Nearly half of our DNA is made up of sequences that are remnants of ancient molecular battles between our cells and invading genetic elements such as viruses. Once considered mere parasites cluttering the genome without function, or “junk DNA”, these elements are now recognized as powerful drivers of genome evolution. In many cases, hosts have turned the tables, repurposing these once-parasitic elements to build new gene regulatory sequences, many of which have been crucial for transformative biological innovations such as the evolution of the mammalian placenta.
Endogenous retroviruses (ERVs) are among these invading elements—genetic fossils of ancient viruses that once infected germ cells and became permanent residents of the genome and passed down through generations. To achieve this, ERVs had to constantly evolve to escape the host’s genetic surveillance systems, sparking an evolutionary arms race that fueled innovation on both sides.
Studying how ERVs adapt, specialize, and interact with host defense systems is key to understanding their double identity as both threats and sources of evolutionary innovation. Until now, however, scientists lacked a model system that could show how entire ERV lineages evolved and diversified within the different cell types of their host.
Now, a team of scientists led by Kirsten Senti and Julius Brennecke at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences offers a unique glimpse at ERV evolution inside a host. The team reveals how an entire clade of ancient ERVs split into different variants, each specialized to exploit a different cellular “niche” in the fruit fly ovary—and how the host’s DNA defense mechanisms adapted in return. Their findings were published in EMBO Journal on June 5th.
To study ERV activity in real time, the team blocked the piRNA system, the cell’s built-in surveillance system that recognizes and silences foreign genetic material. This genomic “unmuting” allowed dormant ERVs in the fruit fly ovary to reawaken and reveal their original behavior.
By combining phylogenetic and gene expression analyses, the team was able to map where and how each ERV was active in the ovary. They discovered that, during their evolution, some ERVs had acquired a special “envelope” gene from another type of virus. This new gene enabled them to form enveloped viral particles, transforming ERVs from genetic hitchhikers, similar to retrotransposons, into active, infectious viruses.
Much like Darwin’s finches on the Galápagos Islands evolved different beak shapes to match the diverse food sources available on each island, these infective ERVs evolved to be expressed in various somatic cell types in the ovary, such as escort or follicle cells, from where they infect the neighboring germile. A key step in this adaptation was developing new regulatory elements – DNA regions that control whether and how strongly genes are expressed in a given cell type – tailored to the gene expression program of each cell type. This specialization allowed each viral lineage to carve out its own “niche,” using specific cell types as springboards to gain access to the germline and ensure their transmission to the next generation.
The team also discovered that many other ERVs lineages lost their infectivity trait through mutations in the acquired envelope gene. Intriguingly, those non-infective lineages didn’t go extinct, but instead shifted their expression to germline cells, where they could continue to quietly copy themselves into the genome and be passed along.
But the viral point of view is only one side of the conflict between ERVs and their host. As ERVs shifted their behavior and territory, the host’s genome defense system fought back. The team discovered that the piRNA pathway, a small RNA-based genome surveillance system, adjusted its defenses, adapting each cell type to identify and silence newly evolving ERVs. This ongoing co-evolution between host and virus creates a back-and-forth dynamic, driving further innovation on both sides.
“Our study provides the first glimpse into how an entire clade of ERVs evolved and diversified within a host organism’s cells,” says Kirsten Senti, lead author. “We’re literally watching evolution unfold on a molecular scale.”
While the study focuses on fruit flies, its findings have far-reaching implications. ERVs also populate the genomes of humans and other vertebrates, where they have been linked to major evolutionary innovations, including immune regulation and placental development. The mechanisms uncovered by the Brennecke team may help explain how such viral remnants adapt and persist across species.
“Our findings provide a key starting point to understanding how retroviruses diversify their regulatory sequences, which the host can then co-opt to shape its own regulatory networks,” explains Julius Brennecke. “It’s one of the many ways viruses have shaped genome evolution.”
This study highlights the remarkable adaptability of ERVs, and underscores how deeply intertwined their evolution is with that of their hosts. Much of this molecular tug-of-war remains unexplored, and further research will surely reveal additional roles for ERVs in driving biological innovation. It’s a story of survival and specialization, and a reminder that genomic foes are essential to generate new diversity.