A study finds that one microbe, a member of the Archaea, tolerates a little flexibility in interpreting the genetic code, contradicting a 60-year-old doctrine.
The beauty of the DNA code is that organisms interpret it unambiguously. Each three-letter nucleotide sequence, or codon, in a gene codes for a unique amino acid that’s added to a chain of amino acids to make a protein.
But University of California, Berkeley, researchers have now shown that one microorganism can live with a bit of ambiguity in its genetic code, overturning a standard dogma of biology.
The organism, a methane-producing member of a group of microbes called Archaea, interprets one three-letter sequence — normally a stop codon that signals the end of a protein — in two different ways, synthesizing two different proteins seemingly at random, though biased by conditions in the environment. The microbe, Methanosarcina acetivorans, survives just fine with this loosey-goosey translation, proving that life can exist with a slightly imprecise genetic code.
The ambiguity may have arisen to allow the microbes to incorporate an uncommon amino acid, pyrrolysine, into an enzyme needed to digest a specific food — methylamine — that is common in the environment, including the human gut.
“Objectively, ambiguity in the genetic code should be deleterious; you end up generating a random pool of proteins,” said Dipti Nayak, a UC Berkeley assistant professor of molecular and cell biology and senior author of a paper describing the findings published Nov. 6 in the journal 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.”
Archaea that eat methylamines, and bacteria that may have acquired that ability too, play an important role in the human body. In the liver, metabolites released by red meat are turned into trimethylamine N-oxide, which is associated with cardiovascular disease. We rely upon these microbes to remove those methylamines before they reach the liver.
The findings have implications for future disease therapies. Some researchers have speculated that introducing some imprecision into the translation machinery might help treat diseases caused by a premature stop codon in important genes, which produces nonfunctional proteins. That includes about 10% of all genetic diseases, including cystic fibrosis and Duchenne muscular dystrophy. Making a stop codon a bit leaky could allow enough of the normal protein to be produced to alleviate symptoms.
The genetic cipher
The DNA in the genome is initially transcribed into RNA, and that genetic code is then read by cellular machinery to produce proteins. The nucleic acids that comprise RNA come in four varieties — adenine (A), cytosine (C), guanine (G) and uracil (U). In most organisms investigated to date, groups of three nucleic acids or codons are either assigned to a single amino acid or a so-called stop codon, which terminates synthesis of that protein. When the RNA gets translated into a string of amino acids, the machinery always abides by this one-to-one association.