Meet your viral ancestors - how bornaviruses have been infiltrating our genomes for 40 million years

Cast your mind back 40 million years and think about your ancestors. You're probably picturing creatures that looked like a bit like today's monkeys, but they're only part of your family tree. To see your other ancestors, you'd have to whip out an imaginary microscope. Meet your great-great-great-etc-grandviruses.

The human genome is littered with the remains of viruses that, in ages past, integrated their genes into the DNA of our ancestors. They became a permanent fixture, passed down from parent to child. Today, these "endogenous retroviruses", or ERVs, make up around 8% of our genome. They're a living fossil record of prehistoric plagues.

Until recently, scientists thought that the only viruses to have left such a legacy were the retroviruses, a group that includes modern members such as HIV and hepatitis B. But they are no longer alone. Masayuki Horie and Tomoyuki Honda from Osaka University have found that another viral dynasty, the bornaviruses, have repeatedly inveigled their way into the genomes of mammals. They're found in humans, the great apes, elephants, rodents and many more. Those that lurk amid our genes have been our partners in evolution for at least 40 million years.

Almost all of these hidden sequences match the N gene of the most famous bornavirus - BDV or Borna disease virus. As a result, Horie and Honda christened their newfound sequences as EBLNs (or "endogenous Borna-like N" elements). We carry four such sequences but many others exist. A scan of over 234 genomes revealed that EBLNs are found in all manner of mammals, including chimps, gorillas, orang-utans, macaques, lemurs, bushbabies, African elephants, hyraxes, ground squirrels, mice, rats, guinea pigs, bats and opossums.

Most of these EBLNs are the result of independent invasions, at different points in the history of mammal evolution. Squirrels have only carried their EBLNs for less than 10 million years but our own genetic passengers have been riding and co-evolving with us for over 40 million years.

The vast majority of them apparently do nothing. Over the course of evolution, they have decayed into functionless 'pseudogenes', now nothing more than genetic garbage. They're like the books on the shelf that you never read, acting as a historical record without doing anything useful. But not all of them - two of the human EBLNs are still active. They're still transcribed into RNA, and they still produce working proteins. One of these even interacts with other proteins that we've inherited from our more direct primate ancestors.

We don't yet know what these proteins do. But their very existence suggests that our ancestors co-opted their viral interlopers and put them to use, domesticating them to act as productive parts of our own cells. In this way, bornaviruses have provided raw material for the evolution of mammals.

This process depends on the viral genes jumping into the right place. Enter the wrong site, and they could cause significant harm by disrupting existing genes. Indeed, there's some tantalising (albeit controversial) evidence suggests that this goes on today and contributes to mental health problems in humans.

BDV targets the neurons of a wide variety of birds and mammals, causing weird movements and behaviour. tT was actually named for the town of Borna, Germany, where a killer epidemic of cavalry horses in 1885 led to its discovery. In humans, the virus has been linked (albeit inconclusively) to various psychiatric disorders including schizophrenia. It's possible that BDV creates disease-causing mutations by inserting its genes into the wrong parts of our genomes.

Horie and Honda have certainly demonstrated that modern BDV can perform the same act of genetic infiltration that its ancestors clearly pulled off. They infected either lab-grown cells or mice with BDV and found that chunks of the virus's DNA had been integrated into that of its host. These additions look a lot like the 'fossil' EBLN sequences found in our own genomes. Whether this could lead to disease is another question, and one for future research.


Reference: Horie et al. 2010. Endogenous non-retroviral RNA virus elements in mammalian genomes. Nature 463: 84-88.

Feschotte. 2010. Bornavirus enters the genome. Nature 436: 39.

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What makes BDV and other EBLNs not qualify as retroviruses? Is it just that all the previously known retroviruses form a clade, and this one isn't in it?

By Nathan Myers (not verified) on 06 Jan 2010 #permalink

@Nathan Myers

My understanding is that retroviruses must first reverse transcribe their RNA into DNA in order to replicate, while supposedly BDV can directly replicate its RNA to make more virions (although it obviously must reverse transcribe into DNA in order to insert itself into a genome, so you do have a good question).


*shakes fist angrily*

You beat me to this, but I beat you to the prions!! :P

Dudes: BDV stole the reverse transcriptase activity of LINE-1 elements to be reverse transcribed-->inserted. Alu elements do the same thing. :)

To clarify, Borna is not a retrovirus, and does not reverse transcribe in its life cycle. It does things which are much more similar to the flu virus, influenza, life cycle, shuttling its negative strand RNA* into the nucleus and replicating more RNA directly from this template with a RNA -> RNA Polymerase.

Borna does not normally infect germ cells and does not have or use a reverse transcriptase, making that finding highly unlikely - but it happened :)
Like ERV wrote, these Borna viruses hijacked a reverse transcriptase activity from some of our genetic elements, parts of animal genomes called LINEs, which are related to retroviruses, to integrate. You can imagine LINEs as parasitic genes, which are normally transcribed and code for a reverse transcriptase (RT). The LINE RT binds to transcribed LINE mRNA and reverse transcribes it to DNA, which is inserted at another place of the genome of the same cell. This is the way the genetic parasite reproduces :-)

LINEs are not Retroviruses or endogenous Retroviruses and never were, as they only have the RT, but not the other genes the virus needs to make its particle and infect other cells. They are retrotransposons, parasitic genes which are most probably somewhat like the ancestors of retroviruses, maybe "living fossils" to retroviral ancestors, and did not envolve the particle-making genes. Endogenous retroviruses are different in that they are DNA elements which were once able to make viral particles, but lost the ability due to mutations - which means they are retrovirus fossils, I suppose.

Next step: finding Influenza endogenous elements in as many mammal and bird species as possible, then reconstructing a multi-lineage 4-dimensional reconstruction of Influenza molecular evolution over +100 Million years (I wish!) back in time. Then we can say want kind of genome the flu had which infected T. rex. That would be totally fucking awesome.

* Negative RNA is something that all viruses that copy RNA directly from RNA have. Positive RNA codes for proteins and acts like a mRNA, negative RNA is complementary to positive RNA and does not code for Proteins. Positive RNA viruses package positive RNA into their viral particles, while negative RNA viruses package positive RNA into particles. Borna and Influenza are negative RNA viruses.

By cakeforme(mo) (not verified) on 06 Jan 2010 #permalink

wrong profile name :P

I hope my english was ok to understand. I wanted to write
"we can say *what* kind of genome the flu had which infected T. rex."

Being one of the "everyones" rather than a molecular biologist, I am wondering how long, in terms of amino acid clumps, these virus (whatever) segments are that get inserted into the animal genomes? I am amazed that technology has advanced so much that you can identify these tiny bits as being "foreign"- it's all a bit Greek to me!

Awfully complicated stuff! Is there some connection between gram positive/negative bacteria and positive/negative viruses, and rH positive/negative blood type, and pH positive/negative, beyond the obvious polarity? I'd guess not. I wonder if retroviruses have ever induced speciation due to behavioral changes in part of the population.

DD: These other +/- have nothing to do with one another or with RNA, never mind antimatter flux. I gather that retroviruses were intimately involved in the transition to placental pregnancy; live birth ought to qualify as a sort of behavioral change.

By Nathan Myers (not verified) on 06 Jan 2010 #permalink

positive/negative is just to indicate polarity. Because positive and negative is a construction of human languages to identify polarities, there are no "real" positive and negative values in nature, as there are no real negative amounts of anything, anywhere (can you imagine a basket with -5 apples in it? If you add +5 apples, there are zero apples in the basket). Just polarities.

Simple polarities can arise fairly easy in evolution, as when a new character arises this one individuum has the character, while the others don't have it. Gram+/- is a simple polarity like that. RNA and DNA are other types of polarity, as they are complimentary.
Charges are also polar. I'm not a physicist, but I don't think that negative charges are the "more negative than zero" absence of positive charges, but just that a negative charge has the opposite behavior in a electric field than a same amount of positive charge.

In my post above, I wanted to write
"Positive RNA viruses package positive RNA into their viral particles, while negative RNA viruses package *negative* RNA into particles."

Murfomurf - they're around 360 amino acids long. So just over 1,000 DNA letters. You find them by taking the viral seqeunces and searching the human genome/proteome for matches.

DD - speciation? Not sure, but check out this awesome document for more on retroviral influence on human evolution, including the placental stuff that Nathan mentions.

Carey - nope. Mitochondria are ex-bacteria that have been captured by complex cells. These are viruses.

oops. That awesome document says LINEs are also ERVs.
I thought they were more ancestral.

Isn't Hep B an hepadnaviridae and not a retrovirus?

Add: Though I do know Hep B has reverse transcriptase, but it's a DNA virus and not an RNA virus like retroviruses.

Also, regarding Gram positive and negative bacteria, it's to indicate if they stain with Gram staining. Positive stains, negative doesn't.

Thank you, Ed, for another well written article. I struggled with some of the comments, but overall this was made very accessible. Well done!