Knowing When to Stop

RESEARCH HIGHLIGHTS

Nature Reviews Genetics | Published online 25 Jul 2016; corrected 5 Aug 2016; doi:10.1038/nrg.2016.100

EVOLUTIONARY GENETICS species and must be differentially interpreted by the translation machinery based on context. There Knowing when to stop was no evidence that immediately flanking nucleotides define whether The genetic code — the rules by which magnum and an unclassified species a stop codon terminates translation. codons are translated into amino acid of the Parduzcia genus are the first Instead the authors noted that ciliates sequences — is almost universally examples for which all three stop codons have strikingly short 3ʹ untranslated functional conserved across all domains of life, (UAA, UAG and UGA) are predicted regions (only ~21–23 nucleotides flexibility although a minority of species are now to have been reassigned to encode between a genuine stop codon and the through known to use variant genetic codes. A amino acids (glutamine or tryptophan), polyadenylation (poly(A)) sequences, new study of diverse eukaryotes has such that all 64 possible codons are compared with >100 nucleotides in context- identified the first examples of species amino-acid-encoding. most other species). This indicates dependent that have recoded all of their stop Evidence that these canonical stop that the same codons are interpreted decoding of codons and instead rely on positional codons indeed encode amino acids was differently based on positional context context within a transcript to mediate provided by several means. The presence in the transcript: the authors propose ciliate codons translational termination. of these codons internally in the coding that ribosomal interactions with may represent To investigate the genetic codes used regions of single-copy essential genes, poly(A)-binding proteins promotes a state of by a broad range of eukaryotes, Swart combined with amino-acid-based translational termination when the et al. mined transcriptome data from evolutionary constraint both upstream stop codons are close to the end of evolutionary 289 species in the Marine Microbial and downstream of these codons, the coding regions, whereas the same flux Eukaryote Transcriptome Sequencing indicated that these ‘stop’ codons codons further upstream result in Project (MMETSP). In the absence of lead to amino-acid incorporation and continuous translation. proteomics data — which would provide continued translation, rather than Such functional flexibility through direct evidence of peptides that are translational termination. In addition, context-dependent decoding of translated using alternative genetic proteomics and ribosome profiling ciliate codons may represent a state codes — the authors inferred variant confirmed continuous productive of evolutionary flux and might explain genetic codes based on bioinformatic translation through these codons. why such diversity in genetic codes analysis of transcriptomic data using Although glutamine is probably has been discovered among ciliate the previously developed FACIL tool incorporated at UAA and UAG species. Given that genomic data are (Fast and Accurate Genetic Code codons in C. magnum using cognate rapidly accumulating for a wide range Inference and Logo). This tool uses tRNAs encoded by the macronuclear of species globally, perhaps we are cross-species protein alignments to genome (similarly to other ciliates), it only at the tip of the iceberg in the predict the most likely genetic code for is still unclear which tRNA recognizes search for biology’s rule-breakers that each species; for example, if a species its UGA codons. For these codons have deviated from the previously consistently uses a canonical stop either a cognate tRNA encoded assumed frozen and fixed nature of codon internally in a protein-coding by the mitochondrial genome or a the genetic code. sequence alignment, it is probable that near-cognate tRNA encoded by the Darren J. Burgess the codon can be amino-acid-encoding macronuclear genome might be used.

in that particular species. So, if all codons are amino-acid- ORIGINAL ARTICLE Swart, E. C. et al. Genetic The vast majority of the species used encoding, how does translational codes with no dedicated stop codon: context- the standard genetic code, but different termination occur at the intended sites dependent translation termination. Cell http:// genetic code variants were found among in these species? The investigators found dx.doi.org/10.1016/j.cell.2016.06.020 (2016) FURTHER READING Baranov, P. V., Atkins, J. F. & the 24 ciliate species analysed, adding that canonical stop codons are still used Yordanova, M. M. Augmented genetic decoding: global, local and temporal alterations of decoding

PIXTAL to previous examples of genetic code for translational termination at the flexibility in this group of species. Most carboxyl termini of proteins, implying processes and codon meaning. Nat. Rev. Genet. 16, 517–529 (2015) notably, the ciliates Condylostoma that stop codons are ambiguous in these

CORRECTION This Research Highlight has been updated from the original version published online. The final part of the fourth paragraph has been modified to correct the likely source (mitochondrial genome versus macronuclear genome) of the Condylostoma magnum tRNAs mediating amino-acid incorporation at the UAA, UAG and UGA stop codons. The editor apologizes for this error.