Viruses are lean, mean, infection machines. Their genomes are tiny, usually limited to a handful of absolutely essential genes, and they shed extra genomic deadweight extremely fast.

Usually.

Coronaviruses, including SARS-CoV-2 (the virus that causes COVID-19), appear at first glance to be an exception. They have some extra “accessory” genes in addition to the usual minimal viral set, and scientists don’t know what most of them do. Scientists believe these extra genes must be doing something important, though, or they would be rapidly lost as the viruses evolved.

Now, University of Utah Health researchers have found that some of these viral genes have stuck around even though they don’t produce a working protein, which is the function of the vast majority of genes. Their work investigating how and why these mystery genes evolve could help researchers better forecast which viral variants might be more dangerous.

“Viruses usually don’t keep genes that aren’t valuable to the virus in some way,” says Stephen Goldstein, PhD, postdoctoral researcher in human genetics in the Spencer Fox Eccles School of Medicine at the University of Utah and the first author on the study. “So what are the evolutionary pressures that determine whether a viral gene sticks around or is kicked out?”

To help understand these extra viral genes, Goldstein watched accessory gene evolution occur in real time in a mouse coronavirus. He was surprised to see that one of the genes was retained in the genome over many generations of viruses, even though it no longer produced a protein.

Something similar appears to be happening in SARS-CoV-2 itself. A gene called ORF8 is found in most strains of the virus, even though in some lineages, the protein it produces is tiny and presumably nonfunctional.

The researchers suspect that these seemingly broken genes may help control the activity of other viral genes in important ways. When the mouse virus lost a different accessory gene, the activity of other genes changed. The team is now investigating the structure of the first accessory gene to figure out if, and how, it could regulate the activity of other genes.

Goldstein says that these findings emphasize the importance of looking beyond the protein a gene makes when trying to understand which viral variants might be most dangerous. “The function of the genetic sequence itself—not just protein function—may affect viral fitness and transmission over time,” he says. “There’s this other evolution going on under the surface that we don’t know much about.”

These results were published in Current Biology as “Hidden evolutionary constraints dictate the retention of coronavirus accessory genes.”