Researchers at the University of California, Berkeley have identified a methane-producing archaeon that interprets a standard stop codon in two ways, challenging a core principle of biology. The microbe, Methanosarcina acetivorans, sometimes adds an amino acid called pyrrolysine instead of halting protein synthesis. This flexibility may aid in metabolizing compounds linked to human health.
The genetic code, which translates DNA into proteins through three-letter codons, has long been viewed as precise, with each codon directing a specific amino acid or signaling the end of a protein chain. However, a study led by Dipti Nayak, an assistant professor of molecular and cell biology at UC Berkeley, reveals an exception in Methanosarcina acetivorans, an archaeon that produces methane.
In this organism, the UAG codon—typically a stop signal—can either terminate protein building or incorporate pyrrolysine, the 21st amino acid beyond the standard 20. This results in two possible proteins from the same genetic sequence, depending on conditions like pyrrolysine availability. When the amino acid is plentiful, UAG is more likely read as pyrrolysine; when scarce, it acts as a stop. Between 200 and 300 genes in the microbe contain UAG, potentially allowing adaptive protein variations.
"Objectively, ambiguity in the genetic code should be deleterious; you end up generating a random pool of proteins," Nayak said in the study published in Proceedings of the National Academy of Sciences. "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."
The finding stems from surveys of Archaea by Nayak and former graduate student Katie Shalvarjian, now at Lawrence Livermore National Laboratory. They noted widespread machinery for pyrrolysine production among methanogenic Archaea that consume methylated amines, such as methylamine found in the human gut and environment.
These microbes play a role in health by breaking down methylamines, reducing formation of trimethylamine N-oxide, a byproduct of red meat digestion linked to cardiovascular disease. The discovery also hints at therapeutic potential: about 10% of inherited disorders, including cystic fibrosis and Duchenne muscular dystrophy, involve premature stop codons. A "leaky" stop like UAG might enable partial protein production to alleviate symptoms.
"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," Shalvarjian explained. No specific sequence triggers were identified; the interpretation remains probabilistic.
The research, supported by grants from the Searle Scholars Program and others, involved co-authors from UC Berkeley and the California Institute of Technology. It was published in 2025 with DOI: 10.1073/pnas.2517473122.
