Imagine performing a cartwheel that transforms your look entirely. Just one twist, and your brown hair becomes dazzling platinum blonde. This concept is similar to what occurs in certain prokaryotes, like bacteria, when they experience genetic inversions. Recent research has revealed that these inversions, which flip a segment of DNA and alter an organism’s genetic identity, can take place within a single gene. This discovery challenges a long-held belief in biology that a single gene can only code for one specific protein.
Imagine performing a cartwheel that transforms your look entirely. Just one twist, and your brown hair becomes dazzling platinum blonde. This concept is similar to what occurs in certain prokaryotes, like bacteria, when they experience genetic inversions.
Researchers from Stanford Medicine found that these inversions physically flip DNA segments, altering an organism’s genetic identity and defying the traditional notion that one gene corresponds to one protein. “Bacteria are even more fascinating than I initially thought, and as a microbiologist, I already found them intriguing,” explained Rachael Chanin, PhD, a postdoctoral researcher in hematology. While scientists have recognized for many years that bacteria can flip small portions of their DNA to activate or deactivate genes, Chanin noted that this study marked the first time such inversions were identified within a single gene.
Much like how rearranging the letters in “dog” can entirely change the meaning of a phrase (consider “I’m a dog.” vs. “I’m a god.”), the inversion that occurs within a gene effectively rewrites the bacterium’s genetic instructions while using the same material. This could lead to the activation of a gene, a stop in gene activity, or even a code for a different protein created when the sequence is flipped.
“When I first saw the data, I thought, ‘No way—this is too wild to be true,'” recalled Ami Bhatt, PhD, a professor of genetics and medicine. “We spent several years trying to convince ourselves we must have made an error. But so far, we haven’t found any mistakes.”
Details of this study were made public on September 25 in Nature. Chanin and former postdoctoral researcher Patrick West, PhD, co-led the research, with Bhatt as the senior author.
Flip-flopping
The first indication of inversions appeared as early as the 1920s when researchers were looking for a treatment for salmonella. They attempted to gather antibodies from animals infected with the bacteria, hoping that these immune molecules would transfer to other animals and prevent infection. However, this approach failed: even genetically identical bacterial strains managed to resist. Scientists now understand that this evasion stemmed from an inversion that recoded the bacterium, allowing it to escape the host’s immune response.
Microbiologists have discovered inversions in small segments of DNA in various prokaryotes. However, Bhatt and her team questioned whether such inversions could also be found within a single gene. West developed an algorithm named PhaVa, designed to locate potential inversions in bacterial genomes.
The software works by downloading thousands of genome sequence segments from various prokaryotes and searching for sections that appear “flippable”—segments containing inverted repeats with a palindromic nature (e.g., ATTCC and CCTTA). The algorithm generates a catalog of what these sequences would resemble if they were flipped and compares the hypothetical genomes with actual sequences. It counts how many regions exhibit both the flipped and non-flipped sequences in an organism’s genome, with each match suggesting a likely inversion.
The algorithm uncovered thousands of inversions in species of bacteria and other prokaryotes, revealing for the first time that inversions can happen within genes. This led the team to think that these single-gene inversions might be more common than previously thought, according to Bhatt.
“This was totally unexpected for us,” Bhatt shared. “As far as we know, this has never been documented before.”
A significant question lingers: What triggers an inversion? The researchers speculate that specific enzymes facilitate the flip, influenced by certain environmental factors.
“That’s our next task,” Bhatt stated. “One of our future goals is to unravel the molecular grammar so we can establish a database of enzymes and a catalog of the inverted repeats they affect.”
Interpreting inversions
Despite the work still ahead, Bhatt envisions numerous potential applications stemming from their insight into inversions. “This represents a heritable and reversible form of genetic regulation,” she remarked.
She proposes that scientists might eventually harness inversions to create a switchable bacterial system for regulating gene expression, which could benefit synthetic biology endeavors. Furthermore, if there are connections between specific diseases and bacterial inversions, this could lead to methods for modifying the bacteria’s state to manage a disease.
“This kind of adaptation has been right in front of us, waiting for the appropriate tools, technology, and biological questions to be addressed,” Chanin noted. “It makes one ponder how many more secrets of bacteria are yet to be discovered.”
Researchers from Princeton University also contributed to this study.
This research received funding from the National Institutes of Health (grants R01 AI148623, R01 AI143757, R01 AI174515, HG000044, HL120824, TL1TR003019, 1S10OD02014101), the AP Giannini Foundation, the National Science Foundation Graduate Research Fellowship, the Stanford DARE fellowship, and the Stand Up 2 Cancer Foundation.
