In Our Genes, Old Fossils Take On New Roles

By David Brown
Washington Post Staff Writer
September 1, 2008

"The past is never dead. It's not even past."
- William Faulkner

Over the past 15 years, scientists have been comparing the inherited genetic material -- the genomes -- of dozens of organisms, acquiring a life history of life itself. What they're finding would impress even novelist William Faulkner, the great chronicler of how the past never really goes away.

It turns out that about 8 percent of the human genome is made up of viruses that once attacked our ancestors. The viruses lost. What remains are the molecular equivalents of mounted trophies, insects preserved in genomic amber, DNA fossils.

The thousands of human endogenous retroviruses, or HERVs, sketch a history of rough times during the 550 million years of vertebrate evolution. The best-preserved one, HERV-K113, probably arrived less than 200,000 years ago, long after human beings and chimpanzees diverged from a common ancestor.

But these retroviruses are more than just curiosities. They are some of the most important enemies we ever had. They helped mold the immune system that is one of the evolutionary marvels of life on Earth.

In the past two years, a laboratory in France and another in the United States independently reconstructed a functioning HERV-K retrovirus from pieces found in the human genome. This summer, both showed that the gene sequences of some of those viruses bear the characteristic fingerprints of APOBEC3, a human enzyme that mutated them into submission.

"It is fascinating there is this fossil record in the genomes of modern organisms, and that we are able to see it, analyze it and reconstruct it," said Paul D. Bieniasz, a virologist at the Rockefeller University and the Aaron Diamond AIDS Research Center in New York, who leads the American lab.

Retroviruses differ from ordinary viruses in that they stitch themselves into the genes of the animals they infect. They become permanent residents of their hosts. Conventional viruses, such as the ones that cause measles, influenza and colds, don't do that.

At the moment, the world is in the middle of a huge retrovirus epidemic: AIDS. Its virus, HIV, attacks cells of the immune system, principally lymphocytes, and stitches itself into them. Once there, HIV is reborn constantly as the cells grow and divide (which is one reason there is no cure for the infection). The AIDS virus dies only when the host does.

HERVs, however, go one better.

HERVs attack the "germline" cells that make sperm and eggs. HERVs become a part of the host's inherited genome. Unlike HIV, they outlive the organism they infect, because they are passed on to the host's offspring and the offspring's offspring. (This is what makes them endogenous, or "born-within.")

All of the thousands of endogenous retroviruses in the human genome appear to be crippled and inactivated by mutations that occurred after their initial, successful invasion. They aren't able to be transcribed from the host DNA to replicate and infect another cell. Many are mere fragments. Most reside in stretches of chromosomes between genes where they aren't disturbing anything.

But parts of a few HERVs have been incorporated into human genes, taking on new roles.

For example, a protein called syncytin, which helps cells fuse together in the placenta, is actually the envelope gene from a HERV. A study published in January found that tissue from women with preeclampsia or intrauterine growth restriction -- two conditions that threaten fetal health -- had abnormally low amounts of syncytin.

Other studies have found that proteins derived from HERV genes -- or antibodies against the proteins -- are common in testicular tumors, breast cancer tissue and melanomas.

Whether the HERVs' reawakening there causes cancer, or is an effect of it, or is neither, isn't known. Nevertheless, "there is quite a bit that suggests there is some clinical significance to these HERVs," said Ravi Subramanian, a molecular biologist at Tufts University who is studying them in breast tumors.

In other species, endogenous retroviruses have evolved into tools for self-defense against their cousins, the retroviruses prowling the outside world (exogenous retroviruses).

For example, mice and chickens make proteins for the envelope, or outer shell, of several remnant retroviruses in their genomes. Once made, those proteins migrate to the surface of the animal cells and attach to receptors that are used by invading retroviruses as initial docking sites. With the receptors occupied, infection can't occur.

In sheep, researchers are discovering an especially interesting story.

Sheep today sometimes develop lung or nasal tumors caused by circulating retroviruses. Ancestors of those viruses began creeping into the genome even before sheep and goats diverged from each other more than 5 million years ago.

A team led by Massimo Palmarini of the University of Glasgow Veterinary School studied two of those endogenous retroviruses. They found that wild species (such as bighorn and Dall sheep) had versions of the two retroviruses that differed slightly from the versions carried by domesticated species. The retroviral genes in those animals contained a mutation that impeded infection by the cancer-causing viruses.

In a paper published in November, the researchers argued that when people began rounding up wild sheep 9,000 years ago, the newly confined herds probably suffered epidemics of the cancer-causing viruses. Only those animals whose endogenous viruses had by chance mutated into the protective form survived.

Today, thanks to natural selection and intentional breeding, all domesticated sheep carry the "updated" versions.


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