Transfer RNA Mutation and the Malleability of the Genetic Code

doi:10.1006/jmbi.1994.1094

Journal of Molecular Biology

Volume 235, Issue 5, 3 February 1994, Pages 1377-1380

https://doi.org/10.1006/jmbi.1994.1094 Get rights and content

Abstract

We propose that evolutionary reassignment of codons is facilitated by a translationally ambiguous intermediate. For example, recently discovered tRNA mutations that allow relatively efficient simultaneous cognate and near-cognate coding (sharing 2 contiguous nt) in vivo may speed reassignment of the near-cognate codon. As predicted by this notion, characterized codon reassignments are strikingly non-random, and half can be immediately explained by unusual tRNA activities already demonstrated. In addition, sequences of reassigned tRNAs contain sequences that promote ambiguity. tRNA structural change may provide a transitional pathway that allows rapid selection of a new specificity, rather than slow mutation toward a new codon-amino acid association.

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Cited by (137)

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Citation Excerpt :
Also, a point mutation in a nucleotide in tRNA, RNA editing, or base modification is included in the mechanism of reassignment of codons (Koonin and Novozhilov, 2009a; Matsuyama et al., 1998; Allmang and Krol, 2006; Alfonzo et al., 1999; Kun and Radványi, 2018; Giegé et al., 1998; Knight et al., 2001). These changes have been addressed in three main theories, the ‘ambiguous intermediate theory’ (Schultz and Yarus, 1994, 1996), ‘codon capture theory’ (Osawa, 1995; Osawa et al., 1992), and ‘genome streamlining theory’ (Andersson and Kurland, 1995, 1998). More detailed studies on this topic are provided by these references (Koonin and Novozhilov, 2009a; Matsuyama et al., 1998; Allmang and Krol, 2006; Alfonzo et al., 1999; Kun and Radványi, 2018; Giegé et al., 1998; Knight et al., 2001; Krzycki, 2005; Wang et al., 2006).
DNA contains the genetic code, which provides complete information about the synthesis of proteins in every living cell. Each gene encodes for a corresponding protein but most of the DNA sequence is non-coding. In addition to this non-coding part of the DNA, there is another redundancy, namely a multiplicity of DNA triplets (codons) corresponding to code for a given amino acid. In this paper we investigate possible physical reasons for the coding redundancy, by exploring free energy considerations and abundance probabilities as potential insights.
Many alternative and theoretical genetic codes are more robust to amino acid replacements than the standard genetic code
2019, Journal of Theoretical Biology
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Missense reassignments can be explained by taking over tRNAs charged by a similar amino acid and posttranscriptional base modifications or point mutations in the tRNAs. Such reassignments could have happened mainly by the mechanisms of ambiguous intermediate (Schultz and Yarus, 1994; Schultz and Yarus, 1996; Sengupta et al., 2007) or unassigned codon (Sengupta and Higgs, 2005; Sengupta et al., 2007). Nevertheless, the significant excess of the beneficial codon changes in the alternative codes implies that at least some of them could have been positively selected or the benefits could have helped with their fixation even if they arose neutrally.
We evaluated the differences between the standard genetic code (SGC) and its known alternative variants in terms of the consequences of amino acids replacements. Furthermore, the properties of all the possible theoretical genetic codes, which differ from the SGC by one, two or three changes in codon assignments were also tested. Although the SGC is closer to the best theoretical codes than to the worst ones due to the minimization of amino acid replacements, from 10% to 27% of the all possible theoretical codes minimize the effect of these replacements better than the SGC. Interestingly, many types of codon reassignments observed in the alternative codes are also responsible for the substantial robustness to amino acid replacements. As many as 18 out of 21 alternatives perform better than the SGC under the assumed optimization criteria. These findings suggest that not all reassignments in the alternative codes are neutral and some of them could be selected to reduce harmful effects of mutations or translation of protein-coding sequences. The results also imply that the standard genetic code can be improved in this respect by a quite small number of changes, which are in fact realized in its variants. It would mean that the tendency to minimize mutational errors was not the main force that drove the evolution of the SGC.
Endogenous Stochastic Decoding of the CUG Codon by Competing Ser- and Leu-tRNAs in Ascoidea asiatica
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Although the “universal” genetic code is now known not to be universal, and stop codons can have multiple meanings, one regularity remains, namely that for a given sense codon there is a unique translation. Examining CUG usage in yeasts that have transferred CUG away from leucine, we here report the first example of dual coding: Ascoidea asiatica stochastically encodes CUG as both serine and leucine in approximately equal proportions. This is deleterious, as evidenced by CUG codons being rare, never at conserved serine or leucine residues, and predominantly in lowly expressed genes. Related yeasts solve the problem by loss of function of one of the two tRNAs. This dual coding is consistent with the tRNA-loss-driven codon reassignment hypothesis, and provides a unique example of a proteome that cannot be deterministically predicted.
Alignment-based and alignment-free methods converge with experimental data on amino acids coded by stop codons at split between nuclear and mitochondrial genetic codes
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Genetic codes mainly evolve by reassigning punctuation codons, starts and stops. Previous analyses assuming that undefined amino acids translate stops showed greater divergence between nuclear and mitochondrial genetic codes. Here, three independent methods converge on which amino acids translated stops at split between nuclear and mitochondrial genetic codes: (a) alignment-free genetic code comparisons inserting different amino acids at stops; (b) alignment-based blast analyses of hypothetical peptides translated from non-coding mitochondrial sequences, inserting different amino acids at stops; (c) biases in amino acid insertions at stops in proteomic data. Hence short-term protein evolution models reconstruct long-term genetic code evolution. Mitochondria reassign stops to amino acids otherwise inserted at stops by codon-anticodon mismatches (near-cognate tRNAs). Hence dual function (translation termination and translation by codon-anticodon mismatch) precedes mitochondrial reassignments of stops to amino acids. Stop ambiguity increases coded information, compensates endocellular mitogenome reduction. Mitochondrial codon reassignments might prevent viral infections.
Mistranslation: from adaptations to applications
2017, Biochimica et Biophysica Acta - General Subjects
The conservation of the genetic code indicates that there was a single origin, but like all genetic material, the cell's interpretation of the code is subject to evolutionary pressure. Single nucleotide variations in tRNA sequences can modulate codon assignments by altering codon-anticodon pairing or tRNA charging. Either can increase translation errors and even change the code. The frozen accident hypothesis argued that changes to the code would destabilize the proteome and reduce fitness. In studies of model organisms, mistranslation often acts as an adaptive response. These studies reveal evolutionary conserved mechanisms to maintain proteostasis even during high rates of mistranslation.
This review discusses the evolutionary basis of altered genetic codes, how mistranslation is identified, and how deviations to the genetic code are exploited. We revisit early discoveries of genetic code deviations and provide examples of adaptive mistranslation events in nature. Lastly, we highlight innovations in synthetic biology to expand the genetic code.
The genetic code is still evolving. Mistranslation increases proteomic diversity that enables cells to survive stress conditions or suppress a deleterious allele. Genetic code variants have been identified by genome and metagenome sequence analyses, suppressor genetics, and biochemical characterization.
Understanding the mechanisms of translation and genetic code deviations enables the design of new codes to produce novel proteins. Engineering the translation machinery and expanding the genetic code to incorporate non-canonical amino acids are valuable tools in synthetic biology that are impacting biomedical research. This article is part of a Special Issue entitled "Biochemistry of Synthetic Biology - Recent Developments" Guest Editor: Dr. Ilka Heinemann and Dr. Patrick O’Donoghue.
The identities of stop codon reassignments support ancestral tRNA stop codon decoding activity as a facilitator of gene duplication and evolution of novel function
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Stop codon reassignments are widely distributed in prokaryotic, eukaryotic and organellar genomes, but are remarkably convergent in terms of the stop codons and amino acids reassigned. Strikingly, the identities of stop codon reassignments are closely matched to the properties of naturally occurring nonsense suppressor (NONS) tRNAs, suggesting that pre-existing nonsense suppression in an ancestral tRNA facilitated the occurrence of stop codon reassignments. Here this idea is expanded, by exploring the mechanism by which the gene duplication of tRNAs has occurred, leading to the reassignment of stop codons. Two types of stop codon reassignment are identified: those that necessitate a tRNA gene duplication, and those that do not because a single tRNA can recognize the reassigned stop codon and the canonical codon(s) for the cognate amino acid. Where tRNA gene duplication has occurred, this implies a multi-functional ancestral NONS tRNA, followed by adaptive mutation in the anticodon of one of the gene duplicates to become complementary to the stop codon, constituting a clear example of escape from adaptive conflict. The best exemplar is the UAA + UAG → gln reassignment, which has occurred 9 times independently in a diverse range of genomes, and appears to reflect the widespread occurrence of naturally occurring nonsense suppression of the UAA + UAG stop codons by glutamine tRNAs. Consideration of pre-existing tRNA functionality and the mechanism of gene duplication provide new insights into the process of stop codon reassignment.

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Journal of Molecular Biology

CommunicationTransfer RNA Mutation and the Malleability of the Genetic Code

Abstract

Communication
Transfer RNA Mutation and the Malleability of the Genetic Code