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Mysterious Noncoding DNA: ‘Junk’ or Genetic Power Player?

On a regular basis, reporter Jenny Marder tackles a question in science and technology news. It’s a feature we call “Just Ask.” Today our topic is DNA.

What is noncoding DNA, and why do we need it?

In 1953, James Watson and Francis Crick built a 3-D cardboard cutout model of a DNA molecule shaped like a double helix, and in so doing, divined the structure of DNA.

Since then, the lion’s share of genetics research has focused on a small fraction of our DNA — the genes: the strands of DNA that code for RNA, which make protein. These genes are the blueprint for everything inherited, from height to hair loss to whether we’re prone to migraines or motion sickness.

It’s all there in the code, but the code is nothing without the stuff that powers the code.

Genes represent only a tiny fraction — 1 percent — of our overall genetic material. Then there’s the other 99 percent of our DNA — the stuff that doesn’t make protein.

This swath of the genome was once considered “junk,” and though a good deal of it is still believed to be nonfunctional, it is now more respectfully referred to as “noncoding DNA.” It is still largely an unexplored wilderness — disorderly and mysterious, but researchers have found that some of this noncoding DNA is in fact essential to how our genes function and plays a role in how we look, how we act and the diseases that afflict us.

Researchers have found that some of this noncoding DNA is in fact essential to how our genes function and plays a role in how we look, how we act and the diseases that afflict us.

Embedded in this 99 percent is DNA responsible for the mechanics of gene behavior: regulatory DNA. Greg Wray of Duke University’s Institute for Genome Sciences and Policy describes the regulatory DNA as the software for our genes, a set of instructions that tells the genome how to use the traditional coding genes.

“It’s like a recipe book,” Wray said. “It tells you how to make the meal. You need to know the amounts. You need to know the order. The noncoding DNA tells you how much to make, when to make it and under what circumstances.”

Transcription factors — proteins that bind to DNA sequences — function like a sort of molecular switch. Shaped like tiny Pac-Mans with clefts, they attach to stretches of noncoding DNA and modulate whether the gene will be turned on or off, whether it will function and how much protein it will produce.

Here’s how it works. When the transcription factors attach, they prompt the regulatory DNA to bend into a hairpin shape in order to make contact with a coding gene, which may be located as far as several thousand base pairs away. Sometimes this contact shuts off the gene altogether; sometimes it makes it go gangbusters making protein.

The location of these binding sites can vary wildly from person to person. And for any one gene, regulatory DNA may include binding sites for 10 or 12 or 20 different transcription factors.

It’s the stuff that tells you how to make a single being from a cell, said Michael Snyder, director of the Stanford Center for Genomics and Personalized Medicine. It tells you what goes wrong when you get cancer. “Many think it’s not the genes themselves, but how they’re regulated that makes us different from one another,” Snyder said.

Some rare diseases, such as cystic fibrosis, hemophilia and sickle cell anemia, are caused by a single mutation in coding DNA. In the case of these so-called Mendelian diseases, if you have the mutation, you have the disease.

“These are the classical “genetic diseases” that people generally think about,” said Olivier Harismendy of University of California, San Diego, who researches variations in regulatory DNA. “There is very little influence from the other genes or from the environment.”

But common diseases are probably more influenced by regulatory differences, Harismendy said. These include Type 2 diabetes, Crohn’s disease, Alzheimer’s Disease and a variety of cancers, including breast, colon, ovarian, prostate and lung. “Common diseases are usually multi-factorial,” he said. “They can have a genetic component, or heritability, but it gives only increased susceptibility, or protection, to the disease.”

According to Wray, research has shown that diseases like bipolar syndrome and clinical depression may be associated with noncoding mutations that determine whether the brain is producing too much or not enough of a particular neurotransmitter. One noncoding mutation gives a person almost complete protection against the nasty malaria parasite, plasmodium vivax.

Another piece of noncoding DNA regulates the enzyme responsible for lactose tolerance, the ability to digest milk. Research by Wray and other scientists has shown that in four populations where dairy consumption is a vital part of the diet, new mutations have appeared that essentially keep the gene that produces the lactase enzyme from switching off.

“I think it’s a neat example of how the smallest genetic change can give you a new capability to have a new dietary adaptation,” Wray said.

And recent research done by evolutionary biologists suggests that differences in regulatory DNA may represent a major part of what separates us from chimpanzees.

But finding the gold among the dross — the functional parts among the junk in these noncoding regions — is a tremendous challenge.

Whereas coding pieces have patterns that are easy to recognize, there are far fewer rules when it comes to noncoding DNA, making it a challenge for scientists to identify to which parts of the stuff in between to pay attention and which to ignore.

“People have written fancy computer programs to pull out patterns, but they’re fuzzy patterns and there are no hard rules,” Wray said. “If you’re just scanning visually, there’s nothing to tell you this is inherently regulatory in nature versus this does nothing.”

Snyder’s lab is trying to map all of the elements of the human genome, much of which is still unexplored territory.

“Most of it is mysterious,” he said. “Even for genes themselves, we don’t always know what they do. And when you get into the noncoding regions, you really don’t know.”

Many scientific questions remain, including why noncoding DNA works the way it does. Scientists, Wray said, are just now beginning to get under to hood to pick these things apart and determine how it all works.

“We know biochemically how it happens, how a transcription factor interacts with DNA,” Wray said. “What’s harder to work out is the logic – why some genes have three transcription factors that regulate them and others have 20 transcription factors. We’re trying to understand the dynamics of how all the elements interact with each other in a living cell.”

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