Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use

Atkins, John F.; Loughran, Gary; Bhatt, Pramod R.; Firth, Andrew E.; Baranov, Pavel V.

Reading of successive non-overlapping triplet codons is so ingrained in our perception of decoding, that it is easy to gloss over the dilemmas faced in the 8 years prior to 1961 in trying to imagine and distinguish between a variety of possible decoding schemes. However, from the discovery of the general nature of decoding (159) until two years after completion in 1966 of the deciphering of codon assignments, the pendulum swung too far and it was thought that framing was so hard-wired that frameshifting did not, and could not be made to, occur. The practical manifestation at the time, some 'ten' years in advance of the development of DNA sequencing, was the perception that a mutation could not be a frameshift mutation if it was leaky (allowed the synthesis of some full-length product), or could not be suppressible by a secondary 'suppressor' mutation of some translational component, i.e by mutation of a gene at a separate location from the gene containing the original frameshift mutation (709) (710) (711) . These misconceptions of sacrosanct framing were corrected with the discovery of (i) frameshift mutant extragenic suppressors (712, 713) that, as expected, were later shown to be mutants of various translation components that compensate for a framing 'problem' (439, 440) , (ii) frameshifting by the WT translational apparatus as evidenced by frameshift mutant 'leakiness' (393, 714) and (iii) the first identified viral encoded frameshift products (73, 74) . However, it took the advent of general availability of synthetic oligonucleotides of specified sequence and more extensive sequencing in 1984 to facilitate the discoveries that brought utilized frameshifting to widespread interest. While this occurred in 1985 with yeast Ty (206, 715) , release factor 2 (350) and retroviral frameshifting (76) , followup work was needed to show at what level it occurred, see above, by which time coronaviral frameshifting was discovered (103) . Parallel developments with other phenomena permitted appreciation of common features involved in various ways of utilizating non-standard decoding, and the dynamic competition with standard decoding. This led to a new word, recoding or reprogrammed genetic decoding (716) (717) (718) . In contrast to this use for naturally occurring organisms, the same word was later used somewhat differently in connection with human intervention to 'genomically recode organisms' (719), though several of the authors involved are now using a different term for that meaning (720) . [Distinctions between natural recoding and complete reassignment of the meaning of a codon wherever it occurs irrespective of context, have been highlighted (721) while word usage evolves, clarity about the intended meaning is key.]