genetic material called "transposons." These snippets copy themselves, move around, and embed themselves within DNA. If left unchecked, transposons can alter how genetic instructions are carried out in the body,usually for the worse, sometimes for the better. But genomes don't leave transposons unchecked. They "look" for tell-tale double-stranded RNA associated with the transposons, chop the strands up and use the pieces to "silence" the invaders.

In the new paper, scientists show that an enzyme called ADAR, which edits RNA in humans, flies, and many other creatures, edits double-stranded RNAs. This loosens the system that keeps "Hoppel" transposons silenced in fruit flies. When transposons are silenced, it's done by keeping them locked tight around tiny balls of material called chromatin.

Since the amount of ADAR varies from one individual to the next, the amount of jailbreaking from those chromatin prison varies too, and that should lead to altered gene expression. After showing that an abundance of ADAR reduces silencing of a common transposon in the flies—and that a lack of ADAR meant widespread silencing—the researchers measured two consequences of different levels of ADAR activity: a 20-percent difference in and difference in eye color (red rather than white).

The study was focused on , ADAR, and the double-stranded RNA of the Hoppel transposon, but the ability of RNA editors to loosen the silencing of at least some transposons may be a source of individual variation in humans and other species too, said Brown University biologist Robert Reenan, senior author of the new study published online. Editing of double-stranded RNA—or a lack of editing—has already been linked to diseases in people, including amyloid lateral sclerosis and, specifically in the case of ADAR, Aicardi-Goutières syndrome.

"ADAR in humans functions the same way it does in flies, and double-stranded RNAs are made in humans the same way," said Reenan, professor of biology in the Department of Molecular Biology, Cell Biology and Biochemistry. "They are all generic, off the shelf staples of the biological toolkit. This is not anything that is particular to flies."

Picking the double strand

Many of Reenan's studies focus on ADAR's editing activity in the development of the nervous system, but this investigation began years ago when lead author and then graduate student Yiannis Savva happened to overexpress ADAR in fruit fly salivary gland cells. He found some bound in an unexpected place: one specific site on chromosome four.

Reenan recalled: "I told him that's either an artifact or it will be the centerpiece of your thesis."

Various tests revealed that the chromosome four site was a home for several Hoppel transposons making a double-stranded RNA.

Savva and Reenan were curious about what business ADAR had with the transposon. A series of experiments in ensuing years did just that. They relocated the transposons to places where they weren't and found that ADAR followed. They deleted the double-stranded RNA from chromosome four and found that ADAR was no longer there. They identified specific editing sites and signs of editing on the double stranded RNA.

Savva and his collaborators then measured silencing of tranposons with varying levels of ADAR and found that the more ADAR there was, the less silencing there was.

Then, working with Stephen Helfand, an expert on the biology of aging, they noticed that a reduction of editing increases life span.

"As a loss of silencing has been associated with aging in Drosophila and other organisms, we performed lifespan analyses on [low-ADAR] adults and wild-type controls and found a ~20-percent increase in the median life span of [low-ADAR] males and females," the authors wrote in Nature Communications.

Look in their eyes

Later they looked at eye color, using natural (wild-type) flies and those where ADAR activity was either artificially hamstrung or excessively active. The natural flies have eyes that run a full continuum from red to white with various "variegating" blends in between that reflect the silencing state of their gene. In the excessively ADAR-active flies there was little silencing and eyes turned out red much more often than normal. In the ADAR-hamstrug flies, virtually all of the eyes were white (reflecting a lot of silencing of the red color gene).

Ultimately, Savva said, ADAR appears to be allowing transposons like Hoppel to exercise their capacity to regulate gene expression, even though they are really just uninvited guests in the genome.

"What ADAR does is fine tune this regulatory network," Savva said. "In cells where you have ADAR, the network is activated. In cells where you don't it's silenced. It provides dynamicity."

In other words, some of the differences among us may be apparent in the eyes of flies.

Explore further: A radar for ADAR: Altered gene tracks RNA editing in neurons

Related Stories

A radar for ADAR: Altered gene tracks RNA editing in neurons

December 25, 2011

To track what they can't see, pilots look to the green glow of the radar screen. Now biologists monitoring gene expression, individual variation, and disease have a glowing green indicator of their own: Brown University biologists ...

Locked down, RNA editing yields odd fly behavior

April 24, 2012

Because a function of RNA is to be translated as the genetic instructions for the protein-making machinery of cells, RNA editing is the body's way of fine-tuning the proteins it produces, allowing us to adapt. The enzyme ...

Fly study finds two new drivers of RNA editing

August 1, 2013

RNA editing gives organisms a way to adapt the instructions that their DNA provides for making proteins. Few people would have described RNA editing as a simple process, but a new paper in Nature Communications demonstrates ...

Largest, most accurate list of RNA editing sites

September 29, 2013

A research team centered at Brown University has compiled the largest and most stringently validated list of RNA editing sites in the fruit fly Drosophila melanogaster, a stalwart of biological research. Their research, which ...

Recommended for you

How cells in the developing ear 'practice' hearing

November 25, 2015

Before the fluid of the middle ear drains and sound waves penetrate for the first time, the inner ear cells of newborn rodents practice for their big debut. Researchers at Johns Hopkins report they have figured out the molecular ...

How cells 'climb' to build fruit fly tracheas

November 25, 2015

Fruit fly windpipes are much more like human blood vessels than the entryway to human lungs. To create that intricate network, fly embryonic cells must sprout "fingers" and crawl into place. Now researchers at The Johns Hopkins ...

Study suggests fish can experience 'emotional fever'

November 25, 2015

(Phys.org)—A small team of researchers from the U.K. and Spain has found via lab study that at least one type of fish is capable of experiencing 'emotional fever,' which suggests it may qualify as a sentient being. In their ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

not rated yet Nov 08, 2013
Maybe bases for longevity research in humans.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.