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PubMed2004

A harmonic structure of the genetic code.

In this paper is presented a new, very harmonic structure of the genetic code (GC) within a system of "4 x 5" (and/or of "5 x 4") of amino acids (AAs) in two variants. In first variant, the five rows within the system start with one polar charged amino acid (AA) each, making first column, consisting from five polar charged AAs (D, R, K, H, E). Five polar non-charged AAs (N, P, Y, W, Q) follow, then five non-polar AAs as last column (A, L, F, V, I) and, finally, five polar or non-polar AAs, in a combination, as first to last column (A as non-polar; S, T as polar, and G, P as ambivalent AAs). A second variant is subsequent to this one-"4 x 5" system with five nitrogen AAs (K, R, P, H, W), five oxygen (D, E, Y, S, T), five solely carbon (A, L, F, V, I) and five "combined" AAs (G with hydrogen as side chain; C and M with carbon and sulfur; N and Q with carbon, oxygen and nitrogen). A strict balance of atom and nucleon number as well as molecule mass follows the classification in both system variants.

Amino Acids↗
PubMed1994

The phylogeny of tRNA molecules and the origin of the genetic code.

The evolutionary relationships between transfer RNA (tRNA) molecules are analyzed by parsimony algorithms. The position of the topologies expected on the basis of the hypotheses made to explain the origin of the genetic code, on the frequency distribution of all the possible tree topologies of the evolutionary relationships between tRNAs seems to lead to the following conclusion: The hypothesis (Wong, J. T., Proc. Natl. Acad. Sci. USA, 1975, 72: 1909-1912) that sees the genetic code as a map of the biosynthetic relationships between amino acids seems to occupy a statistically significant position on these frequency distributions, thus reflecting a significant part of the tRNA phylogeny.

Base Sequence↗
PubMed2004

A two-unnatural-base-pair system toward the expansion of the genetic code.

Toward the site-specific incorporation of amino acid analogues into proteins, a two-unnatural-base-pair system was developed for coupled transcription-translation systems with the expanded genetic code. A previously designed unnatural base pair between 2-amino-6-(2-thienyl)purine (denoted by s) and pyridin-2-one (denoted by y) was used for the site-specific incorporation of yTP into RNA opposite s in templates by T7 RNA polymerase. For the site-specific incorporation of sTP into RNA, a newly developed unnatural base, imidazolin-2-one (denoted by z), is superior to y as a template base for pairing with s in T7 transcription. The combination of the s-y and s-z pairs provides a powerful tool to prepare both y-containing mRNA and s-containing tRNA for efficient coupled transcription-translation systems, in which the genetic code is expanded by the codon-anticodon interactions mediated by the s-y pair. In addition, the nucleoside of s is strongly fluorescent, and thus the s-z pair enables the site-specific fluorescent labeling of RNA molecules. These unnatural-base-pair studies provide valuable information for understanding the mechanisms of replication and transcription.

Base Pairing↗
PubMed1975

Speculations on the evolution of the genetic code.

An evolutionary scheme is postulated in which the bases enter the genetic code in a definite temporal sequence and the correlated amino acids are assigned definite functions in the evolving system. The scheme requires a singlet code (guanine coding for glycine) evolving into a doublet code (guanine-cytosine doublet coding for gly (GG), ala (GC), arg (CG), pro (CC). The doublet code evolves into a triplet code. Polymerization of nucleotides is thought to have been by block polymerization rather than by a template mechanism. The proteins formed at first were simple structural peptides. No direct nucleotide-amino acid stereo-chemical interaction was required. Rather an adaptor-type indirect mechanism is thought to have been functioning since the origin.

Biological Evolution↗
PubMedDate not supplied

The rearranged genetic code and its implications in evolution and biochemistry.

We rearrange the genetic code and present a table of codons. The chemical properties of the amino acids coded by codons, and the evolutionary trend of codons are well reflected in the order of this table, from which two rules can be drawn: (1) the polarity/non-polarity and hydrophilicity/hydrophobicity of amino acids coded for by codons alternate row by row in the table; (2) in general, the lower down in the table, the earlier the codons are in terms of evolution.

Amino Acids↗
PubMed1991

An RNA-amino acid complex and the origin of the genetic code.

The group I RNAs, of which the Tetrahymena ribosomal RNA intron is the most investigated example, catalyze their own splicing reactions. Splicing is initiated at a conserved site on the RNA that facilitates attack by exogenous guanosine (or its nucleotides) on the exon-intron junction. The guanosine site in the RNA's catalytic center also binds arginine, and is quite selective for the arginine side chain. This amino acid-RNA interaction is stereoselective, and L-arginine is preferred. Immediately at the site at which arginine binds there is one of only four RNA triplets in 92 group I RNA sequences: AGA/G and CGA/G. Thus the arginine contact site is within any of four different codons for arginine. Mutation of the conserved G in the middle of the triplet decreases affinity for the amino acid, showing that binding is sequence-specific. A pathway for the origin of the genetic code for arginine is suggested, based on the existence and properties of this sequence-specific, amino acid-specific RNA complex. The existence of a proto-ribosome related to the group I RNAs seems the most likely hypothesis. This notion is used to distinguish three periods in the development of the code. Restrained and exuberant hypotheses about the origin of the genetic code are distinguished, and some objections to these hypotheses are considered.

Animals↗
PubMed2006

The response of amino acid frequencies to directional mutation pressure in mitochondrial genome sequences is related to the physical properties of the amino acids and to the structure of the genetic code.

The frequencies of A, C, G, and T in mitochondrial DNA vary among species due to unequal rates of mutation between the bases. The frequencies of bases at fourfold degenerate sites respond directly to mutation pressure. At first and second positions, selection reduces the degree of frequency variation. Using a simple evolutionary model, we show that first position sites are less constrained by selection than second position sites and, therefore, that the frequencies of bases at first position are more responsive to mutation pressure than those at second position. We define a measure of distance between amino acids that is dependent on eight measured physical properties and a similarity measure that is the inverse of this distance. Columns 1, 2, 3, and 4 of the genetic code correspond to codons with U, C, A, and G in their second position, respectively. The similarity of amino acids in the four columns decreases systematically from column 1 to column 2 to column 3 to column 4. We then show that the responsiveness of first position bases to mutation pressure is dependent on the second position base and follows the same decreasing trend through the four columns. Again, this shows the correlation between physical properties and responsiveness. We determine a proximity measure for each amino acid, which is the average similarity between an amino acid and all others that are accessible via single point mutations in the mitochondrial genetic code structure. We also define a responsiveness for each amino acid, which measures how rapidly an amino acid frequency changes as a result of mutation pressure acting on the base frequencies. We show that there is a strong correlation between responsiveness and proximity, and that both these quantities are also correlated with the mutability of amino acids estimated from the mtREV substitution rate matrix. We also consider the variation of base frequencies between strands and between genes on a strand. These trends are consistent with the patterns expected from analysis of the variation among genomes.

Amino Acids↗
PubMed1998

Amino acid contribution to the genetic code structure: end-atom chemical rules of doublet composition.

Up-to-date knowledge is not yet enough to prove or reject completely one of the leading alternative hypotheses considering external or internal origin of the genetic code organization (term "internal" means a peculiarity of amino acids and nucleotides which can propose some logical basis for explanation why definite codons are assigned to particular and not to other amino acids; term "external" in this context implies tRNAs and aminoacyl-tRNA synthetases which provide accuracy of translation but are not presented in the code table in the evident from). New data in favour of the internal approach have been proposed. A close correlation exists between chemical nature of single, the most remote from C alpha, end atoms of amino acid side chains and types of bases in appropriate codon doublets. There are two main rules reflecting this correspondence: (1) all O- or N-ended amino acids (i.e. with O, OO, N, NN, ON, OC and NC end patterns) possess the A-containing codon doublets; (2) all solely C-ended (excluding Ala) and S-ended amino acids (i.e. residues with C, CC and S ends) have the U-containing codon doublets. The discovered asymmetry is characterized by the following high reliable differences of A and U distribution among 21 patterns of individual doublets belonging to 18 amino acids (Pro and Gly are discarded): (a) proportion of A plus U bases corresponding to the two rules, 22/26 is much more than proportion of such bases in violating cases, 4/26; (b) A and U are dominant bases over each of other base types in the doublets of O/N- and C/S-ending amino acids, respectively; (c) the numbers of doublets bearing (18) and not bearing (3) dominant A or U bases are also significantly different. The concept of indicative amino acid end atoms (O/N and non-O/non-N) and doublet A/U bases has been proposed and discussed as so far unknown regulative system of submolecular level of heredity which, additionally to possible key role in the process of the genetic code arising, provides now control of its universality, stability and fidelity.

Amino Acids↗
PubMed1997

Vestiges of early molecular processes leading to the genetic code.

We compare predictions from a proposed model for the origin of the genetic code (J. Theor. Biol (1993) 164, 291-305) with existing information on the base content of codons and abundance of amino acid in different organisms. A comparison is also made between the three groups of amino acids suggested by the model and the two classes of aminoacetyl-tRNA synthetases. The observed agreements tend to support the model.

Amino Acids↗
PubMed1994

On the syntactic structure and redundancy distribution of the genetic code.

By means of an algorithm for finding rules in data, it is shown that the genetic code may be written as a codon-tree, independent of amino acid assignments. Considering this tree as a structural description, a low-complexity, context-free grammar of the code is built and its grammar complexity and grammar redundancy calculated. The relationship between the codon-tree and the hierarchy of amino acid categorizations previously introduced by the author is investigated. Interpreting the obtained code's structure as a record of its evolution, some inferences about the divergences of the code series are made.

Algorithms↗
PubMed1996

The puzzling origin of the genetic code.

Recent results add to the mystery of the origin of the genetic code. In spite of early doubts, RNA can discriminate between hydrophobic amino acids under certain contexts. Moreover, codon reassignment, which has taken place in several organisms and mitochondria, is not a random process. Finally, phylogenies of some aminoacyl-tRNA synthetases suggest that the entire code was not completely assigned at the time of the divergence of bacteria from nucleated cells.

Amino Acids↗
PubMed1995

The phylogeny of tRNAs seems to confirm the predictions of the coevolution theory of the origin of the genetic code.

An extensive analysis of the evolutionary relationships existing between transfer RNAs, performed using parsimony algorithms, is presented. After building up an estimate of the tRNA ancestral sequences, these sequences are then compared using certain methods. The results seem to suggest that the coevolution hypothesis (Wong, J.T., 1975, Proc. Natl. Acad. Sci. USA 72, 1909-1912) that sees the genetic code as a map of the biosynthetic relationships between amino acids is further supported by these results, as compared to the hypotheses that see the physicochemical properties of amino acids as the main adaptative theme that led to the structuring of the genetic code.

Amino Acid Sequence↗
PubMed1995

A deviation from the universal genetic code in Candida maltosa and consequences for heterologous expression of cytochromes P450 52A4 and 52A5 in Saccharomyces cerevisiae.

We demonstrate that serine instead of leucine is specified by the CUG codon in the yeast Candida maltosa. Evidence for this deviation from the universal genetic code was obtained by means of in vitro translation experiments. Depending on the cell-free system used, either serine, in the C. maltosa system, or leucine, in the control with the conventional wheat germ system, was found to be incorporated into the translation products of artificial CUG-containing mRNAs. Moreover, we were able to transfer the non-universal decoding of CUG to the wheat germ system by adding a tRNA fraction isolated from C. maltosa. This finding indicates the presence in C. maltosa of an unusual serine tRNA that recognizes CUG. As a consequence of the altered genetic code, expression in Saccharomyces cerevisiae of C. maltosa cytochrome P450 genes required an exchange of their CTG triplets by TCT encoding serine in order to produce the authentic proteins. In contrast, heterologous expression of the original C. maltosa genes resulted in the formation of still active but unstable enzymes probably subject to selective proteolysis in the host cells.

Base Sequence↗
PubMed2026

Robust error-minimization in the genetic code across physicochemical metrics and variant codes: A graph-theoretic analysis in GF(2)6.

The standard genetic code reduces the impact of point mutations, but the robustness of this property across physicochemical metrics, naturally occurring variant codes, and codon-reassignment mechanisms remains incompletely quantified. Embedding the 64 codons in GF(2)6 represents the hypercube Q6 as a coordinate-dependent subgraph of the encoding-independent single-nucleotide mutation graph H(3,4), and enables continuous &#x3c1;-interpolation between the two. Under a quartet-pattern shuffle null (n=10,000), the standard code is significantly low-cost across four established, code-independent physicochemical distance metrics with partially overlapping content (Grant ham p=0.0062; Miyata p<0.001; Woese polar requirement p=0.003; Kyte-Doolittle hydropathy p=0.001), and the signal strengthens monotonically as &#x3c1; moves Q6&#x2192;H(3,4). A structure-aware sensitivity analysis under the alignment-derived ProtSub matrix (Jia & Jernigan 2021) yields the most extreme percentile of any measure tested (p=0.0004; all five p-values pass Bonferroni at &#x3b1;=0.05). Across the 27 NCBI translation tables, near-optimality is preserved: 11 of 12 informative-distance variants retain top-5% placement after BH-FDR correction. Natural codon reassignments avoid disrupting codon-family connectivity: under the encoding-independent H(3,4) adjacency, observed events are topology-breaking at relative risk 0.32 versus the candidate landscape (permutation p&#x2264;10-4). The H(3,4) result is stable by construction; the Q6 decomposition is representation-specific and fails to show depletion under 8 of 24 base-to-bit encodings, so we report H(3,4) as the primary test and Q6 as a sensitivity. Event-level conditional-logit modelling shows that topology avoidance and local physicochemical cost provide complementary, only weakly correlated signal (rs=0.15), and that topology adds explanatory value beyond physicochemistry under both Q6 and encoding-independent H(3,4) adjacency. Retrospective reanalysis of nine genome-recoding datasets is consistent with codon-family topology operating as an evolutionary-trajectory constraint distinct from acute engineering fitness. The contribution is the second axis: code evolution is jointly constrained by physicochemical smoothness and codon-family topological integrity, and these two constraints are partly independent.

Codon reassignment↗
PubMed1980

The genetic code in bovine mitochondria: sequence of genes for the cytochrome oxidase subunit II and two tRNAs.

Bovine-heart mitochondrial DNA from a single animal was isolated and fragments representative of the entire genome cloned into multicopy plasmid vectors to facilitate determination of its complete nucleotide sequence. We present here the sequence of the region covering the gene for cytochrome oxidase subunit II. Comparison of this sequence with the amino acid sequence of the homologous beef-heart protein has enabled the determination of most of the bovine mitochondrial genetic code. The code differs from the "universal" genetic code in that UGA codes for tryptophan and not termination, and AUA codes for methionine and not isoleucine. The only codon family not represented is the AGA/AGG pair normally used for arginine; evidence from other genes suggests that these code for termination in bovine mitochondria. The sequence presented also includes the adjacent tRNAAsp and tRNALys genes. The tRNAAsp gene is separated by one nucleotide from the 5' end of the COII gene and only three bases separate the 3' end of this gene and the adjacent tRNALys gene. This highly compact gene organisation is very similar to that found in the corresponding region of the human mitochondrial genome and the gene arrangement is identical. The structure of the respective bovine and human tRNAs vary primarily the "D-" and "T psi C-loops".

Animals↗
PubMed2002

Origin of most primitive mRNAs and genetic codes via interactions between primitive tRNA ribozymes.

The origin and early evolution of genetic codon system and early mRNAs were analyzed from a viewpoint of primordial gene theory and the poly-tRNA theory. A hypothetical 25-amino acid (aa)-primordial peptide was deduced from internal aa-sequence homology of adenylate kinases. Theoretical models were made which can reasonably explain how primitive tRNA(s) could have had converted to be earliest mRNAs via interactions between presumptive anticodons and (poly-)tRNA ribozyme. Transfer-RNA gene clusters in the trrnD- and rrnB-operons of Bacillus subtilis seemed to be relics of early peptide-synthesizing RNA machine. Detailed analyses revealed that the poly-tRNA regions in these operons are true relics of RNA-machine for making a 16-aa trrnD-peptide and a 21-aa rrnB-peptide, whose aa sequences are in the order of aa specificities of tRNAs in the tRNA gene clusters of the trrnD-operon and rrnB-operon, respectively. The primordial gene-encoded peptide deduced from adenylate kinases were found to be a genuine homologue of the rrnB-peptide. Various protein superfamilies were found to have evolved from either of these two types of primitive peptides. Earliest mRNAs were concluded to have evolved from tRNAGly (trrnD-mRNA) or tRNAHis (rrnB-mRNA), where trrnD- and rrnB-mRNAs are hypothetical primitive mRNAs complementary to the tandem arrangement of 16 or 21 anticodons of tRNAs in the trrnD-operon and rrnB-operon, respectively. The poly-tRNA model is considered to be an excellent theory, because it can reasonably explain origins of both genetic codes and earliest mRNAs, and because the hypothesis can be statistically evaluated by base-identity levels in proper alignments. The genetic codon system is a typical mature semeiotic system within a cell, and the genesis of the genetic codon system was discussed from an aspect of de Saussure's semeiology. Arbitrary correspondence between (anti)codon and aa would be most plausibly a result of semeiotic culture system of intracellular tRNA-riboorganismic society.

Adenylate Kinase↗