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NOT AS SIMPLE AS A-T-C-G:
There are stretches of DNA that don’t produce protein // But they're far from useless // Could new treatments focus on these gene influencers?

Our Dark Matter

By Cathryn Delude // Illustrations by Riley Hoonan // Spring 2014
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Dark Matter

Riley Hoonan

For more than 10 years, John Rinn, a cellular biologist who now teaches at Harvard Medical School, had been hunting for strands of genetic material that could explain the intricate orchestration of genes that switch on and off as embryos form and develop. But for just as many years, Rinn had heard that his quest was futile—that the objects he was seeking were bogus, mere phantoms that had no real functions.

Rinn was at the forefront of a generation coming of age in the wake of the rather humbling draft publication of the human genome in 2000. It turns out that people have only about 20,000 genes—more than a fruit fly (14,000) but fewer than rice (51,000) and well short of the 100,000 or so that had been estimated for humans. Also, of the 3.5 billion base pairs of DNA in the human genome (pairs combining the chemicals designated as A, T, C and G), a mere 1.5% spell out genes that encode proteins—essential substances ranging from actin and myosin that build muscles to keratin for hair and fingernails.

The remaining 98.5% of the genome is noncoding, meaning it does not produce proteins. Once dismissed as “junk DNA” and often dubbed “dark matter” in a nod to the characterization of the invisible matter that fills the universe, noncoding DNA is difficult to study and interpret. Much of it—just how much is a matter of hot debate—is transcribed into a complementary strand of RNA. But unlike the messenger RNA that carries information from genes to code proteins, this noncoding RNA (ncRNA) has no obvious purpose. However, Rinn and others believed that many long noncoding RNAs (lncRNAs) play crucial roles in the formation of embryos, development and disease.

The evidence they had, though, came mostly from studies of cells isolated in the laboratory—and uniform, cultured cells aren’t always reliable for predicting what happens in cells within the complex tissues and organs of a living animal. “I felt like I was at a poker table facing cowboys with guns,” says Rinn. “So I decided to put in all my chips and stake my career on the ultimate genetic test. If I lost, it would answer an important question: Yes, this noncoding RNA is junk after all. But if the cards came up right…”

Rinn and his colleagues’ gamble was to select 18 lncRNAs that prior research suggested might have biological importance, “knock out” each one in breeding a separate line of mice, and observe the impact on the animals for a study in the Dec. 31, 2013 eLife journal. Mice born without these noncoding RNAs had a variety of defects in anatomy, development and viability. Some had stunted growth, and quite a few died before birth. One had kidney and lung defects, another had epilepsy and seizures, and another was missing part of its brain. “We still don’t know what these lncRNAs are doing or how they work,” Rinn says. “We just know that if we take them away, bad things happen.”

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What Is Genetic Dark Matter?

Researchers are only beginning to understand genetic dark matter's many mysteries.

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hed-dossier

1. “Genome Regulation by Long Noncoding RNAs,” by John L. Rinn and Howard Y. Chang, Annual Review of Biochemistry, July 2012. The authors, who have made major contributions to the understanding of long noncoding RNAs, review technologies enabling these studies and highlight emerging themes.

2. “The Evolution of Lineage-Specific Regulatory Activities in the Human Embryonic Limb,” by James P. Noonan et al., Cell, July 3, 2013. Noonan describes enhancers associated with the embryonic development of the distinctive human hand and foot.

3. “Xist RNA Is a Potent Suppressor of Hematologic Cancer in Mice,” by Jeannie T. Lee et al., Cell, Feb. 14, 2013. Some breast cancers have extra copies of the X chromosome, suggesting that these cancers may have malfunctioning Xist, a long noncoding RNA responsible for silencing the second X chromosome in females. Here, Lee and colleagues investigate whether Xist dysregulation might cause cancer, using blood cancer in mice as a test case.

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