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Hidden Treasures in Junk DNA

What was once known as junk DNA turns out to hold hidden treasures, says computational biologist Ewan Birney

In other words, there is more complex regulation of genes, and more rapid evolution of these regulatory elements, in humans?
Absolutely.

That’s a rather different way of thinking about genes—and evolution.
I get this strong feeling that previously I was ignorant of my own ignorance, and now I understand my ignorance. It’s slightly depressing as you realize how ignorant you are. But this is progress. The first step in understanding these things is having a list of things that one has to understand, and that’s what we’ve got here.

Earlier studies suggested that only, say, 3 to 15 percent of the genome had functional significance—that is, actually did something, whether coding for proteins, regulating how the genes worked or doing something else. Am I right that the ENCODE data imply, instead, that as much as 80 percent of the genome may be functional?
One can use the ENCODE data and come up with a number between 9 and 80 percent, which is obviously a very big range. What’s going on there? Just to step back, the DNA inside of our cells is wrapped around various proteins, most of them histones, which generally work to keep everything kind of safe and happy. But there are other types of proteins called transcription factors, and they have specific interactions with DNA. A transcription factor will bind only at 1,000 places, or maybe the biggest bind is at 50,000 specific places across the genome. And so, when we talk about this 9 percent, we’re really talking about these very specific transcription-factor-to-DNA contacts.

On the other hand, the copying of DNA into RNA seems to happen all the time—about 80 percent of the genome is actually transcribed. And there is still a raging debate about whether this large amount of transcription is a background process that’s not terribly important or whether the RNA that is being made actually does something that we don’t yet know about.

Personally, I think everything that is being transcribed is worth further exploration, and that’s one of the tasks that we will have to tackle in the future.

There is a widespread perception that the attempts to identify common genetic variants related to human disease through so-called genome-wide association studies, or GWAS, have not revealed that much. Indeed, the ENCODE results now show that about 75 percent of the DNA regions that the GWAS have previously linked to disease lie no­­where near protein-coding genes. In terms of disease, have we been wrong to focus on mutations in protein-coding DNA?
Genome-wide association studies are very interesting, but they are not some magic bullet for medicine. The GWAS situation had everyone sort of scratching their heads. But when we put these genetic associations alongside the ENCODE data, we saw that although the loci are not close to a protein-coding gene, they really are close to one of these new elements that we’re discovering. That’s been a lovely thing. In fact, when I first saw it, it was a slightly too-good-to-be-true moment. And we spent a long time double-checking everything.

How does that discovery help us understand disease?
It’s like opening a door. Think about all the different ways you can study a particular disease, such as Crohn’s: Should we look at immune system cells in the gut? Or should we look at the neurons that fire to the gut? Or should we be looking at the stomach and how it does something else?

All those are options. Now suddenly ENCODE is letting you examine those options and say, “Well, I really think you should start by looking at this part of the immune system—the helper T cells— first.” And we can do that for a very, very big set of diseases. That’s really exciting.

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