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PubMed1987

Phases of degeneracy of the genetic code.

The universally valid genetic code is the final result of a multi-stage course of development. Degeneracy, as an important property of the genetic code, was possibly not yet present in the earliest code, first appearing at a later stage of development (Code III). Possibly this step in development is coupled with the presence of a total of four amino acid groups (L, I, E, F). Each group contains a specific number of amino acid (AL, AI, AE, AF). Amino acid groups: - (L) hydrophobic - (I) weakly hydrophobic or polar but uncharged - (E) hydrophilic, acidic - (F) hydrophilic, basic - (D) hydrophobic, aromatic (only in Code IV and Code M. This group is not considered in the calculations below.) In a subsequent stage of development the number of amino acids increases further. At the same time the code becomes more degenerate. The universal genetic code is characterized by three constants of being degenerate. Its immediate predecessor has linear degeneration with two constants. The mitochondrial code represents a transitional form between these two codes.

Amino Acid Sequence↗
PubMed1963

RATIONALE FOR A UNIVERSAL GENETIC CODE.

A mutation in the genetic code would place new amino acids in certain loci and entirely eliminate amino acids from other loci of practically all proteins in an organism. It is reasonable to postulate that mutations of this kind cannot supplant the original code. The genetic code, once established, would therefore remain invariant.

Amino Acids↗
PubMed2005

A unified model of codon reassignment in alternative genetic codes.

Many modified genetic codes are found in specific genomes in which one or more codons have been reassigned to a different amino acid from that in the canonical code. We present a new framework for codon reassignment that incorporates two previously proposed mechanisms (codon disappearance and ambiguous intermediate) and introduces two further mechanisms (unassigned codon and compensatory change). Our theory is based on the observation that reassignment involves a gain and a loss. The loss could be the deletion or loss of function of a tRNA or release factor. The gain could be the gain of a new type of tRNA or the gain of function of an existing tRNA due to mutation or base modification. The four mechanisms are distinguished by whether the codon disappears from the genome during the reassignment and by the order of the gain and loss events. We present simulations of the gain-loss model showing that all four mechanisms can occur within the same framework as the parameters are varied. We investigate the way the frequencies of the mechanisms are influenced by selection strengths, the number of codons undergoing reassignment, directional mutation pressure, and selection for reduced genome size.

Anticodon↗
PubMed2005

Structural basis of nonnatural amino acid recognition by an engineered aminoacyl-tRNA synthetase for genetic code expansion.

The genetic code in a eukaryotic system has been expanded by the engineering of Escherichia coli tyrosyl-tRNA synthetase (TyrRS) with the Y37V and Q195C mutations (37V195C), which specifically recognize 3-iodo-L-tyrosine rather than L-tyrosine. In the present study, we determined the 3-iodo-L-tyrosine- and L-tyrosine-bound structures of the 37V195C mutant of the E. coli TyrRS catalytic domain at 2.0-A resolution. The gamma-methyl group of Val-37 and the sulfur atom of Cys-195 make van der Waals contacts with the iodine atom of 3-iodo-L-tyrosine. The Val-37 and Cys-195 side chains are rigidly fixed by the neighboring residues forming the hydrophobic core of the TyrRS. The major roles of the two mutations are different for the 3-iodo-L-tyrosine-selective recognition in the first step of the aminoacylation reaction (the amino acid activation step): the Y37V mutation eliminates the fatal steric repulsion with the iodine atom, and the Q195C mutation reduces the L-tyrosine misrecognition. The structure of the 37V195C mutant TyrRS complexed with an L-tyrosyladenylate analogue was also solved, indicating that the 3-iodo-L-tyrosine and L-tyrosine side chains are similarly discriminated in the second step (the aminoacyl transfer step). These results demonstrate that the amino acid-binding pocket on the 37V195C mutant is optimized for specific 3-iodo-L-tyrosine recognition.

Amino Acid Sequence↗
PubMed2007

A natural genetic code expansion cassette enables transmissible biosynthesis and genetic encoding of pyrrolysine.

Pyrrolysine has entered natural genetic codes by the translation of UAG, a canonical stop codon. UAG translation as pyrrolysine requires the pylT gene product, an amber-decoding tRNA(Pyl) that is aminoacylated with pyrrolysine by the pyrrolysyl-tRNA synthetase produced from the pylS gene. The pylTS genes form a gene cluster with pylBCD, whose functions have not been investigated. The pylTSBCD gene order is maintained not only in methanogenic Archaea but also in a distantly related Gram-positive Bacterium, indicating past horizontal gene transfer of all five genes. Here we show that lateral transfer of pylTSBCD introduces biosynthesis and genetic encoding of pyrrolysine into a naïve organism. PylS-based assays demonstrated that pyrrolysine was biosynthesized in Escherichia coli expressing pylBCD from Methanosarcina acetivorans. Production of pyrrolysine did not require tRNA(Pyl) or PylS. However, when pylTSBCD were coexpressed with mtmB1, encoding the methanogen monomethylamine methyltransferase, UAG was translated as pyrrolysine to produce recombinant monomethylamine methyltransferase. Expression of pylTSBCD also suppressed an amber codon introduced into the E. coli uidA gene. Strains lacking one of the pylBCD genes did not produce pyrrolysine or translate UAG as pyrrolysine. These results indicated that pylBCD gene products biosynthesize pyrrolysine using metabolites common to Bacteria and Archaea and, furthermore, that the pyl gene cluster represents a "genetic code expansion cassette," previously unprecedented in natural organisms, whose transfer allows an existing codon to be translated as a novel endogenously synthesized free amino acid. Analogous cassettes may have served similar functions for other amino acids during the evolutionary expansion of the canonical genetic code.

Amino Acid Sequence↗
PubMed2005

Error minimization and coding triplet/binding site associations are independent features of the canonical genetic code.

The canonical genetic code has been reported both to be error minimizing and to show stereochemical associations between coding triplets and binding sites. In order to test whether these two properties are unexpectedly overlapping, we generated 200,000 randomized genetic codes using each of five randomization schemes, with and without randomization of stop codons. Comparison of the code error (difference in polar requirement for single-nucleotide codon interchanges) with the coding triplet concentrations in RNA binding sites for eight amino acids shows that these properties are independent and uncorrelated. Thus, one is not the result of the other, and error minimization and triplet associations probably arose independently during the history of the genetic code. We explicitly show that prior fixation of a stereochemical core is consistent with an effective later minimization of error.

Base Sequence↗
PubMed2005

A genetic code Boolean structure. II. The genetic information system as a Boolean information system.

A Boolean structure of the genetic code where Boolean deductions have biological and physicochemical meanings was discussed in a previous paper. Now, from these Boolean deductions we propose to define the value of amino acid information in order to consider the genetic information system as a communication system and to introduce the semantic content of information ignored by the conventional information theory. In this proposal, the value of amino acid information is proportional to the molecular weight of amino acids with a proportional constant of about 1.96 x 10(25) bits per kg. In addition to this, for the experimental estimations of the minimum energy dissipation in genetic logic operations, we present two postulates: (1) the energy Ei (i=1,2,...,20) of amino acids in the messages conveyed by proteins is proportional to the value of information, and (2) amino acids are distributed according to their energy Ei so the amino acid population in proteins follows a Boltzmann distribution. Specifically, in the genetic message carried by the DNA from the genomes of living organisms, we found that the minimum energy dissipation in genetic logic operations was close to kTLn(2) joules per bit.

Algorithms↗
PubMed2000

RNA-ligand chemistry: a testable source for the genetic code.

In the genetic code, triplet codons and amino acids can be shown to be related by chemical principles. Such chemical regularities could be created either during the code's origin or during later evolution. One such chemical principle can now be shown experimentally. Natural or particularly selected RNA binding sites for at least three disparate amino acids (arginine, isoleucine, and tyrosine) are enriched in codons for the cognate amino acid. Currently, in 517 total nucleotides, binding sites contain 2.4-fold more codon sequences than surrounding nucleotides. The aggregate probability of this enrichment is 10(-7) to 10(-8), had codons and binding site sequences been independent. Thus, at least some primordial coding assignments appear to have exploited triplets from amino acid binding sites as codons.

Amino Acids↗
PubMed2003

On the evolution of primitive genetic codes.

The primordial genetic code probably has been a drastically simplified ancestor of the canonical code that is used by contemporary cells. In order to understand how the present-day code came about we first need to explain how the language of the building plan can change without destroying the encoded information. In this work we introduce a minimal organism model that is based on biophysically reasonable descriptions of RNA and protein, namely secondary structure folding and knowledge based potentials. The evolution of a population of such organism under competition for a common resource is simulated explicitly at the level of individual replication events. Starting with very simple codes, and hence greatly reduced amino acid alphabets, we observe a diversification of the codes in most simulation runs. The driving force behind this effect is the possibility to produce fitter proteins when the repertoire of amino acids is enlarged.

Amino Acid Sequence↗
PubMed2006

Parallel evolution of the genetic code in arthropod mitochondrial genomes.

The genetic code provides the translation table necessary to transform the information contained in DNA into the language of proteins. In this table, a correspondence between each codon and each amino acid is established: tRNA is the main adaptor that links the two. Although the genetic code is nearly universal, several variants of this code have been described in a wide range of nuclear and organellar systems, especially in metazoan mitochondria. These variants are generally found by searching for conserved positions that consistently code for a specific alternative amino acid in a new species. We have devised an accurate computational method to automate these comparisons, and have tested it with 626 metazoan mitochondrial genomes. Our results indicate that several arthropods have a new genetic code and translate the codon AGG as lysine instead of serine (as in the invertebrate mitochondrial genetic code) or arginine (as in the standard genetic code). We have investigated the evolution of the genetic code in the arthropods and found several events of parallel evolution in which the AGG codon was reassigned between serine and lysine. Our analyses also revealed correlated evolution between the arthropod genetic codes and the tRNA-Lys/-Ser, which show specific point mutations at the anticodons. These rather simple mutations, together with a low usage of the AGG codon, might explain the recurrence of the AGG reassignments.

Animals↗
PubMed2002

Chemical interactions between amino acid and RNA: multiplicity of the levels of specificity explains origin of the genetic code.

The emergence of the genetic code remains an enigma. Proposed mechanisms are based on random, historical, thermodynamic and natural selection. However, they introduce chance as a key factor for overcoming the difficulties encountered by the model. We propose here a model in which three successive levels of chemical specificity generated the nucleotide assignments of amino acids in the genetic code. The first level results from hydrophobic and stereospecific interactions between amino acids and short oligonucleotides (termed oligons). The second and third levels of specificity are determined by conditions of energy transfer from loaded oligons (amino acid-oligomer covalently linked) to formation of phosphodiester bond (second level of specificity) and peptidic bond (third level of specificity), while these reactions are catalyzed by RNA templates. This model is sustained by the relationships observed between dipole moments of the nucleotides (forming the anticodon) and reactivity of the amino acyl linkage of the loaded oligon. Moreover, analysis of modern tRNAs reveals that they were probably generated by loose duplication of the nucleotide sequence forming the oligons, after emergence of the 'genetic code.' Indeed, the similarity of nucleotide composition with that of the anticodon decreases with the tRNA domain's distance from the anticodon, but the acceptor stem is relatively more similar to the anticodon than other stems closer to it. This would be because energy transfer constraints that existed between anticodon and amino acid in prebiotic loaded oligonucleotides still affect the structures of modern tRNA acceptor stems. In the model presented, the genetic code is inherent to the most archaic 'molecular physiology' in protolife, even before emergence of a functional 'protein world.' Simple physical processes, in which a level of specificity is integrated in an emerging meta-structure expressing new properties, generate a parsimonious and realistic explanation of emergence of the genetic code.

Amino Acids↗
PubMedDate not supplied

[The molecular mechanism of evolution of changes in the genetic code].

Alterations to the standard genetic code have been found in both prokaryotes and eukaryotes. This finding demolished the central dogma of molecular biology, postulated by Crick in 1968, of an immutable and universal genetic code and raised the question of how organisms survive genetic code alterations? Recent studies suggest that genetic code alterations are driven by selection using a mechanism that requires translational ambiguity. In C. albicans, the leucine CUG codon is decoded as serine through structural alterations of the translational machinery, in particular, of a Ser-tRNACAG which has dual identity and novel decoding properties. Here, we review the molecular mechanism of CUG reassignment focusing on the structural change of the translational machinery and on the impact that such alteration had on the evolution of the Candida albicans genome.

Base Sequence↗
PubMed2003

Arithmetic inside the universal genetic code.

The first information system emerged on the earth as primordial version of the genetic code and genetic texts. The natural appearance of arithmetic power in such a linguistic milieu is theoretically possible and practical for producing information systems of extremely high efficiency. In this case, the arithmetic symbols should be incorporated into an alphabet, i.e. the genetic code. A number is the fundamental arithmetic symbol produced by the system of numeration. If the system of numeration were detected inside the genetic code, it would be natural to expect that its purpose is arithmetic calculation e.g., for the sake of control, safety, and precise alteration of the genetic texts. The nucleons of amino acids and the bases of nucleic acids seem most suitable for embodiments of digits. These assumptions were used for the analyzing the genetic code. The compressed, life-size, and split representation of the Escherichia coli and Euplotes octocarinatus code versions were considered simultaneously. An exact equilibration of the nucleon sums of the amino acid standard blocks and/or side chains was found repeatedly within specified sets of the genetic code. Moreover, the digital notations of the balanced sums acquired, in decimal representation, the unique form 111, 222...., 999. This form is a consequence of the criterion of divisibility by 037. The criterion could simplify some computing mechanism of a cell if any and facilitate its computational procedure. The cooperative symmetry of the genetic code demonstrates that possibly a zero was invented and used by this mechanism. Such organization of the genetic code could be explained by activities of some hypothetical molecular organelles working as natural biocomputers of digital genetic texts. It is well known that if mutation replaces an amino acid, the change of hydrophobicity is generally weak, while that of size is strong. The antisymmetrical correlation between the amino acid size and the degeneracy number is known as well. It is shown that these and some other familiar properties may be a physicochemical effect of arithmetic inside the genetic code. The "frozen accident" model, giving unlimited freedom to the mapping function, could optimally support the appearance of both arithmetic symbols and physicochemical protection inside the genetic code.

Amino Acid Sequence↗
PubMedDate not supplied

On the evolution of redundancy in genetic codes.

We simulate a deterministic population genetic model for the coevolution of genetic codes and protein-coding genes. We use very simple assumptions about translation, mutation, and protein fitness to calculate mutation-selection equilibria of codon frequencies and fitness in a large asexual population with a given genetic code. We then compute the fitnesses of altered genetic codes that compete to invade the population by translating its genes with higher fitness. Codes and genes coevolve in a succession of stages, alternating between genetic equilibration and code invasion, from an initial wholly ambiguous coding state to a diversified frozen coding state. Our simulations almost always resulted in partially redundant frozen genetic codes. Also, the range of simulated physicochemical properties among encoded amino acids in frozen codes was always less than maximal. These results did not require the assumption of historical constraints on the number and type of amino acids available to codes nor on the complexity of proteins, stereochemical constraints on the translational apparatus, nor mechanistic constraints on genetic code change. Both the extent and timing of amino-acid diversification in genetic codes were strongly affected by the message mutation rate and strength of missense selection. Our results suggest that various omnipresent phenomena that distribute codons over sites with different selective requirements--such as the persistence of nonsynonymous mutations at equilibrium, the positive selection of the same codon in different types of sites, and translational ambiguity--predispose the evolution of redundancy and of reduced amino acid diversity in genetic codes.

Codon↗
PubMed1986

[Unambiguous correspondence and complementarity of the chemical properties of amino acids and anticodons of the genetic code].

The chemical language of genetic code is proposed. As a result of chemical language application for the analysis of the modern genetic code, the existence of an unambiguous correspondence between the chemical properties of amino acids and their coding triplets (codons and anticodons) is shown. This confirms the hypothesis of the code chemical determination. The complementarity between the chemical properties of amino acids and their anticodons (but not the codons) has been found also to exist. This observation supports the hypothesis of the genetic code determination by the direct recognition and also underlines the primary role of anticodon in the origin of genetic code in comparison with codons.

Amino Acids↗
PubMed1990

Prokaryotic genetic code.

The prokaryotic genetic code has been influenced by directional mutation pressure (GC/AT pressure) that has been exerted on the entire genome. This pressure affects the synonymous codon choice, the amino acid composition of proteins and tRNA anticodons. Unassigned codons would have been produced in bacteria with extremely high GC or AT genomes by deleting certain codons and the corresponding tRNAs. A high AT pressure together with genomic economization led to a change in assignment of the UGA codon, from stop to tryptophan, in Mycoplasma.

Anticodon↗