Origin Of Genetic Code Research Articles

DNA as information.

This article reviews contributions to this theme issue covering the topic 'DNA as information' in relation to the structure of DNA, the measure of its information content, the role and meaning of information in biology and the origin of genetic coding as a transition from uninformed to meaningful computational processes in physical systems.

Evolution of the Genetic Code: The Ribosome-Oriented Model

There are currently three major theories on the origin and evolution of the genetic code: the stereochemical theory, the coevolution theory, and the error-minimization theory. The first two assume that the genetic code originated respectively from chemical affinities and from metabolic relationships between codons and amino acids. The error-minimization theory maintains that in primitive systems the apparatus of protein synthesis was extremely prone to errors, and postulates that the genetic code evolved in order to minimize the deleterious effects of the translation errors. This article describes a fourth theory which starts from the hypothesis that the ancestral genetic code was ambiguous and proposes that its evolution took place with a mechanism that systematically reduced its ambiguity and eventually removed it altogether. This proposal is distinct from the stereochemical and the coevolution theories because they do not contemplate any ambiguity in the genetic code, and it is distinct from the error-minimization theory because ambiguity-reduction is fundamentally different from error-minimization. The concept of ambiguity-reduction has been repeatedly mentioned in the scientific literature, but so far it has remained only an abstract possibility because no model has been proposed for its mechanism. Such a model is described in the present article and may be the first step in a new approach to the study of the evolution of the genetic code.

A Model for the Origin of the First mRNAs.

I present a model for the evolution of the genetic code that seems to predict, in a totally natural way, the origin of the first mRNAs. In particular, the model--bestowing to peptidated-RNAs the major catalytic role in the phase that triggered the genetic code origin--suggests that interactions between peptidated-RNAs led to the synthesis of these ancestral catalysts. Within every group of these interactions, a pre-mRNA molecule evolved that was able to direct all interactions between peptidated-RNAs of that particular group. This represented an improvement in the coding of these interactions compared to the interaction groups that did not evolve these pre-mRNAs. This would represent a natural and intrinsic tendency. Therefore, these molecules of pre-mRNAs were positively selected because they improved the synthesis of the catalysts through this first form of coding of interactions among peptidated-RNAs. Thus, according to the model were the pairings--involving a base number greater than three (ennuplet code)-between peptidated-RNAs and pre-mRNAs that would represent the first form of the genetic code. The evolution of this ennuplet code to the triplet code might have been simply triggered by the natural tendency to make the reading module-that is the interactions between peptidated-RNAs and pre-mRNAs--of the different ennuplets to the triplet uniform, because in this way the heterogeneity existing in interactions between the aminoacylated or peptidated-RNAs and pre-mRNAs was eliminated. That is to say, there might have been the natural tendency toward the triplets because these would have made these interactions more efficient, given that the ennuplets were at least more cumbersome and therefore less economic and with an inferior adaptive value; and also because the triplets would represent the simpler choice among that available given that the doublets would have codified too few meanings and quartets instead too many. Therefore, the genetic code would result from a very long era of interactions among peptidated-RNAs under the continuous and fundamental selective pressure for improving catalysts' syntheses and thus catalysis. The model is strongly corroborated by the explanation that the tmRNA molecule (transfer-messenger RNA) would seem to be the very molecule of pre-mRNAs that the model predicts. In other words, the tmRNA would be the molecular fossil of the evolutionary stages that led to the appearance of the first mRNAs.

The Hypothesis that the Genetic Code Originated in Coupled Synthesis of Proteins and the Evolutionary Predecessors of Nucleic Acids in Primitive Cells.

Although analysis of the genetic code has allowed explanations for its evolution to be proposed, little evidence exists in biochemistry and molecular biology to offer an explanation for the origin of the genetic code. In particular, two features of biology make the origin of the genetic code difficult to understand. First, nucleic acids are highly complicated polymers requiring numerous enzymes for biosynthesis. Secondly, proteins have a simple backbone with a set of 20 different amino acid side chains synthesized by a highly complicated ribosomal process in which mRNA sequences are read in triplets. Apparently, both nucleic acid and protein syntheses have extensive evolutionary histories. Supporting these processes is a complex metabolism and at the hub of metabolism are the carboxylic acid cycles. This paper advances the hypothesis that the earliest predecessor of the nucleic acids was a β-linked polyester made from malic acid, a highly conserved metabolite in the carboxylic acid cycles. In the β-linked polyester, the side chains are carboxylic acid groups capable of forming interstrand double hydrogen bonds. Evolution of the nucleic acids involved changes to the backbone and side chain of poly(β-d-malic acid). Conversion of the side chain carboxylic acid into a carboxamide or a longer side chain bearing a carboxamide group, allowed information polymers to form amide pairs between polyester chains. Aminoacylation of the hydroxyl groups of malic acid and its derivatives with simple amino acids such as glycine and alanine allowed coupling of polyester synthesis and protein synthesis. Use of polypeptides containing glycine and l-alanine for activation of two different monomers with either glycine or l-alanine allowed simple coded autocatalytic synthesis of polyesters and polypeptides and established the first genetic code. A primitive cell capable of supporting electron transport, thioester synthesis, reduction reactions, and synthesis of polyesters and polypeptides is proposed. The cell consists of an iron-sulfide particle enclosed by tholin, a heterogeneous organic material that is produced by Miller-Urey type experiments that simulate conditions on the early Earth. As the synthesis of nucleic acids evolved from β-linked polyesters, the singlet coding system for replication evolved into a four nucleotide/four amino acid process (AMP = aspartic acid, GMP = glycine, UMP = valine, CMP = alanine) and then into the triplet ribosomal process that permitted multiple copies of protein to be synthesized independent of replication. This hypothesis reconciles the “genetics first” and “metabolism first” approaches to the origin of life and explains why there are four bases in the genetic alphabet.

Two perspectives on the origin of the standard genetic code.

The origin of a genetic code made it possible to create ordered sequences of amino acids. In this article we provide two perspectives on code origin by carrying out simulations of code-sequence coevolution in finite populations with the aim of examining how the standard genetic code may have evolved from more primitive code(s) encoding a small number of amino acids. We determine the efficacy of the physico-chemical hypothesis of code origin in the absence and presence of horizontal gene transfer (HGT) by allowing a diverse collection of code-sequence sets to compete with each other. We find that in the absence of horizontal gene transfer, natural selection between competing codes distinguished by differences in the degree of physico-chemical optimization is unable to explain the structure of the standard genetic code. However, for certain probabilities of the horizontal transfer events, a universal code emerges having a structure that is consistent with the standard genetic code.

RNA editing and modifications of RNAs might have favoured the evolution of the triplet genetic code from an ennuplet code

Here we suggest that the origin of the genetic code, that is to say, the birth of first mRNAs has been triggered by means of a widespread modification of all RNAs (proto-mRNAs and proto-tRNAs), as today observed in the RNA editing and in post-transcriptional modifications of RNAs, which are considered as fossils of this evolutionary stage of the genetic code origin. We consider also that other mechanisms, such as the trans-translation and ribosome frameshifting, could have favoured the transition from an ennuplet code to a triplet code. Therefore, according to our hypothesis all these mechanisms would be reflexive of this period of the evolutionary history of the genetic code.

Genetic Information, Physical Interpreters and Thermodynamics; The Material-Informatic Basis of Biosemiosis

The sequence of nucleotide bases occurring in an organism’s DNA is often regarded as a codescript for its construction. However, information in a DNA sequence can only be regarded as a codescript relative to an operational biochemical machine, which the information constrains in such a way as to direct the process of construction. In reality, any biochemical machine for which a DNA codescript is efficacious is itself produced through the mechanical interpretation of an identical or very similar codescript. In these terms the origin of life can be described as a bootstrap process involving the simultaneous accumulation of genetic information and the generation of a machine that interprets it as instructions for its own construction. This problem is discussed within the theoretical frameworks of thermodynamics, informatics and self-reproducing automata, paying special attention to the physico-chemical origin of genetic coding and the conditions, both thermodynamic and informatic, that a system must fulfil in order for it to sustain semiosis. The origin of life is equated with biosemiosis.

Fundamental role of start/stop regulators in whole DNA and new trinucleotide classification

The origin and logic of genetic code are two of greatest mysteries of life sciences. Analyzing DNA sequences we showed that the start/stop trinucleotides have broader importance than just marking start and stop of exons in coding DNA. On this basis, here we introduced new classification of trinucleotides and showed that all A+T rich trinucleotides consisting of three different nucleotides arise from start-ATG, stop-TGA and stop-TAG using their complement, reverse complement and reverse transformations. Due to the same transformations during generations of crossing-over they can switch from one form to the other. By direct process the start-ATG and stop-TAG can irreversibly transform into stop-TAA. By transformation into A+T rich trinucleotides and 16/32 C+G rich they can lose the start/stop function and take the role of a sense codon in reversible way. The remaining 16 C+G trinucleotides cannot directly transform into start/stop trinucleotides and thus remain a firm skeleton for structuring the C+G rich DNA. We showed that start/stops strongly enrich the A+T rich noncoding DNA through frequently extended forms. From the evolutionary viewpoint the start/stops are chief creators of prevailing A+T rich noncoding DNA, and of more stable coding DNA. We propose that start/stops have basic role as “seeds” in trinucleotide evolution of noncoding and coding sequences and lead to asymmetry between A+T and C+G rich DNA. By dynamical transformations during evolution they enabled pronounced phylogenetic broadness, keeping the regulator function.

The origin of the genetic code in the ocean abysses: New comparisons confirm old observations

I have analysed the amino acid substitution pattern between two pairs of nonbarophilic–barophilic organisms in order to confirm previous results. Indeed, the pattern deriving from a different pair of such organisms led to establish that the origin of the genetic code might have occurred in the ocean abysses. The hydrostatic pressure asymmetry indices computable from these matrices of amino acid substitutions confirm the correlation previously observed, even when differences in GC content are accounted for. As the three substitution matrices are independent between them, the old conclusion that the genetic code originated in the ocean abysses is considerably strengthened.

On the origin of the mitochondrial genetic code: Towards a unified mathematical framework for the management of genetic information

The origin of the genetic code represents one of the most challenging problems in molecular evolution. The genetic code is an important universal feature of extant organisms and indicates a common ancestry of different forms of life on earth. Known variants of the genetic code can be mainly divided in mitochondrial and nuclear classes. Here we provide a new insight on the origin of the mitochondrial genetic code: we found that its degeneracy distribution can be explained by using a mathematical approach recently developed for the description of the Euplotes nuclear variant of the genetic code. The results point to a primeval mitochondrial genetic code composed of four base codons, which we call tesserae, that, among other features, exhibit outstanding error detection capabilities. The theoretical description suggests also a formulation of a plausible biological theory about the origin of protein coding. Such theory is based on the symmetry properties of hypothetical primeval chemical adaptors between nucleic acids and amino acids (ancient tRNA’s). Our paper provides a unified mathematical framework for different hypotheses on the origin of genetic coding. Also, it contributes to revisit our present view about the evolutionary steps that led to extant genetic codes by giving a new first-principles perspective on the difficult problem of the origin of the genetic code, and consequently, on the origin of life on earth.

On the origin of the mitochondrial genetic code: Towards a unified mathematical framework for the management of genetic information

AbstractThe origin of the genetic code represents one of the most challenging problems in molecular evolution. The genetic code is an important universal feature of extant organisms and indicates a common ancestry of different forms of life on earth. Known variants of the genetic code can be mainly divided in mitochondrial and nuclear classes. Here we provide a new insight on the origin of the mitochondrial genetic code: we found that its degeneracy distribution can be explained by using a mathematical approach recently developed for the description of the Euplotes nuclear variant of the genetic code. The results point to a primeval mitochondrial genetic code composed of four base codons, which we call tesserae, that, among other features, exhibit outstanding error detection capabilities. The theoretical description suggests also a formulation of a plausible biological theory about the origin of protein coding. Such theory is based on the symmetry properties of hypothetical primeval chemical adaptors between nucleic acids and amino acids (ancient tRNA’s). Our paper provides a unified mathematical framework for different hypotheses on the origin of genetic coding. Also, it contributes to revisit our present view about the evolutionary steps that led to extant genetic codes by giving a new first-principles perspective on the difficult problem of the origin of the genetic code, and consequently, on the origin of life on earth.

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.

Alphabet of Life: Searching for clues to the genetic code's origin

Alphabet of Life: Searching for clues to the genetic code's origin

On origin of genetic code and tRNA before translation.

BackgroundSynthesis of proteins is based on the genetic code - a nearly universal assignment of codons to amino acids (aas). A major challenge to the understanding of the origins of this assignment is the archetypal "key-lock vs. frozen accident" dilemma. Here we re-examine this dilemma in light of 1) the fundamental veto on "foresight evolution", 2) modular structures of tRNAs and aminoacyl-tRNA synthetases, and 3) the updated library of aa-binding sites in RNA aptamers successfully selected in vitro for eight amino acids.ResultsThe aa-binding sites of arginine, isoleucine and tyrosine contain both their cognate triplets, anticodons and codons. We have noticed that these cases might be associated with palindrome-dinucleotides. For example, one-base shift to the left brings arginine codons CGN, with CG at 1-2 positions, to the respective anticodons NCG, with CG at 2-3 positions. Formally, the concomitant presence of codons and anticodons is also expected in the reverse situation, with codons containing palindrome-dinucleotides at their 2-3 positions, and anticodons exhibiting them at 1-2 positions. A closer analysis reveals that, surprisingly, RNA binding sites for Arg, Ile and Tyr "prefer" (exactly as in the actual genetic code) the anticodon(2-3)/codon(1-2) tetramers to their anticodon(1-2)/codon(2-3) counterparts, despite the seemingly perfect symmetry of the latter. However, since in vitro selection of aa-specific RNA aptamers apparently had nothing to do with translation, this striking preference provides a new strong support to the notion of the genetic code emerging before translation, in response to catalytic (and possibly other) needs of ancient RNA life. Consistently with the pre-translation origin of the code, we propose here a new model of tRNA origin by the gradual, Fibonacci process-like, elongation of a tRNA molecule from a primordial coding triplet and 5'DCCA3' quadruplet (D is a base-determinator) to the eventual 76 base-long cloverleaf-shaped molecule.ConclusionTaken together, our findings necessarily imply that primordial tRNAs, tRNA aminoacylating ribozymes, and (later) the translation machinery in general have been co-evolving to ''fit'' the (likely already defined) genetic code, rather than the opposite way around. Coding triplets in this primal pre-translational code were likely similar to the anticodons, with second and third nucleotides being more important than the less specific first one. Later, when the code was expanding in co-evolution with the translation apparatus, the importance of 2-3 nucleotides of coding triplets "transferred" to the 1-2 nucleotides of their complements, thus distinguishing anticodons from codons. This evolutionary primacy of anticodons in genetic coding makes the hypothesis of primal stereo-chemical affinity between amino acids and cognate triplets, the hypothesis of coding coenzyme handles for amino acids, the hypothesis of tRNA-like genomic 3' tags suggesting that tRNAs originated in replication, and the hypothesis of ancient ribozymes-mediated operational code of tRNA aminoacylation not mutually contradicting but rather co-existing in harmony.ReviewersThis article was reviewed by Eugene V. Koonin, Wentao Ma (nominated by Juergen Brosius) and Anthony Poole.

Complexity at large

Complexity at large

Topological, statistical, and dynamical origins of genetic code: Comment on “A colorful origin for the genetic code: Information theory, statistical mechanics and the emergence of molecular codes” by T. Tlusty

How has the genetic code evolved to link genetic sequences to corresponding amino acids? Why are only 20 amino acids used from 64 possible triplet codes when forming proteins? Since the discovery of codons, these two questions have been integral to evolutionary biology, and addressed by distinguished biologists. For example, a beautiful theory by Crick et al. [1] to explain the number 20 from the optimal code without stopping symbol (comma) was selected as the most elegant ‘wrong’ theory ever to be proposed in science by Maynard-Smith [2]. Later on, Crick himself described the ‘universal’ genetic code as luck with the ‘frozen accident’ in the common ancestor of living organisms [3]. In the present paper [4], the author presented a statistical-physics based explanation for the evolution of the genetic code by using a more sophisticated mathematical theory than that of Crick et al. Topological and information-theoretic approaches were adopted by imposing the optimization of a certain quantity that consists of diverse amino acids, errortolerance and minimal energy cost. A second-order phase transition from random to non-random mapping between codons and amino acids was found to coincide with changes in this quantity. This resembles known behavior in magnetic spin systems, which is analogous to the error-catastrophe seen in chemical evolutions [5]. Furthermore, the author introduced the topology of the codon graph determining the lowest modes of the graph-Laplacian and related it to the mathematical map coloring problem. By removing the ambiguity in the third position of the codon and considering the optimization process under this topological constraint, the maximum number of amino acids to be coded is predicted to be 25. This is an elegant theory that can be experimentally verified.

Amino Acid Homochirality may be Linked to the Origin of Phosphate-Based Life

Phosphorylation has to have been one of the key events in prebiotic evolution on earth. In this article, the emergence of phosphoryl amino acid 5'-nucleosides having a P-N bond is described as a model of the origin of amino acid homochirality and Genetic Code. It is proposed that the intramolecular interaction between the nucleotide base and the amino acid side-chain influences the stability of particular amino acid 5'-nucleotides, and the interaction also selects for the chirality of amino acids. The differences between L: - and D: -conformation energies (DeltaE (conf)) are evaluated by DFT methods at the B3LYP/6-31G(d) level. Although, as expected, these DeltaE (conf) values are not large, they do give differences in energy that can distinguish the chirality of amino acids. Based on our calculations, the chiral selection of the earliest amino acids for L: -enantiomers seems to be determined by a clear stereochemical/physicochemical relationship. As later amino acids developed from the earliest amino acids, we deduce that the chirality of these late amino acids was inherited from that of the early amino acids. This idea reaches far back into evolution, and we hope that it will guide further experiments in this area.

Origin of an Alternative Genetic Code in the Extremely Small and GC–Rich Genome of a Bacterial Symbiont

The genetic code relates nucleotide sequence to amino acid sequence and is shared across all organisms, with the rare exceptions of lineages in which one or a few codons have acquired novel assignments. Recoding of UGA from stop to tryptophan has evolved independently in certain reduced bacterial genomes, including those of the mycoplasmas and some mitochondria. Small genomes typically exhibit low guanine plus cytosine (GC) content, and this bias in base composition has been proposed to drive UGA Stop to Tryptophan (Stop→Trp) recoding. Using a combination of genome sequencing and high-throughput proteomics, we show that an α-Proteobacterial symbiont of cicadas has the unprecedented combination of an extremely small genome (144 kb), a GC–biased base composition (58.4%), and a coding reassignment of UGA Stop→Trp. Although it is not clear why this tiny genome lacks the low GC content typical of other small bacterial genomes, these observations support a role of genome reduction rather than base composition as a driver of codon reassignment.

The close relationship between the biosynthetic families of amino acids and the organisation of the genetic code

By generating random codes and applying Fisher's exact test, we confirm that the biosynthetic families of amino acids are intimately involved in the organisation of the genetic code. This observation corroborates the coevolution theory of genetic code origin. As the amino acids belonging to the single biosynthetic families have codons that are contiguous in the genetic code, they must have entered the code itself by means of a clustering mechanism, which must clearly have been compatible with the mechanism on which this theory is based because this too envisages the clustering of biosynthetically correlated amino acids within the code.

An extension of the coevolution theory of the origin of the genetic code.

BackgroundThe coevolution theory of the origin of the genetic code suggests that the genetic code is an imprint of the biosynthetic relationships between amino acids. However, this theory does not seem to attribute a role to the biosynthetic relationships between the earliest amino acids that evolved along the pathways of energetic metabolism. As a result, the coevolution theory is unable to clearly define the very earliest phases of genetic code origin. In order to remove this difficulty, I here suggest an extension of the coevolution theory that attributes a crucial role to the first amino acids that evolved along these biosynthetic pathways and to their biosynthetic relationships, even when defined by the non-amino acid molecules that are their precursors.ResultsIt is re-observed that the first amino acids to evolve along these biosynthetic pathways are predominantly those codified by codons of the type GNN, and this observation is found to be statistically significant. Furthermore, the close biosynthetic relationships between the sibling amino acids Ala-Ser, Ser-Gly, Asp-Glu, and Ala-Val are not random in the genetic code table and reinforce the hypothesis that the biosynthetic relationships between these six amino acids played a crucial role in defining the very earliest phases of genetic code origin.ConclusionAll this leads to the hypothesis that there existed a code, GNS, reflecting the biosynthetic relationships between these six amino acids which, as it defines the very earliest phases of genetic code origin, removes the main difficulty of the coevolution theory. Furthermore, it is here discussed how this code might have naturally led to the code codifying only for the domains of the codons of precursor amino acids, as predicted by the coevolution theory. Finally, the hypothesis here suggested also removes other problems of the coevolution theory, such as the existence for certain pairs of amino acids with an unclear biosynthetic relationship between the precursor and product amino acids and the collocation of Ala between the amino acids Val and Leu belonging to the pyruvate biosynthetic family, which the coevolution theory considered as belonging to different biosyntheses.ReviewersThis article was reviewed by Rob Knight, Paul Higgs (nominated by Laura Landweber), and Eugene Koonin.