Phage viruses, used to tackle antibiotic resistance, benefit by disrupting the reproductive ability of competitors

Curious bits of DNA tucked within genomes in all kingdoms of life have historically been overlooked because they don’t seem to have any role to play in the competition for survival, or so researchers thought.

These pieces of DNA became known as “selfish genetic elements” because they exist, as far as scientists could tell, simply to reproduce and propagate themselves, with no benefit to their host organisms. They were seen as genetic hitchhikers who have been insignificantly passed down from one generation to the next.

Research conducted by scientists at the University of California, San Diego has provided new evidence that such elements of DNA may not be so selfish after all. Instead, they now appear to significantly influence the dynamics between competing organisms.

Journal publication science, researchers in the School of Biological Sciences studied selfish genetic elements in bacteriophages (phages), viruses that are considered the most abundant organisms on Earth. To their surprise, the researchers discovered that selfish genetic elements known as “mobile introns” give their virus hosts a distinct advantage when competing with other viruses: Phages have weaponized the mobile introns to disrupt the viruses’ ability to competing phage to reproduce.

“This is the first time that a selfish genetic element has been demonstrated to confer a competitive advantage on the host organism it has invaded,” said study co-author Erica Birkholz, a postdoctoral researcher in the Department of Molecular Biology. “Understanding that selfish genetic elements are not always just ‘selfish’ has far-reaching implications for better understanding the evolution of genomes in all kingdoms of life.”

Decades ago, biologists noticed the existence of selfish genetic elements but were unable to characterize any role they played in helping the host survive and reproduce. In the new study, which focused on investigating “jumbo” phages, the researchers analyzed the dynamics after two phages infected a single bacterial cell and competed against each other.

They looked closely at endonuclease, an enzyme that serves as a tool for cutting DNA. Studies have shown that the endonuclease from the mobile intron of a phage interferes with the genome of the competing phage. Therefore, the endonuclease is now considered a combat tool as it has been documented to cut an essential gene in the genome of the competing phage. This sabotages the competitor’s ability to properly assemble its offspring and reproduce.

“This armed intronic endonuclease gives a competitive advantage to the phage that harbors it,” Birkholz said.

The researchers say the discovery is particularly important in the evolutionary arms race between viruses because of the constant competition in co-infection.

“We were able to pinpoint the mechanism that confers an advantage and how it happens at the molecular level,” said graduate student in Biological Sciences Chase Morgan, co-first author of the paper. “This incompatibility between selfish genetic elements becomes molecular warfare.”

The results of the study are important as phage viruses are emerging as therapeutic tools in the fight against antibiotic-resistant bacteria. As doctors deploy “cocktails” of phages to fight infections in this growing crisis, new information will likely come into play when multiple phages are implemented. Knowing that some phages use selfish genetic elements as weapons against other phages can help researchers understand why some phage combinations may not reach their full therapeutic potential.

“The phages in this study could be used to treat patients with bacterial infections associated with cystic fibrosis,” said Professor of Biological Sciences Joe Pogliano. “Understanding how they compete with each other will allow us to make better cocktails for phage therapy.”

The authors of the paper are: Erica Birkholz, Chase Morgan, Thomas Laughlin, Rebecca Lau, Amy Prichard, Sahana Rangarajan, Gabrielle Meza, Jina Lee, Emily Armbruster, Sergey Suslov, Kit Pogliano, Justin Meyer, Elizabeth Villa, Kevin Corbett and Pogliano.