Reading Between the Genomes Once upon a time, biologists believed that large sections of the genome had no obvious purpose. Now, scientists say there's a wealth of information in between the genes coded into our DNA. ENCODE, short for ENCyclopedia Of DNA Elements, aims to identify all the functional elements in the human genome.
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Reading Between the Genomes

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Reading Between the Genomes

Reading Between the Genomes

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And now, we're changing gears for the rest of the hour - reading between the genes. When scientists first began to decode the human genome, the big news was and still is, in many ways, the genes, parts of the DNA that held the blueprint for creating all our parts of our bodies or malfunction to create disease. And the race was on to find the genes that cause diabetes or cancer or depression. The bits between the genes, the repeating sequences that didn't seem to do anything, were referred to as junk DNA and not really worth anything.

But the genes, it turns out, make up only a small part of the genome, and scientists are learning that much of that so-called junk DNA may play a major role in regulating how the not-junk DNA or regular DNA is expressed. And this week, a consortium of researchers from around the world released a study looking at a sample of that junk DNA. And joining me now to talk about what they found is John M. Greally - he is assistant professor at Albert Einstein College of Medicine in the Bronx, and he's here with in our New York studio. Thank you for coming in today.

Dr. JOHN M. GREALLY (Epigenomics and Human Disease, Albert Einstein College of Medicine): Thanks for inviting me.

FLATOW: So the junk is not really junk after all?

Dr. GREALLY: It'd be a very brave person who would call it junk at this stage.


Dr. GREALLY: Well, even before this study, when people were looking at small areas of the genome, the regions that were neighboring the genes that we knew were doing functional things like producing the red pigment in our red cells to carry oxygen - what they realized was that there were - some of these sequences that were not genes were actually responsible for switching on or off the gene expression. So we knew that it wasn't all junk, but this is the first study to kind of formally look at a large region of the genome and be systematic in research.

FLATOW: And did you discover that that was the function of the so-called junk DNA, switching the other DNA on and off?

Dr. GREALLY: They found a lot of different things in this particular study, but possibly the most interesting one was the ability of the DNA that was neighboring the genes to have a regulatory role. There are - it seems like there's a lot more happening in the genome than just the expression of these genes.

FLATOW: And this is most of what's in the genome (unintelligible)…

Dr. GREALLY: That's exactly right.

FLATOW: Give us some idea of how much of it is not that normal DNA we think of.

Dr. GREALLY: Well, if you were to try to visualize this, it would be like driving on a highway. And every time you pass an exit, it's like a snippet of the gene, an exon of a gene as we'd call it. Most of the time, we're on the highway; we're not at exits. And in fact, the genome is very like that. About 96 percent, conservatively, of the genome is not genes, so it's a little bit of a shock, I think to realize just how much of it is stuff that we don't understand.

FLATOW: Would this switching function and the presence of this other kind of DNA explain things that we've seen everyday life but really couldn't, you know, explain before about how things work, like why somebody gets a disease while somebody does not get disease.

Dr. GREALLY: Yeah. There are a couple of ways of looking at this. One is that these sequences that sit between the genes or beside the genes are determining which genes should be switched on or off in a specific cell type because the DNA itself is the same in a liver cell or a muscle cell or a brain cell, but the exact repertoire of genes that we switch on or off in each of those cell types differs. And those instructions are mediated by these sequences that live nearby.

In terms of disease, that - this is where it gets very interesting - because some of the recent studies that were performed, for example, to look at large numbers of patients with adult diabetes, they realized that there were certain genes that looked like they were associated with the disease, but when you look at their results, you realize that a lot of the changes that they were seeing in the DNA sequence were not in the genes themselves, they were nearby.

And it's - you know that those sequences are very associated with diabetes. You're much more likely to see it in a diabetic individual than somebody else. But the precise function, the way that it might be causing the diabetes, is still a mystery.

FLATOW: Do we have a name for this DNA, instead of calling it none or other or something? Have scientists given these genes a name and the sequences or these parts?

Dr. GREALLY: It depends on their function, and this particular study didn't really try to assign a function to the sequences. The study was really to try to identify the subset of this 96 percent that might be doing something functionally. When you start studying these in more detail, which would presumably be a follow-up study, some of these sequences act to increase the local gene expression, and they would be known as enhancers.

Others tend to dampen down local gene expression. They would be known as silencers or perhaps repressors. And there are others that have this amazing property where if you have two genes side by side and you want to regulate them independently, the sequence in between will actually act as an insulator, and that's how they are referred.

FLATOW: Could these genes - whatever we're calling them now - might have great influence in early embryology?

Dr. GREALLY: Absolutely.

FLATOW: I mean, things on and off - might that be a good place to study what they do?

Dr. GREALLY: Yes, definitely. Yeah.


Dr. GREALLY: It's already known that there are huge changes in the expression of genes during early development. There have been human malformation syndromes - things where children have been born with, you know, limb problems or problems with the - the formation of their brain - where the events have occurred out in the wilderness between the genes but not in the genes themselves. So clearly, that is going to be a very important area.

FLATOW: But we inherit these as the same way we inherit the other.

Dr. GREALLY: It all comes as one package, one long string of DNA. It has all the intervening stuff and the genes.

FLATOW: And so this may add a whole new layer of complexity; things are not as simple as we thought they used to be.

Dr. GREALLY: Absolutely. And a further layer of complexity is when you impose epigenetics on top of that, which is an area of interest to a lot of people at the moment.

FLATOW: Well, explain what that is.

Dr. GREALLY: Yeah. What the ENCODE guys were doing - the consortium was doing -they were looking to see where the sequences are located that might be doing something. But having found those sequences, the - something has to mediate their role, and the broad group of regulatory mechanisms, biochemical mechanisms that do something to those sequences, have been loosely referred to as epigenetic.

And what can happen at those sites is that sometimes, the epigenetic regulators can have one pattern that might be associated, perhaps, with strong activation of a gene nearby. And sometimes, it may have a different pattern where it may actually have exactly the opposite effect. And the reason that this becomes particularly interesting is that it's this epigenetic regulation that is our means of responding to the environment and to noxious stimuli and basically reorganize the way that we express genes in a way that will allow us to adopt to our environment.

FLATOW: What does this mean for genetic testing? We do genetic testing - there are home genetic kits coming on the market. We're in an era where now we know what your genome is. Doesn't that make these genetic tests really inadequate? Because it may show you you have the gene, but we may not know if it gets -ever gets switched on or not by another gene.

Dr. GREALLY: If you have a mutation in a gene, the gene is dead or the gene has got a problem. So it doesn't matter if the local regulatory mechanisms are acting inappropriately or not. Thinking very simplistically, you can put gas in the tank, you can put new brake pads on, but if the engine is blown, it's not going to go anywhere. And the engine, in this case, would be the gene, so it doesn't matter what you do nearby.

However, in terms of the issue of DNA testing, what it does is it broadens the opportunities available to us. It may be that we are able to start focusing on these sequences that have regulatory functions in between the genes, look for the sequence changes that are occurring there, and actually be able to understand that they are as important as the changes in the genes and thus be able to do something predictive and accurate with our patients.

FLATOW: So you'd have to look to those also. You just couldn't say you have this gene for, let's say, breast cancer or something. And you - you have to have the activator gene that might also turn on or switch it off.

Dr. GREALLY: Well, the…

FLATOW: That may be a bad example because of the…



Dr. GREALLY: It's actually not a bad example in term of another type of cancer, which is colon cancer. There are some familial cases of colon cancer where these are very unfortunate families. The individuals get a very difficult type of cancer to diagnose, and they get it early in life, and it's called hereditary nonpolyposis colon cancer. And that is due to mutations, generally, in a gene called MLH1.

But recently, there was a very intriguing report where the gene was perfectly healthy. There was no mutation in either copy of the gene that this individual had. But what they had instead was a change in the regulation of the gene, so it was silenced. And it is important in this instance because it illustrates that silencing of both copies of the gene is as devastating to the cell or to the body as mutations of both of those copies.

FLATOW: This is TALK OF THE NATION: SCIENCE FRIDAY from NPR News. I'm Ira Flatow, talking with John Greally, assistant professor at the Albert Einstein College of Medicine in the Bronx. So we're talking about rethinking the human genome with these - with these genes, these helper genes, the switcher genes, all kinds of genes. Well, maybe our listeners will come up with a name for what we can call the whole group of genes. Let's go to Jessica in Denver. Hi, Jessica.

JESSICA (Caller): Hi. Nice to be on the show.

FLATOW: Hi. Thank you.

JESSICA: I was just going to point out that the idea there may have been junk DNA in the first place seems quite absurd to me. It seems as if shortly after the genome was mapped, that James Watson has formulated some sort of language for the genome, and it was quite simple at first. But after a year of the scientific discovery, we have discovered that the genome can play a lot of tricks on us, that things aren't initially what they first appear. And we are still discovering things like that every day. It seems like most mappings of the genome play a very important part in the human body.

FLATOW: Dr. Greally?

Dr. GREALLY: Jessica, I think it's a fair point that there's a lot more complexity to the genome than we have realized up to now. I think even Dr. Watson was probably surprised at how little of the genome-encoded genes and -you know, we've had to deal with that in terms of our emotional well-being. But at the end of the day, the challenge is not to throw our hands up and say we don't understand the challenges, to say all of this material is out there in the genome. It's there to be understood. Let's tackle the problem. And that's what this - that's why this recent publication was such a landmark that these guys went after it systematically.

FLATOW: Well, you bring up a good point. If only just a few percentage of the genome encodes for genes, and let's say 95 - could be a 98 - yeah, 95 percent of it is these other kinds of genes?

Dr. GREALLY: Other kinds of sequences.

FLATOW: Sequences.

Dr. GREALLY: Yeah.

FLATOW: And we haven't encoded those?

Dr. GREALLY: We haven't figured…

FLATOW: And we haven't - so we haven't figured - it's like the universe. We don't know what 95 percent of the universe is. We don't know what 95 percent of this other dark - it's called the dark genes, you know?

Dr. GREALLY: People have referred to it as the dark matter, the genome.

FLATOW: Yeah. So our work has just begun.

Dr. GREALLY: It's a good thing if you're - if you're in this line of business.

(Soundbite of laughter)

FLATOW: I mean, here we've been celebrating the deciphering of a human genome, but we haven't deciphered now, and now we see how important to know what it is - 95 percent of the genome.

Dr. GREALLY: If we didn't have the Human Genome Project, we wouldn't have this problem. So the Human Genome Project was a great foundation for discovery. And now, we're going to take that one step further.

FLATOW: What made this breakthrough possible?

Dr. GREALLY: The usual combination, intellectual curiosity and technology. It would have been very difficult to do this about 10 years ago. But there have been advances in technology that allow you to look at lots and lots of DNA sequences simultaneously, and particularly in areas such as microarray technology which is quite popular in the field at the moment. And because of the fact that people start to get clever about how they could use these microarrays and sequencing technologies, that, in particular, was a breakthrough.

FLATOW: Was there one sequence that lit a light bulb up in someone's head and said, whoa - we can't explain it any other way but these dark genes?

Dr. GREALLY: There - not in this particular project. This particular project was most notable for the sheer number of sequences it was pulling in simultaneously. So we have a bit of information overload to deal with.

FLATOW: And so now, the work will go on to decipher.

Dr. GREALLY: Absolutely.

FLATOW: Are there any - could - how long do you think it would take? How many years?

Dr. GREALLY: Well, through my retirement, I guess.

(Soundbite of laughter)

FLATOW: You're going to look very old. There's other - there's a lot of work to be shared and done by everybody.

Dr. GREALLY: Absolutely. But it's an accelerating pace, so being a typical, cautious scientist, I'm not going to put a number on it.

FLATOW: And we won't force you. Thank you for taking time to be with us.

Dr. GREALLY: Thank you for inviting me.

FLATOW: John M. Greally is assistant professor at the Albert Einstein College of Medicine right here in the Bronx in New York.

(Soundbite of music)

FLATOW: Have a great weekend. I'm Ira Flatow in New York.

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