Battle of the Genetic Codes

A surprising number of microbes use alternate genetic codes, different from the standard genetic code that governs the large majority of life. A census of these "recoded" genomes was recently reported in the journal Science. Although the number of microbial species with recoded genomes tallies (by their count) to only 0.044% of the total, buried within their data lay an interesting story that could easily have gone uninvestigated.

Their findings challenge the assumption that a virus and its host must have the same genetic code. Instead, their discovery suggests that the genetic code could be yet another battlefield where pathogen and host clash.

Viruses lack the biological machinery for self-replication. Instead, they infiltrate host cells, hijack their machinery, and use the host's resources to make new viruses. The viral genome, made of the nucleic acids DNA or RNA, like all genomes, has the full set of instructions required to mass-produce the virus. The host cell translates the nucleic acid genome into viral proteins, in the same way it translates the messenger RNA transcribed from its own genes.

The genetic code is simply the lookup table that cells, and biologists, use to convert the nucleic acid language to the protein language. To encode the 20 amino acids used to assemble proteins, cells rely on 64 triplets of DNA bases (G, C, A, or T/U), called codons. Each codon uniquely specifies an amino acid, such as TCA for the amino acid serine.

Three of the 64 codons are "punctuation marks," reserved for signaling the end of a protein chain. Called stop codons, the three sequences are UAG, UAA, and UGA. Historically, the stop codons have the nicknames: amber, UAG; ochre, UAA; and opal, UGA.

The 61 codons that encode amino acids are recognized by RNA molecules, called tRNAs, that act as molecular translators between the nucleic acid and protein languages. However, stop codons are instead recognized by proteins called release factors. The release factor proteins have an uncanny resemblance to the shapes of tRNAs, and they can specifically recognize the stop codons. (See the structure at the top and the release factor, RF, scheme to the side.)

The authors of this study were particularly interested in microbes that reassigned stop codons to amino acids. In other words, they contained "recoded" stop codons; their genetic codes contain a single tweak.

Among the many viral genomes with recoded stop codons examined, one stood out as particularly interesting. The team identified a bacteriophage (or phage, a virus that infects bacteria) isolated from the human mouth, with the unassuming name Phage 2. Phage 2 reads the amber stop codon UAG as glutamine, rather than a stop signal.

But Phage 2 has more tricks up its sleeve. Its genome contains an unexpected gene: a release factor, RF-2. In bacteria, RF-2 terminates protein synthesis at ochre and opal stop codons.

The authors reasoned that if Phage 2 contains the RF-2 gene, its host must not. In fact, the human mouth is a hotspot for bacteria that have recoded a different stop codon: the UGA opal codon. Because RF-2 terminates at opal codons, bacteria with recoded opal codons should by definition lack RF-2.

The researchers were now confronted with an amber-recoded virus that, presumably, infects an opal-recoded bacterium. The two organisms' genetic codes differ in two positions, both stop codons, which initially appears to make the two genomes incompatible. How can a virus hijack a host that speaks a different genetic language?

The authors of the study propose an intriguing model that resolves this apparent problem (see the figure). They found that, while Phage 2 has the amber codon reassigned, it is only used in about half of the genome. The amber-free portion of the genome contains genes predicted to be active early in the infection, including RF-2.

By avoiding amber codons early on, Phage 2 avoids interference of its genetic code by the host bacterium's RF-1, which terminates translation at amber codons. The expression of RF-2 from the Phage 2 genome begins to interfere with translation by terminating at the host bacterium's opal codons, which it otherwise uses to encode glycine.

For Phage 2, RF-2 is a weapon. Its presence jams the synthesis of the host cell's own proteins, presumably diverting more resources to make viral proteins. The genes encoding viral coat proteins contain many amber codons, which suggests that by the time new viruses are assembling, the host has deteriorated, unable to interfere with the replication of Phage 2.

The life history of Phage 2 is still an outline, not a complete story. More important, this study shows that there is new biology hidden in existing databases waiting to be discovered. The presence of Phage 2, a virus that contains RF-2, in the same habitat (our mouths) as opal-recoded bacteria is strong circumstantial evidence of a clash of genetic codes. Rather than a barrier to infection, Phage 2 appears to use its genetic code difference to weaken its host. It's a battle of genetic codes.

Image credits:

RF-2 in translation structure: Rendered in Jmol from PDB file 2WH3

Remaining figures by Eric Sawyer