University of California, Berkeley researchers have discovered that a microorganism from the Archaea group challenges a long-held principle in biology by interpreting a specific genetic code sequence in two different ways. This finding, published in the Proceedings of the National Academy of Sciences, suggests that not all life forms translate DNA into proteins with complete precision.
The study focused on Methanosarcina acetivorans, a methane-producing archaeon. Unlike most organisms where each three-letter codon corresponds to only one amino acid or serves as a stop signal during protein synthesis, this microbe sometimes interprets the UAG codon both as a stop and as coding for the amino acid pyrrolysine. The decision appears to depend on environmental conditions and the availability of pyrrolysine within the cell.
“Objectively, ambiguity in the genetic code should be deleterious; you end up generating a random pool of proteins,” said Dipti Nayak, assistant professor of molecular and cell biology at UC Berkeley and senior author of the paper. “But biological systems are more ambiguous than we give them credit to be and that ambiguity is actually a feature — it’s not a bug.”
This mechanism allows Methanosarcina acetivorans to incorporate pyrrolysine into an enzyme necessary for digesting methylamine, which is found in various environments including the human gut. Researchers believe that this flexibility could provide evolutionary advantages by enabling access to new metabolic pathways.
“We found that the machinery required to create pyrrolysine is widespread in the Archaea, especially amongst these methanogenic archaea that consume methylated amines,” said Katie Shalvarjian, former graduate student at UC Berkeley and now postdoctoral researcher at Lawrence Livermore National Laboratory.
Shalvarjian observed that whether UAG acts as a stop codon or codes for pyrrolysine may serve as a regulatory cue within cells: “The UAG codon is like a fork in the road, where it can be interpreted either as a stop codon or as a pyrrolysine residue. We think whether or not a protein exists primarily in its elongated or in its truncated form might form a regulatory cue for the cell.”
Nayak noted there are no apparent sequence or structural cues guiding this dual interpretation: “The methanogens have not recoded UAG, nor have they added any new factors to make it deterministic,” she said. “They’re flip-flopping back and forth between whether they should call this a stop or whether they should keep going by adding this new amino acid. They cannot decide. They just do both and they seem to be fine by making this random choice.”
Preliminary findings suggest that when there is abundant pyrrolysine available inside cells, interpretation favors its incorporation into proteins; otherwise, UAG functions as usual as a stop signal.
The implications go beyond microbial metabolism. Introducing controlled ambiguity into protein synthesis could potentially help treat genetic diseases caused by premature stop codons—such conditions account for about 10% of all genetic disorders such as cystic fibrosis and Duchenne muscular dystrophy—by allowing cells to produce enough functional protein despite faulty genes.
“This really opens the door to finding interesting ways to control how cells interpret stop codons,” Nayak said.
The research received funding from several organizations including the Searle Scholars Program, Rose Hills Innovator Grant, Beckman Young Investigator Award, Alfred P. Sloan Research Fellowship, Simons Foundation Early Career Investigator Award in Marine Microbial Ecology and Evolution, Packard Fellowship in Science and Engineering, and support from Chan-Zuckerberg Biohub-San Francisco.
Other contributors included Grayson Chadwick and Paloma Pérez from UC Berkeley along with Philip Woods and Victoria Orphan from California Institute of Technology.
