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Researchers have discovered that inversions, which involve the physical flipping of a DNA segment and change an organism’s genetic identity, can occur within a single gene. This finding challenges the long-held belief that one gene codes for only one protein.

"Bacteria are even cooler than I originally thought, and I’m a microbiologist, so I already thought they were pretty cool," said Rachael Chanin, PhD, a postdoctoral scholar in hematology. Microbiologists have known for decades that bacteria can flip small sections of their DNA to activate or deactivate genes. However, these somersaulting pieces had never been found within the confines of a single gene until now.

Ami Bhatt, PhD, professor of genetics and medicine at Stanford Medicine, expressed initial skepticism about the findings: "I remember seeing the data, and I thought, ‘No way, this can’t be right because it’s too crazy to be true.’ We then spent the next several years trying to convince ourselves that we had made a mistake. But as far as we can tell, we have not."

The study detailing these findings was published on September 25 in Nature. The research was co-led by Chanin and former postdoctoral scholar Patrick West, PhD. Bhatt is the senior author.

Inversions were first hinted at in the 1920s when scientists were searching for a salmonella treatment. They observed that bacterial strains known to be genetically identical could evade immunity thanks to an inversion recoding the bacterium.

West developed an algorithm called PhaVa to identify possible inversions within bacterial genomes. The software downloads thousands of genome sequence segments from various prokaryotes and scans for regions with inverted repeats on either side of potential inversions. It then creates a catalog of what these sequences would look like if flipped and compares them with true sequences.

"This was really surprising to us," Bhatt said. "To our knowledge, this has never been seen before."

One big question remains: What causes an inversion? The team suspects specific enzymes mediate the flip and certain environmental cues drive the change.

"That’s a to-do now," Bhatt said. "One of our next steps is to try to decode the molecular grammar so we can build a database of enzymes and a database of the inverted repeats that they flip."

Bhatt sees potential applications for this discovery in synthetic biology research and disease regulation through bacterial state switching.

"This type of adaptation has just been hiding in front of us," Chanin said. "And it makes me wonder how many more bacterial secrets are just waiting for us to uncover them?"

Researchers from Princeton University contributed to this study. Funding came from multiple sources including grants from the National Institutes of Health and support from foundations such as AP Giannini Foundation and Stand Up 2 Cancer Foundation.