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PubMed2006

Mutational unmasking of a tRNA-dependent pathway for preventing genetic code ambiguity.

Aminoacyl-tRNA synthetases establish the genetic code by matching each amino acid with its cognate tRNA. Aminoacylation errors lead to genetic code ambiguity and statistical proteins. Some synthetases have editing activities that clear the wrong amino acid (aa) by hydrolysis of either of two substrates: misactivated aminoacyl-adenylates ("pretransfer" of aa to tRNA) or misacylated aa-tRNA ("posttransfer"). Whereas posttransfer editing can be directly measured, pretransfer editing is difficult to demonstrate, because adenylates are inherently labile and transient, and activity occurs against a background of posttransfer editing. Herein, different mutations in Escherichia coli leucyl-tRNA synthetase are combined to unmask the pretransfer pathway. The mutant enzymes completely lack posttransfer editing but prevent misacylations by clearing misactivated adenylates. We hypothesize that these mutations isolate a pretransfer translocation step that moves misactivated adenylates from the activation site for editing. The results highlight how evolution redundantly created two distinct pathways to prevent genetic code ambiguity.

Amino Acid Sequence↗
PubMed1998

The historical factor: the biosynthetic relationships between amino acids and their physicochemical properties in the origin of the genetic code.

Two forces are in general, hypothesized to have influenced the origin of the organization of the genetic code: the physicochemical properties of amino acids and their biosynthetic relationships. In view of this, we have considered a model incorporating these two forces. In particular, we have studied the optimization level of the physicochemical properties of amino acids in the set of amino acid permutation codes that respects the biosynthetic relationships between amino acids. Where the properties of amino acids are represented by polarity and molecular volume we obtain indetermination percentages in the organization of the genetic code of approximately 40%. This indicates that the contingent factor played a significant role in structuring the genetic code. Furthermore, this result is in agreement with the genetic code coevolution hypothesis, which attributes a merely ancillary role to the properties of amino acids while it suggests that it was their biosynthetic relationships that organized the code. Furthermore, this result does not favor the stereochemical models proposed to explain the origin of the genetic code. On the other hand, where the properties of amino acids are represented by polarity alone, we obtain an indetermination percentage of at least 21.5%. This might suggest that the polarity distances played an important role and would therefore provide evidence in favor of the physicochemical hypothesis of genetic code origin. Although, overall, the analysis might have given stronger support to the latter hypothesis, this did not actually occur. The results are therefore discussed in the context of the different theories proposed to explain the origin of the genetic code.

Algorithms↗
PubMed1992

A statistical test of hypotheses on the organization and origin of the genetic code.

Theories of the origin of the genetic code assign different weights to amino acid properties such as polarity and precursor-product relationship. Previous statistical work on the origin of the genetic code has produced controversial results. We analyze relationships between various amino acid and tRNA properties by one and the same statistical method. It is shown that polarities as well as precursor-product relationships are both likely to have been important in shaping the genetic code, together with codon swapping that left protein sequences intact.

Amino Acids↗
PubMed1998

The role of the genetic code in generating new coding sequences inside existing genes.

The genetic code has a very interesting property--it generates an open reading frame (ORF) inside a coding sequence, in a specific phase of the antisense strand with much higher probability than in the random DNA sequences. Furthermore, these antisense ORFs (A-ORFs) possess the same features as real genes--the asymmetry in the nucleotide composition at the first and second positions in codons. About two thirds of the 2997 overlapping ORFs in the yeast genome possess this feature. Thus, the question arises: has this feature of the genetic code been exploited in the evolution of genes? We have searched the FASTA data bases for homologies with the antisense translation products of a specific class of genes and we have found some sequences with relatively high homology. Many of them have scores which could be randomly found in the searched data bases with a probability lower than 10(-6). We conclude that some genes could arise by positioning a copy of the original gene under a promoter in the opposite direction in such a way that both, the original gene and its copy initially use the same nucleotides in the third, degenerated positions in codons.

DNA, Antisense↗
PubMed2005

The standard genetic code enhances adaptive evolution of proteins.

The standard genetic code, by which most organisms translate genetic material into protein metabolism, is non-randomly organized. The Error Minimization hypothesis interprets this non-randomness as an adaptation, proposing that natural selection produced a pattern of codon assignments that buffers genomes against the impact of mutations. Indeed, on the average any given point mutation has a lesser effect on the chemical properties of the utilized amino acid than expected by chance. Might it also, however, be the case that the non-random nature of the code effects the rate of adaptive evolution? To investigate this, here we develop population genetic simulations to test the rate of adaptive gene evolution under different genetic codes. We identify two independent properties of a genetic code that profoundly influence the speed of adaptive evolution. Noting that the standard genetic code exhibits both, we offer a new insight into the effects of the "error minimizing" code: such a code enhances the efficacy of adaptive sequence evolution.

Evolution, Molecular↗
PubMed1993

An operational RNA code for amino acids and possible relationship to genetic code.

RNA helical oligonucleotides that recapitulate the acceptor stems of transfer RNAs, and that are devoid of the anticodon trinucleotides of the genetic code, are aminoacylated by aminoacyl tRNA synthetases. The specificity of aminoacylation is sequence dependent, and both specificity and efficiency are generally determined by only a few nucleotides proximal to the amino acid attachment site. This sequence/structure-dependent aminoacylation of RNA oligonucleotides constitutes an operational RNA code for amino acids. To a rough approximation, members of the two different classes of tRNA synthetases are, like tRNAs, organized into two major domains. The class-defining conserved domain containing the active site incorporates determinants for recognition of RNA mini-helix substrates. This domain may reflect the primordial synthetase, which was needed for expression of the operational RNA code. The second synthetase domain, which generally is less or not conserved, provides for interactions with the second domain of tRNA, which incorporates the anticodon. The emergence of the genetic from the operational RNA code could occur when the second domain of synthetases was added with the anticodon-containing domain of tRNAs.

Amino Acid Sequence↗
PubMed1999

Physicochemical optimization in the genetic code origin as the number of codified amino acids increases.

We have assumed that the coevolution theory of genetic code origin (Wong JT, Proc Natl Acad Sci USA 72:1909-1912, 1975) is essentially correct. This theory makes it possible to identify at least 10 evolutionary stages through which genetic code organization might have passed prior to reaching its current form. The calculation of the minimization level of all these evolutionary stages leads to the following conclusions. (1) The minimization percentages increased linearly with the number of amino acids codified in the codes of the various evolutionary stages when only the sense changes are considered in the analysis. This seems to favor the physicochemical theory of genetic code origin even if, as discussed in the paper, this observation is also compatible with the coevolution theory. (2) For the first seven evolutionary stages of the genetic code, this trend is less clear and indeed is inverted when we consider the global optimisation of the codes due to both sense changes and synonymous changes. This inverse correlation between minimization percentages and the number of amino acids codified in the codes of the intermediate stages seems to favor neither the physicochemical nor the stereochemical theories of genetic code origin, as it is in the early and intermediate stages of code development that these theories would expect minimization to have played a crucial role, and this does not seem to be the case. However, these results are in agreement with the coevolution theory, which attributes a role to the physicochemical properties of amino acids that, while important, is nevertheless subordinate to the mechanism which concedes codons from the precursor amino acids to the product amino acids as the primary factor determining the evolutionary structuring of the genetic code. The results are therefore discussed in the context of the various theories proposed to explain genetic code origin.

Algorithms↗
PubMed2000

Mitochondrial genetic code in cestodes.

The flatworm mitochondrial genetic code, which has been used for all species of the Platyhelminthes, is mainly characterized by AUA codon for isoleucine, AAA codon for asparagine and UAA codon for tyrosine. In eight species of cestodes (Echinococcus multilocularis, Echinococcus granlosus, Taenia solium Taenia saginata, Taenia hydatigena, Taenia crassiceps, Hymenolepis nama and Mesocestoides corti), the cytochrome c oxidase subunit I (COI) genes were partially sequenced to verify this genetic code. Comparison of the COI-encoding nucleotide sequences with those of human, sea urchin, fruit fly, nematode and yeast indicated that the assignments of AUA and AAA codons are adequate for cestodes. In addition, the nucleotide sequences of ATPase subunit 6 (ATP6) gene and its flanking region were compared to examine initiation and stop codons. In the related species of T. solium and T. saginata, the deduced amino acid sequences of ATP6 were homogeneous; however, the conversion of initiation codon AUG into GUG was observed in T. saginata. We also found the similar conversion in T. crassiceps. The C-terminal sequences of putative ATP6 proteins were highly conserved among the eight species and the stop codon UAG was altered to UAA in all Taenia species. The features of the gene-junctional region between NADH dehydrogenase subunit 4 (ND4) and glutamine tRNA (tRNAGln) genes also supported that UAA serves as a stop codon. Based on these results, we propose that the flatworm mitochondrial code should be modified for cestodes, particularly, in an initiating methionine codon (GUG) and a terminating codon (UAA).

Animals↗
PubMed1986

Laws governing degeneration of the genetic code.

The laws governing degeneration of the genetic code are discussed below. Of fundamental importance in this context is the classification of the amino acids into groups on the basis of the physicochemical behaviour of their residues. From this, it is possible to formulate arithmetic relationships between the number of amino acids in the same group and the number of coding triplets. It is found that the degeneration of the genetic code obeys certain laws, the reasons for this being related to the number and the qualitative properties of the amino acids and triplets. The fact that the three bases of a coding triplet have different priorities must also be a critical factor.

Amino Acid Sequence↗
PubMed1982

In search of more complex genetic codes--can linguistics be a guide?

Striking similarities have been pointed out between the structures of the human language and the genetic code. The primary genetic code utilizes the principle of linear representation much like e.g. the Indo-European languages do. There are numerous indications that more complex secondary and tertiary structural elements in DNA direct highly specific interactions with proteins. Thus, more complex genetic codes might exist which might be superimposed on DNA sequences coding for polypeptides or might be extended to "non-coding" DNA sequences. Structural features of highly complex languages, like Chinese or Egyptian hieroglyphics using conceptual expression patterns have been compared to the more complex ways of encoding. It is proposed that the application of linguistic principles may be helpful in the computer analyses of known DNA sequences. There is considerable evidence for the innate specification at least for the basic structural elements of human languages. This innate specification may be the cause for language university. Based on the striking structural similarities between language and genetic code, the question is raised to what extent and in what way DNA sequences might be related to the innate specification of human languages.

Computers↗
PubMed2004

Codon usage bias and mutation constraints reduce the level of error minimization of the genetic code.

Studies on the origin of the genetic code compare measures of the degree of error minimization of the standard code with measures produced by random variant codes but do not take into account codon usage, which was probably highly biased during the origin of the code. Codon usage bias could play an important role in the minimization of the chemical distances between amino acids because the importance of errors depends also on the frequency of the different codons. Here I show that when codon usage is taken into account, the degree of error minimization of the standard code may be dramatically reduced, and shifting to alternative codes often increases the degree of error minimization. This is especially true with a high CG content, which was probably the case during the origin of the code. I also show that the frequency of codes that perform better than the standard code, in terms of relative efficiency, is much higher in the neighborhood of the standard code itself, even when not considering codon usage bias; therefore alternative codes that differ only slightly from the standard code are more likely to evolve than some previous analyses suggested. My conclusions are that the standard genetic code is far from being an optimum with respect to error minimization and must have arisen for reasons other than error minimization.

Base Composition↗
PubMed2000

Evolution of genetic codes through isologous diversification of cellular states.

Evolution of genetic codes is studied as change in the choice of enzymes that are used to synthesize amino acids from the genetic information of nucleic acids. We propose the following theory: the differentiation of physiological states of a cell allows for a choice of enzymes, and this choice is later fixed genetically through evolution. To demonstrate this theory, a dynamical systems model consisting of the concentrations of metabolites, enzymes, amino acyl tRNA synthetase, and tRNA - amino acid complexes in a cell is introduced and studied numerically. It is shown that the biochemical states of cells are differentiated by cell-cell interactions, and each differentiated type starts to use a different synthetase. Through the mutation of genes, this difference in the genetic code is amplified and stabilized. The relevance of this theory to the evolution of non-universal genetic code in mitochondria is suggested. The present theory is based on our recent theory of isologous symbiotic speciation, which is briefly reviewed. According to the theory, phenotypes of organisms are first differentiated into distinct types through the interaction and developmental dynamics, even though they have identical genotypes; later, with mutation in the genotype, the genotype also differentiates into discrete types, while maintaining the "symbiotic" relationship between the types. Relevance of the theory to natural as well as artificial evolution is discussed.

Biological Clocks↗
PubMed2004

Can the genetic code be mathematically described?

From a mathematical point of view, the genetic code is a surjective mapping between the set of the 64 possible three-base codons and the set of 21 elements composed of the 20 amino acids plus the Stop signal. Redundancy and degeneracy therefore follow. In analogy with the genetic code, non-power integer-number representations are also surjective mappings between sets of different cardinality and, as such, also redundant. However, none of the non-power arithmetics studied so far nor other alternative redundant representations are able to match the actual degeneracy of the genetic code. In this paper we develop a slightly more general framework that leads to the following surprising results: i) the degeneracy of the genetic code is mathematically described, ii) a new symmetry is uncovered within this degeneracy, iii) by assigning a binary string to each of the codons, their classification into definite parity classes according to the corresponding sequence of bases is made possible. This last result is particularly appealing in connection with the fact that parity coding is the basis of the simplest strategies devised for error correction in man-made digital data transmission systems.

Algorithms↗
PubMed1999

Selective advantages created by codon ambiguity allowed for the evolution of an alternative genetic code in Candida spp.

Several species of the genus Candida decode the standard leucine CUG codon as serine. This and other deviations from the standard genetic code in both nuclear and mitochondrial genomes invalidate the notion that the genetic code is frozen and universal and prompt the questions 'why alternative genetic codes evolved and, more importantly, how can an organism survive a genetic code change?' To address these two questions, we have attempted to reconstruct the early stages of Candida albicans CUG reassignment in the closely related yeast Saccharomyces cerevisiae. These studies suggest that this genetic code change was driven by selection using a molecular mechanism that requires CUG ambiguity. Such codon ambiguity induced a significant decrease in fitness, indicating that CUG reassignment can only be selected if it introduces an evolutionary edge to counteract the negative impact of ambiguity. We have shown that CUG ambiguity induces the expression of a novel set of stress proteins and triggers the general stress response, which, in turn, creates a competitive edge under stress conditions. In addition, CUG ambiguity in S. cerevisiae induces the expression of a number of novel phenotypes that mimic the natural resistance to stress characteristic of C. albicans. The identification of an evolutionary advantage created by CUG ambiguity is the first experimental evidence for a genetic code change driven by selection and suggests a novel role for codon reassignment in the adaptation to new ecological niches.

Adaptation, Biological↗
PubMed2005

Structuring of the genetic code took place at acidic pH.

I have observed that in multiple regression the number of codons specifying amino acids in the genetic code is positively correlated with the isoelectric point of amino acids and their molecular weight. Therefore basic amino acids are, on average, codified in the genetic code by a larger number of codons, which seems to imply that the genetic code originated in an acidic 'intracellular' environment. Moreover, I compare the proteins from Picrophilus torridus and Thermoplasma volcanium, which have different intracellular pH and I define the ranks of acidophily for the amino acids. A simple index of acidophily (AI), which can be easily obtained from acidophily ranks, can be associated to any protein and, therefore, can also be associated to the genetic code if the number of synonymous codons attributed to the amino acids in the code is assumed to be the frequency with which the amino acids appeared in ancestral proteins. Finally, the sampling of the variable AI among organisms having an intracellular pH less than or equal to 6.6 and those having a non-acidic intracellular pH leads to the conclusion that the value of the genetic code's AI is not typical of proteins of the latter organisms. As the genetic code's AI value is also statistically not different from that of proteins of the organisms having an acidic intracellular pH, this supports the hypothesis that the structuring of the genetic code took place in acidic pH conditions.

Amino Acid Sequence↗
PubMed2006

Degeneracy in the genetic code and its symmetries by base substitutions.

Degeneracy in the genetic code is known to minimise the deleterious effects of the most frequent base substitutions: transitions at the third base of codons are generally synonymous substitutions. Transversions that alter degeneracy were reported by Rumer. Here the other transversions are shown to leave invariant degeneracy when applied to the first base of codons. As a summary, degeneracy is considered with respect to all three types of base substitutions, the transitions and the two types of transversions. The symmetries of degeneracy by base substitutions are independent of the representation of the genetic code and discussed with respect to the quasi-universality of the genetic code.

Amino Acids↗
PubMed1988

The degeneracy rule of genetic code.

The degeneracy rules of genetic code including the distribution of terminators have been deduced through the minimization of mutational deterioration (MD). The MD of a given group of codons is divided into three parts: transitional, transversional and wobble's. The averaged mutational deteriorations (AMD) of various amino acids have been proved in order of their degrees of irreplaceability.

Amino Acids↗