Genetic Code

A computer program was used to test Wong's coevolution theory of the genetic code. The codon correlations between the codons of biosynthetically related amino acids in the universal genetic code and in randomly generated genetic codes were compared. It was determined that many codon correlations are also present within random genetic codes and that among the random codes there are always several which have many more correlations than that found in the universal code. Although the number of correlations depends on the choice of biosynthetically related amino acids, the probability of choosing a random genetic code with the same or greater number of codon correlations as the universal genetic code was found to vary from 0.1% to 34% (with respect to a fairly complete listing of related amino acids). Thus, Wong's theory that the genetic code arose by coevolution with the biosynthetic pathways of amino acids, based on codon correlations between biosynthetically related amino acids, is statistical in nature.

How did the "universal" genetic code arise? Several hypotheses have been put forward, and the code has been analyzed extensively by authors looking for clues to selection pressures that might have acted during its evolution. But this approach has been ineffective. Although an impressive number of properties has been attributed to the universal code, it has been impossible to determine whether selection on any of these properties was important in the code's evolution or whether the observed properties arose as a consequence of selection on some other characteristic. Therefore we turned the question around and asked, what would a genetic code look like if it had evolved in response to various different selection pressures? To address this question, we constructed a genetic algorithm. We found first that selecting on a particular measure yields codes that are similar to each other. Second, we found that the universal code is far from minimized with respect to the effects of mutations (or translation errors) on the amino acid compositions of proteins. Finally, we found that the codes that most closely resembled real codes were those generated by selecting on aspects of the code's structure, not those generated by selecting to minimize the effects of amino acid substitutions on proteins. This suggests that the universal genetic code has been selected for a particular structure-a structure that confers an important flexibility on the evolution of genes and proteins-and that the particular assignments of amino acids to codons are secondary.

The standard genetic code is well known to be optimized for minimizing the phenotypic effects of single-nucleotide substitutions, a property that was likely selected for during the emergence of a universal code. Given the fitness advantage afforded by high standing genetic diversity in a population in a dynamic environment, it is possible that selection to explore a large fraction of the space of functional proteins also occurred. To determine whether selection for such a property played a role during the emergence of the nearly universalstandard genetic code, we investigated the number of functional variants of the Escherichia coli PhoQ protein explored at different time scales under translation using different genetic codes. We found that the standard genetic code is highly optimal for exploring a large fraction of the space of functional PhoQ variants at intermediate time scales as compared to random codes. Environmental changes, in response to which genetic diversity in a population provides a fitness advantage, are likely to have occurred at these intermediate time scales. Our results indicate that the ability of the standard code to explore a large fraction of the space of functional sequence variants arises from a balance between robustness and flexibility and is largely independent of the property of the standard code to minimize the phenotypic effects of mutations. We propose that selection to explore a large fraction of the functional sequence space while minimizing the phenotypic effects of mutations contributed toward the emergence of the standard code as the universal genetic code.

Information is the currency of life, but the origin of prebiotic information remains a mystery. We propose transitional pathways from the cosmic building blocks of life to the complex prebiotic organic chemistry that led to the origin of information systems. The prebiotic information system, specifically the genetic code, is segregated, linear, and digital, and it appeared before the emergence of DNA. In the peptide/RNA world, lipid membranes randomly encapsulated amino acids, RNA, and peptide molecules, which are drawn from the prebiotic soup, to initiate a molecular symbiosis inside the protocells. This endosymbiosis led to the hierarchical emergence of several requisite components of the translation machine: transfer RNAs (tRNAs), aminoacyl-tRNA synthetase (aaRS), messenger RNAs (mRNAs), ribosomes, and various enzymes. When assembled in the right order, the translation machine created proteins, a process that transferred information from mRNAs to assemble amino acids into polypeptide chains. This was the beginning of the prebiotic information age. The origin of the genetic code is enigmatic; herein, we propose an evolutionary explanation: the demand for a wide range of protein enzymes over peptides in the prebiotic reactions was the main selective pressure for the origin of information-directed protein synthesis. The molecular basis of the genetic code manifests itself in the interaction of aaRS and their cognate tRNAs. In the beginning, aminoacylated ribozymes used amino acids as a cofactor with the help of bridge peptides as a process for selection between amino acids and their cognate codons/anticodons. This process selects amino acids and RNA species for the next steps. The ribozymes would give rise to pre-tRNA and the bridge peptides to pre-aaRS. Later, variants would appear and evolution would produce different but specific aaRS-tRNA-amino acid combinations. Pre-tRNA designed and built pre-mRNA for the storage of information regarding its cognate amino acid. Each pre-mRNA strand became the storage device for the genetic information that encoded the amino acid sequences in triplet nucleotides. As information appeared in the digital languages of the codon within pre-mRNA and mRNA, and the genetic code for protein synthesis evolved, the prebiotic chemistry then became more organized and directional with the emergence of the translation and genetic code. The genetic code developed in three stages that are coincident with the refinement of the translation machines: the GNC code that was developed by the pre-tRNA/pre-aaRS /pre-mRNA machine, SNS code by the tRNA/aaRS/mRNA machine, and finally the universal genetic code by the tRNA/aaRS/mRNA/ribosome machine. We suggest the coevolution of translation machines and the genetic code. The emergence of the translation machines was the beginning of the Darwinian evolution, an interplay between information and its supporting structure. Our hypothesis provides the logical and incremental steps for the origin of the programmed protein synthesis. In order to better understand the prebiotic information system, we converted letter codons into numerical codons in the Universal Genetic Code Table. We have developed a software, called CATI (Codon-Amino Acid-Translator-Imitator), to translate randomly chosen numerical codons into corresponding amino acids and vice versa. This conversion has granted us insight into how the genetic code might have evolved in the peptide/RNA world. There is great potential in the application of numerical codons to bioinformatics, such as barcoding, DNA mining, or DNA fingerprinting. We constructed the likely biochemical pathways for the origin of translation and the genetic code using the Model-View-Controller (MVC) software framework, and the translation machinery step-by-step. While using AnyLogic software, we were able to simulate and visualize the entire evolution of the translation machines, amino acids, and the genetic code.

The genetic code establishes the relationship between all 64 possible arrangements of triplets (codons) of the four nucleotide bases contained in either DNA (A, T, G and C) or RNA (A, U, G and C) and the 20 amino acids that are used to construct proteins via ‘translation’ system as well as signals of translation initiation and termination. The historical events from 1950s to 1960s that contributed to the deciphering of the genetic code led to the development of the field of molecular biology. In 1960s, the genetic code was established to be ‘universal’ for all living organisms. However, from late 1970s, variations of genetic code have been found in various genetic systems. Variations of genetic code promote studies on the origin and evolution of the genetic code. Key Concepts: Genetic code is the correlation between nucleotide triplet and the corresponding amino acid. Genetic code consists of 64 triplet codons and sometimes ‘degenerate’. Central dogma states that genetic information flows unidirectionally from DNA to protein via RNA as an intermediary. A cell‐free protein system contains ribosome, S100 fraction, tRNA, amino acids, ATP, an energy recycling system and a template. Termination codon consists of UAG (amber codon), UAA (ochre codon) and UGA (opal codon), which code for no amino acid but instead cause protein synthesis to terminate. Initiation codon is AUG, which initiates protein synthesis with formyl‐methionine in bacteria and phage. Universal genetic code shows the way of assignment of 64 triplet codons to each of 20 amino acids and 3 termination codons, which is common to almost all extant organisms – bacteria, yeasts, viruses, plants and animals.

Evolution of the first genetic cells and the universal genetic code: A hypothesis based on macromolecular coevolution of RNA and proteins

The universal genetic code is a common language for almost all organisms to translate nucleotide sequences of DNA and RNA to amino acid sequences of proteins. Some organisms and organelles use variants of the universal genetic code.

Natural and artificial variations of the standard genetic code.

The coevolution theory suggests that origin and evolution of the genetic code proceed along with development of synthetic pathway of amino acids. The coevolution theory is undoubtedly a correct idea, because the genetic code could not evolve, if synthetic pathways of new amino acids were not invented and the new amino acids did not accumulate at a large amount in the cells. On the other hand, studies on metabolic pathways have progressed and information about metabolic pathways obtained thus far has been stored in KEGG PATHWAY Database. Then, amino acid metabolic pathways were analyzed in detail in order to answer to the following questions. (1) The genetic code originated from what type of genetic code? (2) The genetic code has reached to the universal genetic code, passing through what type of intermediate genetic code, SNS code or RNY code? From the results, it could be reconfirmed that the genetic code originated from the GNC primeval genetic code and evolved to the universal genetic code passing through SNS genetic code. Lastly, limits and future prospects of the coevolution theory are also discussed.

A "simplified genetic code", with only 19 amino acids assigned to the sense codons, was recently developed. In this study, we describe novel simplified codes in which multiple amino acids are simultaneously excluded from the universal code. In the simplest code, tryptophan, cysteine, tyrosine, and asparagine codons are assigned to serine by using four kinds of tRNA (Ser) variants. The results revealed that various sets of amino acids can easily be excluded from the universal code, using our strategy for genetic code simplification. A simplified genetic code is useful as an engineering tool for the improvement of industrial enzymes and pharmaceuticals, and also provides new insights into the assessment of protein evolution. Simplified codes in which multiple amino acids are simultaneously excluded from the code can be more effective tools than codes excluding only one amino acid.

Codon reassignment and the evolving genetic code: problems and pitfalls in post-genome analysis

The discovery in the 1960s of an identical genetic code in Escherichia coli viruses and mammalian cells suggested that all living organisms use the same genetic code. The existence of a universal genetic code prompted Crick to propose the “Frozen Accident Theory” which states that the genetic code does not evolve. This theory was based on the assumption that in the last common ancestor, life-forms had reached a level of complexity that would not tolerate alterations in the identity of their codons. That is, once proteins had ac-quired a certain level of functionality, any alteration in codon identity would introduce struc-tural and functional disruption with a high probability that this would be lethal or highly detrimental.

The standard genetic code (SGC) is the set of rules by which genetic information is translated into proteins, from codons, i.e. triplets of nucleotides, to amino acids. The questions about the origin and the main factor responsible for the present structure of the code are still under a hot debate. Various methodologies have been used to study the features of the code and assess the level of its potential optimality. Here, we introduced a new general approach to evaluate the quality of the genetic code structure. This methodology comes from graph theory and allows us to describe new properties of the genetic code in terms of conductance. This parameter measures the robustness of codon groups against the potential changes in translation of the protein-coding sequences generated by single nucleotide substitutions. We described the genetic code as a partition of an undirected and unweighted graph, which makes the model general and universal. Using this approach, we showed that the structure of the genetic code is a solution to the graph clustering problem. We presented and discussed the structure of the codes that are optimal according to the conductance. Despite the fact that the standard genetic code is far from being optimal according to the conductance, its structure is characterised by many codon groups reaching the minimum conductance for their size. The SGC represents most likely a local minimum in terms of errors occurring in protein-coding sequences and their translation.

A deviation from the universal genetic code was first discovered in mammalian mitochondria in 1979. In the 1980s, several unusual genetic codes were also reported in animal organella. However, the genetic code in nuclear systems is less changeable than in organella.

With the ultimate intent to establish a transformation system for eukaryotic organelles, the structure and organization of mitochondrial genes from the unicellular algaChlamydomonas reinhardii has been investigated. Using DNA hybridisation and DNA sequencing techniques, 3.9 kb of DNA, comprising about 25% of the mitochondrial genome, have been analysed in detail. By comparing the primary structure of homologous genes from other eukaryotic systems, we were able to identify the continuous genes coding for cytochrome oxidase subunit I (COI) and a NADH dehydrogenase subunit (ND5). The two genes are coded by opposite DNA strands and are not overlapping. The COI and the ND5 genes code for 505 and 567 amino acids, respectively. Interestingly, the comparative analysis with homologous genes from other eukaryotes shows that the universal genetic code is used in mitochondria ofC. reinhardii. This situation is different from all other mitochondrial systems studied so far. The results provide evidence thatC. reinhardii would be the appropriate organism for development of a transformation and expression system, where foreign genes, translated via the universal genetic code, are introduced into mitochondria.