Traces of ancient viruses are littered throughout the human genome, embedded within the DNA’s structure. Scientists already knew that some of these viral artifacts can “activate” in cancer cells and potentially contribute to the disease’s progression — but now, a new study reveals that the viruses are active in dozens of healthy tissues, too.
“Fifteen or 20 years ago, it was largely thought that almost all of these endogenous retroviruses that are in the genome — there’s thousands of them — most of them in normal tissue are silenced,” said Matthew Bendall (opens in new tab), an assistant professor of computational biology research in medicine at Weill Cornell Medicine in New York, who was not involved in the study. “They were kind of relegated to this category of ’junk DNA,’ parts of our genome that have no function.”
This assumption has been challenged in the last six years or so, as scientists developed more sensitive methods of studying gene activation, Bendall told Live Science. But most recent studies have only focused on ancient virus activation in cancerous tumors and in a small amount of healthy tissue near those tumors. The new study, published Tuesday (Oct. 18) in the journal PLOS Biology, provides a wider snapshot of how active these viral remnants really are throughout the body.
“This study is really one of the first looks at what is happening in normal tissue,” Bendall said. “We all are expressing, in all of our tissues, in all our cells, some of these viral remnants, and I think this study is really important in showing that.”
The new research pulled data from the Genotype Tissue and Expression (GTEx) project, a database that includes tissue samples taken after death from nearly 950 individuals. These samples include 54 types of non-diseased tissue found throughout the body, including in the brain, heart, kidney, lung and liver.
To build the database, researchers analyzed these tissues to see which of their genes were switched “on,” as evidenced by the presence of specific strands of RNA within their cells. RNA, a molecular cousin of DNA, copies instructions from spots in the genome and then shuttles them to protein-building factories in cells, so that the factories can pump out the necessary proteins. Some RNA molecules fulfill other roles in the cell, including helping to build those new proteins or switching genes “on” and “off.”
Within the vast GTEx database, the study authors looked for evidence of active “human endogenous retroviruses” (HERVs), meaning bits of ancient viruses woven into the genome. Specifically, they screened for a group of HERVs called “HML-2,” which was introduced to the human lineage relatively recently — at least by evolutionary standards. Some of the youngest examples of HML-2 viruses are mere hundreds of thousands of years old and are only found in the human genome, meaning they’re not seen in any of our primate relatives, Bendall said.
The authors found evidence of active HML-2 viruses in all 54 non-diseased tissue types in the GTEx database, but they found the highest levels of activation in the cerebellum, situated just behind the brainstem; the pituitary gland, a pea-size structure at the base of the brain that churns out hormones; the thyroid gland in the neck, which helps regulate metabolism; and the testis.
“The cerebellum and testis also supported the widest range of provirus expression of any tissue, with 17 and 19 proviruses expressed, respectively,” the researchers wrote in their report. ("Provirus" refers to a remnant of viral genetic material embedded in the genome.)
What these viruses do in healthy tissue is still a mystery, and the answer is likely different in each tissue type.
“Why is the cerebellum different from the cortex? I think that’s kind of an open question,” Bendall said. But it’s not surprising that some tissues showed a greater degree and variety of HML-2 activation than others, he said.
When HERVs are switched on, the viral fragments don’t give rise to whole, functional viruses capable of infecting cells, Bendall noted. Rather, their activation usually prompts the cell to build specific RNA molecules that may then prompt the cell to build proteins. For example, one type of HERV that’s present in primates, including humans, produces a protein that’s key for constructing the placenta, according to a 2012 report in the journal Placenta (opens in new tab).
Scientists are still working to discover how most of these ancient viruses affect human biology. Having comprehensive data on what the viruses are up to in healthy tissues provides a baseline to compare against diseased cells, the study authors wrote.
Some scientists have proposed that HERVs could act as potential biomarkers for cancer, meaning a measurable signal that doctors could use to screen for the disease, Bendall added. Additionally, some HERVs could theoretically serve as targets for cancer treatments, if they were found to be unique to specific tumor types. But to use HERVs in this way, scientists would need to know how HERVs behave in healthy cells versus cancerous ones.
Followup work should look at endogenous retrovirus families beyond HML-2, Bendall said. “It’s an important family, but it’s also a small family,” he said, and there are dozens more types of ancient viruses lurking in our genomes, still waiting to be investigated.
