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Avoiding Catastrophic Mutations Accurately Predicts Amino Acid to Codon Pairing.

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Title: Avoiding Catastrophic Mutations Accurately Predicts Amino Acid to Codon Pairing.
Authors: Nonacs, Peter1 (AUTHOR) peter.nonacs@gmail.com, Nonacs, Thomas2 (AUTHOR)
Source: Journal of Molecular Evolution. Feb2026, Vol. 94 Issue 1, p164-176. 13p.
Subjects: Stop codons, Genetic mutation, Genetic code, Evolutionary theories, Protein folding
Abstract: DNA codon mutations involving Stop signals or the amino acid cysteine can be especially damaging. The former can break protein sequences or add extraneous amino acids. The latter can add or subtract disulfide bonds crucial in protein folding. We present a hypothetical scenario where Stop codons were present early in the evolution of the genetic code; and minimizing catastrophic mutations for code networks affected all subsequent amino acid/codon pairings. Predicted features of this "Catastrophic Mutation Minimization Hypothesis" (CMMH) are that: (1) Cysteine is mutationally adjacent to Stop, isolating a contiguous codon 'neighborhood' with high potential for catastrophe. (2) The sequence of amino acid additions order determines codon assignments through minimizing network-wide mutation costs. Overall, codon locations for 16 of the 20 amino acids in the genetic code are consistent with the CMMH, as are multiple other predictions. We propose an antecedent genetic code consisted of 16 doublet codons specifying 13–14 amino acids. Two variations of these networks are less susceptible to catastrophic mutations than 88.2–97.5% of randomly generated ones. Unlike some previous hypotheses, CMMH does not require the total replacement or rearrangement of amino acids at codons, with its disruptive potential for protein synthesis. Finally, the composition of this ancestral doublet genetic code has all the modern code's utility: amino acids from four chemical types; start and stop signals; metal-binding ability; disulfide bridging for creating protein shapes; and possible epigenetic gene regulation. Thus, the modern code likely evolutionarily fine-tuned antecedent capabilities, rather than significantly increasing competence for making complex proteins. [ABSTRACT FROM AUTHOR]
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Abstract:DNA codon mutations involving Stop signals or the amino acid cysteine can be especially damaging. The former can break protein sequences or add extraneous amino acids. The latter can add or subtract disulfide bonds crucial in protein folding. We present a hypothetical scenario where Stop codons were present early in the evolution of the genetic code; and minimizing catastrophic mutations for code networks affected all subsequent amino acid/codon pairings. Predicted features of this "Catastrophic Mutation Minimization Hypothesis" (CMMH) are that: (1) Cysteine is mutationally adjacent to Stop, isolating a contiguous codon 'neighborhood' with high potential for catastrophe. (2) The sequence of amino acid additions order determines codon assignments through minimizing network-wide mutation costs. Overall, codon locations for 16 of the 20 amino acids in the genetic code are consistent with the CMMH, as are multiple other predictions. We propose an antecedent genetic code consisted of 16 doublet codons specifying 13–14 amino acids. Two variations of these networks are less susceptible to catastrophic mutations than 88.2–97.5% of randomly generated ones. Unlike some previous hypotheses, CMMH does not require the total replacement or rearrangement of amino acids at codons, with its disruptive potential for protein synthesis. Finally, the composition of this ancestral doublet genetic code has all the modern code's utility: amino acids from four chemical types; start and stop signals; metal-binding ability; disulfide bridging for creating protein shapes; and possible epigenetic gene regulation. Thus, the modern code likely evolutionarily fine-tuned antecedent capabilities, rather than significantly increasing competence for making complex proteins. [ABSTRACT FROM AUTHOR]
ISSN:00222844
DOI:10.1007/s00239-025-10294-0