Vertebrate Genomes Hide Ancient Viruses

JOE PALCA, host:

From NPR, this is SCIENCE FRIDAY. I'm Joe Palca.

When researchers began to analyze the human genome, they found that about 8 percent of the genetic code that's there actually came from viruses. It's not all that surprising some viruses contain special enzymes for inserting themselves in their host's genome. But most viruses don't do that, so their genetic sequences shouldn't be showing up in the genomes of the animals they infect. But they are.

In the latest issue of the journal PLoS Pathogens, researchers report that they found chunks of genetic code from viruses such as Ebola and Marburg in the genomes of vertebrates from mice to marmosets. Even we humans have the markings of ancient Borna virus in our genomes. So how did they get there, and what are they doing there? Well, joining me now to talk about that is the author of a new study. Dr. Anna Skalka is a professor and the director emeritus of the Institute for Cancer Research at the Fox Chase Center in Philadelphia, Pennsylvania. Welcome to the program.

Dr. ANNA SKALKA (Director Emeritus, Institute for Cancer Research, Fox Chase Cancer Center): Fine to be here.

PALCA: And if you'd like to talk with us about viruses in your genome, or at least viral sequences in your genome, call us. The number's 800-989-8255, 800-989-TALK.

So going back to that initial point - I mean, the viral sequences - I mean, these oncogenes and other things, those have been around for a while. What - I mean, am I right? Is that not surprising, and these new ones are?

Dr. SKALKA: It certainly was surprising to us, yes.

(Soundbite of laughter)

PALCA: Okay. Well, that's good enough for me. Why did you look for them in the first place if they're not supposed to be there?

Dr. SKALKA: Well, I've been studying retroviruses for many years. And as you know, they are unique. But - they're an RNA virus, but they're unique in the property of being able to put their DNA into genomes. But the vast majority of other viruses are RNA viruses that can't do this. And so I was really fascinated when I learned from an Israeli colleague, Dr. Ilan Sela, of recent studies in plants and insects in which DNA corresponding to genes from RNA viruses other than the retroviruses were found. And indeed, Sela had evidence that this process could be biologically important because bees that had such an insertion, he found, are resistant to infection by the corresponding virus.

So last fall, while I was on sabbatical at the Institute for Advanced Studies in Princeton, I mentioned this work to a colleague, a genomics expert, Dr. Vladimir Belyi, and we both thought it would be a great idea to see if we could find any evidence of such integrations in vertebrate species. And, as you mentioned, now that we have the - almost all of the sequences of known viruses and many vertebrate genomes, these - that such a search would be possible.

PALCA: Wow. So I'm just thinking - there's a couple of questions - I want to make sure that everybody understands the difference or the importance or the significance of an RNA virus versus a DNA virus, and an RNA virus that's a retrovirus and an RNA virus that's not a retrovirus.

Dr. SKALKA: Yes. It's complicated.

PALCA: It's a little complicated. But the point is that RNA virus just has RNA for its genetic material instead of DNA, and usually, the sequence is DNA to RNA to protein. But in this case, there are some that can go backwards. So maybe we'll just leave it at that. But how is it that these sequences that get back into the genome become protective somehow? How would that work?

Dr. SKALKA: Well, there are lots of scenarios you could think about. If the sequences are there and they're expressed, that RNA that's produced by itself could be protective by a mechanism that we know - now know about called RNAi, or RNA interference.

PALCA: Oh, okay.

Dr. SKALKA: The other kind of mechanism would be if the sequence actually encodes protein and makes proteins in the cell. And in that case, you can think of lots of ways in which a similar, but not quite the same protein of an infecting virus might kind of gum up its works when it - when that virus try to get into the cell and make some more progeny.

PALCA: Wow. That's really interesting. But then the other thing that I was surprised by when I read this research is that the viruses that you were finding, the viral sequences, things like Ebola virus and Marburg virus and Borna virus, these are pretty deadly viruses. And they're also kind of - I mean, we don't think of them as particularly common. Are you surprised at all that these are the ones that you were finding?

Dr. SKALKA: We were absolutely floored. We first were surprised that we had so many integrations, and then that they were just these two classes of viruses. And - but as you said, these are pretty deadly viruses to the species that they infect naturally. And so we imagined that if there was anything that could help protect them from infection, that kind of sequence might be selected over eons, just as in the case of the bees. So that was one possibly mechanism for why these particular sequences were maintained over long enough periods of time, and we could see them.

The other things about these viruses is that they generally, at least the Borna virus, have pretty stable genomes. They don't seem to make mutations as rapidly. And it could be that that property is why we were able to look so far back in time and see things that resemble them. It could be that other viruses, other RNA viruses, have also integrated their sequences into the genome by the same mechanism we think these occur, but we can't see them anymore because they - the currently circulating viruses have evolved so rapidly.

PALCA: Yeah. It's just such an interesting idea that the viruses that integrated millions and millions of years ago became stable because the DNA that's copied in our cells is pretty reliably copied over generations, whereas RNA viruses tend to change a lot over the years. And it's funny that - they sort of - it's like you took a photocopy of them 40 million years ago and they kept changing the edition and you didn't.

Dr. SKALKA: That's correct.

(Soundbite of laughter)

PALCA: It's such a funny idea. Well, let's see if our listeners are as amused as I am. Sorry. Maybe they find a different part of this interesting. But let's go and ask Troy(ph) in Iowa City, Iowa. Welcome to SCIENCE FRIDAY. You're on the air.

TROY (Caller): Great. Cool. I've got a question for you. Maybe the viruses are actually made by people, and that's why they have the DNA. And I was listening to one of the radio, you know, on one of the shows on NPR over the weekend and they said 80 percent of the DNA of a pumpkin occurs in people too. So maybe it's just an occurrence of DNA.

PALCA: Wow. That's an interesting thought. So the idea would be somehow that we made the viruses and then they went off and did something? What do you think about that idea?

Dr. SKALKA: Well, it's kind of interesting. It's a kind of chicken-and-eggs idea, isn't it?

PALCA: Hmm, yeah.

Dr. SKALKA: And actually, the living organisms, they're really kind of scrambled up. And there's a lot more genetic interaction going on than we ever thought about years ago. Years ago, we thought one animal's genes were privileged to that animal, but now we know that things go back and forth. It's unlikely that the sequences that we see, however, are naturally occurring vertebrate sequences. It's pretty clear that these particular fossils that we're looking at came from infecting viruses, although way back when, who came first, is a very good question.

PALCA: Yeah. Wow. Very - very solipsistic there, I think, is the word I'm looking for. Anyway, let's take another call now and go to Mark in San Francisco. Mark, you're on SCIENCE FRIDAY.

MARK (Caller): Thank you for taking the call.

PALCA: Sure.

MARK: I'm just wondering about the class of virus called the envelope viruses. Are you seeing any connection with them showing up in this way? And I'll take my answer off the air.

PALCA: Okay.

Dr. SKALKA: Ah, okay. Well, these viruses do have envelopes, actually. So having an envelope or not doesn't seem to be that important, but they do have envelopes. And in fact we found some genes, some insertions that seemed to be copies of the envelope genes of these viruses as well.

PALCA: Hmm. And the envelope we're talking about is this - the coding, essentially, that goes around the genetic material of the virus.

Dr. SKALKA: Yes. And so viruses are made of genetic material, DNA and RNA, usually a nuclear capsid protein that protects that genetic material. And then some viruses have a surrounding envelope usually generated from the cell in which they grow. And then the virus has usually special proteins that it puts into that envelope so that it can use them like - as in a fish - a hook mechanism to attach itself later on to other susceptible cells.

PALCA: Mm-hmm. You know, in the paper I notice that you made a point of saying that you didn't find sequences that were - from things like influenza virus.

Dr. SKALKA: That's right.

PALCA: And I was wondering about that, because does that suggests that perhaps there was a lot more Ebola and Marburg floating around once upon a time than there is today? And that if we look - if we live another 40 million years, you might see influenza sequences in human genomes in that period of time?

Dr. SKALKA: Well, it - well, you know, it could be. If you notice that we found the sequences in a lot of different kinds of animals, all the way up and down the evolutionary tree. So it looks like about 40 millions years ago these viruses were fairly prevalent. But the other explanation could be - as we were talking about before - that influenza virus mutates so rapidly, and we know it does that. We have to make new vaccines for it all the time. It replicates or it mutates so rapidly that we can no longer see the ancient fossils that have been embedded in genomes. The sequences are so different, we can't find a match by our computer analyses.

PALCA: So I want to ask you a question - and I hope this isn't embarrassing, and maybe your bosses at Fox Chase aren't listening. But you're a cancer researcher and you're at the Fox Chase Cancer Center -what are you wandering around looking at viruses for? Don't you have a job?

(Soundbite of laughter)

Dr. SKALKA: My boss will probably ask that same question.

PALCA: Yeah, right.

Dr. SKALKA: Well, actually, we know that cancer is a genetic disease, and I have been interested for years and years about genome stability. And I've used viruses like retroviruses to kind of - to understand how genomes make - maintain their stability, how genomes express their genes. And so this is really another question in that same direction.

These viruses get their DNA integrated. You could imagine that sometimes such an integration could be deleterious. We know that integration of retroviruses in some locations can lead to cancer. So it's not really that far afield. It's really a fundamental question about genome stability and what kinds of things affect that stability.

PALCA: Okay. I accept your answer. (Laughing)

Dr. SKALKA: Good. Thank you.

PALCA: We're talking with Dr. Anna Skalka. She's a professor and director emeritus of the Institute for Cancer Research at Fox Chase Cancer Center in Philadelphia. And we're taking your calls about how viral sequences found their way into vertebrate genomes.

I'm Joe Palca and this is SCIENCE FRIDAY from NPR.

And let's take another call now and go to Philip(ph) in Birmingham, Alabama. Philip, you're on the air with SCIENCE FRIDAY.

PHILIP (Caller): What's going on? How are you doing? How you all doing?

PALCA: We're great. How about you?

PHILIP: I'm fine. I'm just - I'm real intrigued about the subject that you guys are talking about. And I was just curious - wondering about these sequences. You know, I'm a layman, I really don't, you know, have any, you know, scientific background or anything like that. You know, I just - I was wondering if these sequences have like a psychological effect on the vertebrates they, you know, is in. I don't know.

PALCA: That's...

PHILIP: I really don't know how to phrase what I'm trying to say, but...

PALCA: No, no...

PHILIP: ...but that's pretty much it, like...

PALCA: Yeah. No, that...

PHILIP: ...do these sequences...

PALCA: That sounds like - sorry, Philip, I was going to say, I think that's a really interesting question because, you know, these are sequences that we don't really know what they're doing. But would you say psychological is a possible explanation or a likely explanation, that it might be having that effect?

Dr. SKALKA: Well, you know, things like the Borna virus, for example, does - it does cause neurological disease in horses.

PALCA: Really?

Dr. SKALKA: Oh, yes.

PALCA: Uh-huh.

Dr. SKALKA: That's what it does. That's its pathological effect. And people have suggested that there is an occasional Borna virus infection of human beings, although that evidence is controversial. So it's, you know, these viruses have very, very different kinds of effects, and neurological ones are not out of the ballpark.

PALCA: All right. Well, we have, I think, time for one more call. Let's go to Carl(ph) in Denver. Carl, welcome to SCIENCE FRIDAY. You're on the air.

CARL (Caller): Hi. Great. Thank you. Dr. Skalka, I heard some years ago, some crazy, I guess, speculation that viruses, retroviruses, could be an avenue through which evolution is occurring, and it might help explain this punctuated equilibrium mechanism that people are talking about. I know it's off the topic, but is it a crazy idea? I've been thinking about that for years.

PALCA: Hmm. Okay. Carl, thanks a lot.

Dr. SKALKA: Well, I don't know about a punctuated equilibrium, but certainly retroviruses are viewed as a kind of pathway between the earliest living things which are now thought to be made of - have their genes made in RNA, and higher forms of today which now have genomes of DNA. And, you know, the retroviruses can go from RNA to DNA. So they're kind of like thought of as a missing link in that part of our evolution. So there's that connection. But now that we know that our genome is really kind of - really scrambled up - one percent of the human genome is - actually encodes proteins, and the rest of it, a good part of it, is just bits and pieces of repeated DNA. And so, you know, who knows how evolution occurs. It certainly is in fits and starts, in this case.

PALCA: Wow. Well, it's really - I mean, these kinds of unexpected findings are just wonderful, and they're so much fun to talk about. So thanks for coming along and talking about it with us today.

Dr. SKALKA: It's been great fun for me too.

PALCA: Okay. That was Dr. Anna Skalka. She's a professor and director emeritus of the Institute for Cancer Research at the Fox Chase Cancer Center in Philadelphia, Pennsylvania.

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