The hepatitis B virus and its ilk have been around for a long, long time. A newly uncovered "viral fossil" buried deep in the genome of the zebra finch indicates that the hepatitis B family of viruses—known as hepadnaviruses—originated at least 19 million years ago. Together with recent findings on other viruses, the work suggests that all viruses may be much older than thought.
No one knows exactly where or when viruses originated. They don't leave fossils, so scientists have begun scouring the DNA of various organisms, looking for evidence of ancient infections. Based on fragments of viral genes found in the DNA of bats and wallabies, for example, researchers have deduced that relatives of the Ebola and Marburg viruses began infecting mammals tens of millions of years ago.
The hepadnavirus discovery came about almost by chance. Late one night, Cédric Feschotte, an evolutionary geneticist at the University of Texas, Arlington, was browsing the DNA sequence database GenBank. On a whim, he typed in the amino acid sequence that makes up the hepatitis B virus. "I was just playing," he says. Feschotte wasn't expecting to find much, but a match appeared in the genome of the zebra finch. Closer inspection revealed that the finch genome contained 15 hepadnavirus fragments spread out over 10 chromosomes.
Feschotte and his postdoc, Clément Gilbert, set about trying to figure out how long ago the virus entered the finch genome. They collected tissue samples from five species related to zebra finches—the olive sunbird, the dark-eyed junco, the gouldian finch, the scaly-breasted munia, and the black-throated finch. When a virus inserts itself into the DNA of its host, it does so at a random spot. So the researchers reasoned that if they found the viral fragment in the same place in two related birds, they could be confident that the insertion must have occurred prior to the divergence of these two species.
A previous study put the age of hepadnaviruses at less than 6000 years. And the hepadnavirus in the finch genome was quite similar to the modern hepatitis B virus that infects ducks. So the researchers assumed that the integration had happened relatively recently.
Yet when they sequenced those spots in the genome where the hepadnavirus fragments appeared in the zebra finch, they found that the virus was very old. Viral fragments were present in all the birds except the olive sunbird, which diverged from the other species some 35 million years ago. The scientists inferred that the first insertion must have taken place between 35 million and 25 million years ago, when the junco, the next oldest relative, split off.
To verify their results, the researchers turned to the molecular clock method, which assumes a constant rate of genetic mutation to date a species. Because the virus was part of the finch genome, they used the standard mutation rate for birds. The analysis revealed that the hepadnavirus first entered the bird genome between 19 million and 40 million years ago, the authors report online today in PLoS Biology. "The 19 million years is a minimum age, and it's one we're very confident about," Feschotte says.
It's an "elegant" study that has "completely changed our understanding of the timescale of the evolution of this virus," says Eddie Holmes, an evolutionary biologist at Pennsylvania State University, University Park. The dates they give are "very believable." Yet modern hepadnavirus sequences appear to be only a few thousand years old. Scientists haven't yet worked out a way to reconcile those two estimates, he says.
The finding that the ancient hepadnavirus is remarkably similar to modern viruses suggests that hepadnaviruses weren't always locked in an evolutionary arms race with their hosts, says Harmit Malik, an evolutionary geneticist at the Fred Hutchinson Cancer Research Center in Seattle, Washington. If they had been, the modern viruses would be more distinct.
As genomes become available for more species, researchers will likely uncover even more viral remnants hiding in them, says Feschotte. And that will lead to a better understanding of the evolutionary history of all viruses.