Chain termination codons and polymerase‐induced frameshift mutations

Abstract

The consensus sequence for single-base deletions in non-reiterated runs during in vitro DNA-dependent DNA polymerisation is refined using data available in the literature. This leads to the observation that chain termination codons are hotspots for single-base deletions. The evolutionary implications are discussed in two models which differ in whether polymerases evolved while the genetic code emerged or after the genetic code was fixed. A possible answer to the question 'Why are stop codons just what they are?' is suggested.© 1997 Federation of European Biochemical Societies.Key words: Genetic code; Stop codon; Deletion; Polymerase AssumptionsThe mutational spectra of in vitro polymerisation [1-9] for DNA polymerases belonging to families found in at least two of the three living kingdoms [10] are considered here as relevant with respect to a primordial polymerase; we will not take into account DNA polymerases ß, as they are family X DNA polymerases so far only found among eukaryotes [11], and HIV reverse transcriptases, which emerged very 'late' in evolution [12].As it is believed that RNA preceded DNA in evolution [13], data for RNA replicases would be more relevant but are not available; recent evidence shows, however, that DNA and RNA replicases are very closely related [14][15][16]: a single substitution of a hydroxyl group by a hydrogen atom in the Y639F mutant of T7 RNA polymerase allows a DNA replicase to function as a RNA replicase [17], and a single mutation confers on Moloney murine leukaemia virus reverse transcriptase the ability to replicate RNA [18]; we also note that Escherichia coli DNA polymerase I is an accurate RNA-dependent DNA polymerase [19]. Polymerase errorsPolymerase-induced mutations are mainly substitutions and frameshifts [1][2][3][4][5][6][7]. For the Klenow polymerase domain [1], which has no nuclease domain, as can be assumed for a primordial polymerase, the frameshift error rate is about half the substitution error rate: frameshift mutations therefore represent a significant proportion of the mutations in such systems. Frameshifts result mostly from deletions and additions of one base [1][2][3][4][5]. Crucially, these are highly deleterious by preventing translation in the correct reading frame of the codons »Corresponding author. Fax: (44) (1223) 402 140. E-mail: jlj@mrc-lmb.cam.ac.uk downstream of the mutation. Frameshifts occurring in directly repeated and palindromic sequences [8] will be addressed in the discussion. Here, we will focus on frameshifts in non-reiterated runs, where single-base deletions occur far more frequently than single-base additions [1,2,4,7]. Additions will therefore be neglected in the following. For polymerases with and without nuclease domains, the data indicate no significant differences in the consensus sequence for single-base deletions in non-reiterated runs. It has been defined as YR [1], TTR [9], YTG [6] and TR [8]. Using the current data [1-9] we here refine it as YTRV (V = C, A or G; Table 1). These singlebase deletions are found to...

Directed Mutations Recode Mitochondrial Genes: From Regular to Stopless Genetic Codes

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Study of the genetic code adaptability by means of a genetic algorithm

“…Single base changes, especially transitions, usually cause either no amino acid change or the change to a chemically similar amino acid. In more recent works, Jestin and Kempf (1997) showed that the codon assignment of stop signals optimized the tolerance of polymerase-induced frameshift mutations, that is, most singlebase deletions are less deleterious at chain termination codons than at codons encoding amino acids. Furthermore, the work of Ardell and Sella (2002) using a population genetic model of code-message coevolution demonstrated that such coevolution tends to produce structure-preserving codes, and in particular it can reproduce some of the structure-preserving patterns of the standard 3 A c c e p t e d m a n u s c r i p t genetic code.…”

Evolution of Nucleotide Punctuation Marks: From Structural to Linear Signals

“…The nucleotide triplets TAA, TAG, TGA, which function as termination codons in translation, are hotspots for single nucleotide deletions during polymerization (Jestin and Kempf, 1997). Putatively, these frameshift mutation signals could have become translation termination signals.…”