Codon Size Reduction as the Origin of the Triplet Genetic Code

The genetic code appears to be optimized in its robustness to missense errors and frameshift errors. In addition, the genetic code is near-optimal in terms of its ability to carry information in addition to the sequences of encoded proteins. As evolution has no foresight, optimality of the modern genetic code suggests that it evolved from less optimal code variants. The length of codons in the genetic code is also optimal, as three is the minimal nucleotide combination that can encode the twenty standard amino acids. The apparent impossibility of transitions between codon sizes in a discontinuous manner during evolution has resulted in an unbending view that the genetic code was always triplet. Yet, recent experimental evidence on quadruplet decoding, as well as the discovery of organisms with ambiguous and dual decoding, suggest that the possibility of the evolution of triplet decoding from living systems with non-triplet decoding merits reconsideration and further exploration. To explore this possibility we designed a mathematical model of the evolution of primitive digital coding systems which can decode nucleotide sequences into protein sequences. These coding systems can evolve their nucleotide sequences via genetic events of Darwinian evolution, such as point-mutations. The replication rates of such coding systems depend on the accuracy of the generated protein sequences. Computer simulations based on our model show that decoding systems with codons of length greater than three spontaneously evolve into predominantly triplet decoding systems. Our findings suggest a plausible scenario for the evolution of the triplet genetic code in a continuous manner. This scenario suggests an explanation of how protein synthesis could be accomplished by means of long RNA-RNA interactions prior to the emergence of the complex decoding machinery, such as the ribosome, that is required for stabilization and discrimination of otherwise weak triplet codon-anticodon interactions.     

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.     

Construction of genetic code from evolutionary stability

The construction of the genetic code is investigated based on a stability principle. The concept and formulation of mutational deterioration (MD) of the genetic code is proposed. It is proved that the degeneracies of codon multiplets obey the rule to best resist MD. The MD for each ideal multiplet of codons is expressed by four parameters and it takes on a minimum value for real distributions of codons in the multiplet. Then the global mutational deterioration (GMD) of code table is calculated and the minimal code is deduced. The domain-like distribution of hydrophobic and hydrophilic amino acids on the genetic code is explained from the minimization of GMD. It is demonstrated that the standard code is approximately GMD-minimal. By introducing some constraints that are related to the initial condition of the system, we have deduced the standard genetic code from the minimization of GMD. The minimization shows the general trend of evolutionary process to some stable state while the constraints reflect a 'frozen accident.' Many deviant codon assignments are also explained through MD minimization assuming the changeable degrees of degeneracies for some multiplets. So, a possible answer to the question of "Why are synonymous codons and amino acids distributed in the code table just as they are?" is given.     

The genetic code and the origin of life

The problem of the origin of life understandably counts as one of the most exciting questions in the natural sciences, but in spite of almost endless speculation on this subject, it is still far from its final solution. The complexity of the functional correlation between recent nucleic acids and proteins can e.g. give rise to the assumption that the genetic code (and life) could not originate on the Earth. It was Portelli (1975) who published the hypothesis that the genetic code could not originate during the history of the Earth. In his opinion the recent genetic code represents the informational message transmitted by living systems of the previous cycle of the Universe. Here however, we defend the existence of a certain strategy in the syntheses of the genetic code during the history of the Earth. The strategy of correlation between amino acid and nucleotide polymers made an increasing velocity of the chemical evolution possible, that is, it increased the velocity of formation of the genetic code. Thus, life with the recent genetic code could originate on the Earth within the present cycle of the Universe.Present address: Institute for Pharmacy and Biochemistry, 533 51 Pardubice, Czechoslovakia.     

A Novel Theory on the Origin of the Genetic Code: A GNC-SNS Hypothesis

We have previously proposed an SNS hypothesis on the origin of the genetic code (Ikehara and Yoshida 1998). The hypothesis predicts that the universal genetic code originated from the SNS code composed of 16 codons and 10 amino acids (S and N mean G or C and either of four bases, respectively). But, it must have been very difficult to create the SNS code at one stroke in the beginning. Therefore, we searched for a simpler code than the SNS code, which could still encode water-soluble globular proteins with appropriate three-dimensional structures at a high probability using four conditions for globular protein formation (hydropathy, α-helix, β-sheet, and β-turn formations). Four amino acids (Gly [G], Ala [A], Asp [D], and Val [V]) encoded by the GNC code satisfied the four structural conditions well, but other codes in rows and columns in the universal genetic code table do not, except for the GNG code, a slightly modified form of the GNC code. Three three-amino acid systems ([D], Leu and Tyr; [D], Tyr and Met; Glu, Pro and Ile) also satisfied the above four conditions. But, some amino acids in the three systems are far more complex than those encoded by the GNC code. In addition, the amino acids in the three-amino acid systems are scattered in the universal genetic code table. Thus, we concluded that the universal genetic code originated not from a three-amino acid system but from a four-amino acid system, the GNC code encoding [GADV]-proteins, as the most primitive genetic code. Received: 11 June 2001 / Accepted: 11 October 2001     

A simple histone code opens many paths to epigenetics

Nucleosomes can be covalently modified by addition of various chemical groups on several of their exposed histone amino acids. These modifications are added and removed by enzymes (writers) and can be recognized by nucleosome-binding proteins (readers). Linking a reader domain and a writer domain that recognize and create the same modification state should allow nucleosomes in a particular modification state to recruit enzymes that create that modification state on nearby nucleosomes. This positive feedback has the potential to provide the alternative stable and heritable states required for epigenetic memory. However, analysis of simple histone codes involving interconversions between only two or three types of modified nucleosomes has revealed only a few circuit designs that allow heritable bistability. Here we show by computer simulations that a histone code involving alternative modifications at two histone positions, producing four modification states, combined with reader-writer proteins able to distinguish these states, allows for hundreds of different circuits capable of heritable bistability. These expanded possibilities result from multiple ways of generating two-step cooperativity in the positive feedback - through alternative pathways and an additional, novel cooperativity motif. Our analysis reveals other properties of such epigenetic circuits. They are most robust when the dominant nucleosome types are different at both modification positions and are not the type inserted after DNA replication. The dominant nucleosome types often recruit enzymes that create their own type or destroy the opposing type, but never catalyze their own destruction. The circuits appear to be evolutionary accessible; most circuits can be changed stepwise into almost any other circuit without losing heritable bistability. Thus, our analysis indicates that systems that utilize an expanded histone code have huge potential for generating stable and heritable nucleosome modification states and identifies the critical features of such systems.     

Block structure and stability of the genetic code

It is known that different codons may be unified into larger groups related to the hierarchical structure, approximate hidden symmetries, and evolutionary origin of the universal genetic code. Using a simplified evolutionary motivated two-letter version of genetic code, the general principles of the most stable coding are discussed. By the complete enumeration in such a reduced code it is strictly proved that the maximum stability with respect to point mutations and shifts in the reading frame needs the fixation of the middle letters within codons in groups with different physico-chemical properties, thus, explaining a key feature of the universal genetic code. The translational stability of the genetic code is studied by the mapping of code onto de Bruijn graph providing both the compact visual representation of mutual relationships between different codons as well as between codons and protein coding DNA sequence and a powerful tool for the investigation of stability of protein coding. Then, the results are extended to four-letter codes. As is shown, the universal genetic code obeys mainly the principles of optimal coding. These results demonstrate the hierarchical character of optimization of universal genetic code with strictly optimal coding being evolved at the earliest stages of molecular evolution. Finally, the universal genetic code is compared with the other natural variants of genetic codes.     

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.     

Coding Rules for Amino Acids in the Genetic Code: The Genetic Code is a Minimal Code of Mutational Deterioration

Coding rules for amino acids in the genetic code are discussed from the point that the genetic code is a minimal code ofmutational deterioration. The global mutational deterioration(GMD) function is defined through several parameters describingsingle base mutations and amino acid distances. The problem ofsearching for the global minimum of the GMD function is discussedin some detail. From GMD minimization under initial constraintswe have succeeded in deducing the standard genetic code.     

The Australian joint inquiry into the Protection of Human Genetic Information

The Australian Law Reform Commission (ALRC) and the Australian Health Ethics Committee are currently engaged in an inquiry into the Protection of Human Genetic Information. In particular, the Attorney-General and the Minister for Health and Ageing have asked us to focus, in relation to human genetic information and tissue samples, on how best to ensure world's best practice in relation to: privacy protection; protection against unlawful discrimination; and the maintenance of high ethical standards in medical research and clinical practice. While initial concerns and controversies have related mainly to aspects of medical research (e.g. consent; re-use of samples) and access to private insurance coverage, relevant issues arise in a wide variety of contexts, including: employment; medical practice; tissue banks and genetic databases; health administration; superannuation; access to government services (e.g. schools, nursing homes); law enforcement; and use by government authorities (e.g. for immigration purposes) or other bodies (e.g. by sports associations). Under the Australian federal system, it is also the case that laws and practices may vary across states and territories. For example, neonatal genetic testing is standard, but storage and retention policies for the resulting 'Guthrie cards' differ markedly. Similarly, some states have developed highly linked health information systems (e.g. incorporating hospitals, doctors' offices and public records), while others discourage such linkages owing to concerns about privacy. The challenge for Australia is to develop policies, standards and practices that promote the intelligent use of genetic information, while providing a level of security with which the community feels comfortable. The inquiry is presently reviewing the adequacy of existing laws and regulatory mechanisms, but recognizes that it will be even more important to develop a broad mix of strategies, such as community and professional education, and the development of official standards and industry codes that reflect emerging international best practice in the area.     

Multiple Stable States of Disease Occurrence: A Note on the Implications for the Anthropological Study of Human Disease

Ecologists model human disease using predator-prey models, with humans as the prey and the pathogen as the predator. Use of these models permits the identification of stable equilibria and stable states of disease prevalence for human host-parasite systems. May (1977) has described the possibility of the presence of multiple stable states of disease prevalence for human disease systems. The model of multiple stable states implies that historical circumstances are important in determining the occurrence of disease. This model offers a theoretical framework in which to examine the occurrence of epidemics in human populations and to develop a more complete understanding of disease processes.     

Parameterization and prediction of community interaction models using stable-state assumptions and computational techniques: an example from the high rocky intertidal

Many ecological communities exist in a stable state where, if undisturbed, no net change will occur in the populations or in the interactions between the component parts of the system. In this paper we present computational methods (evolutionary algorithms and random searches) to parameterize mathematical models that describe communities in stable states. The initial parameterization of the model requires only "best guess" estimates for parameters and can therefore be used in data-poor situations. The technique locates the stable state that occurs with minimum deviation from these parameters. Alternative stable states in which the community may exist after a disturbance event can also be assessed using this technique, even though the number of alternative states may be large. Using available but incomplete data from an intertidal grazer/biofilm community, we created a prediction of the dynamics of both a pre- and post-disturbance community. Using limited data, we then predicted the most likely post-disturbance community, which proved to be a good match to experimental data, indicating the usefulness of this technique as a predictive tool.     

Genetic and strategic models for the evolution of mating systems

Male and female fitnesses in the Shaw-Mohler equation are partitioned into components which putatively determine mating systems. The resultant genetic models provide criteria for evolutionary stable population states and yield strategic models based on maximization principles and fitness sets.     

Inheritance and state switching of genetic toggle switch in different culture growth phases

Using the gene engineering methods, one can construct simple artificial gene networks with two stable functioning regimes (bistable genetic systems). Such genetic systems make it possible for cells with identical genotype to inherit two alternative phenotypes. The toggle switch is just one of the types of bistable genetic systems. In this work, we investigate the inheritance and switching of toggle switch functioning regimes in the cells at different culture growth phases. It is shown that during transition into the stationary growth phase the inheritance of stable states is disturbed and variations in the toggle-switching rate are more possible in different cells. Also, simultaneous expression of two genes of the system has been experimentally modelled. According to our results, the culture growth phase in this period determines later on the ratio between cell phenotypes in a population.     

The evolution of the mitochondrial genetic code in arthropods revisited

A variant of the invertebrate mitochondrial genetic code was previously identified in arthropods (Abascal et al. 2006a, PLoS Biol 4:e127) in which, instead of translating the AGG codon as serine, as in other invertebrates, some arthropods translate AGG as lysine. Here, we revisit the evolution of the genetic code in arthropods taking into account that (1) the number of arthropod mitochondrial genomes sequenced has triplicated since the original findings were published; (2) the phylogeny of arthropods has been recently resolved with confidence for many groups; and (3) sophisticated probabilistic methods can be applied to analyze the evolution of the genetic code in arthropod mitochondria. According to our analyses, evolutionary shifts in the genetic code have been more common than previously inferred, with many taxonomic groups displaying two alternative codes. Ancestral character-state reconstruction using probabilistic methods confirmed that the arthropod ancestor most likely translated AGG as lysine. Point mutations at tRNA-Lys and tRNA-Ser correlated with the meaning of the AGG codon. In addition, we identified three variables (GC content, number of AGG codons, and taxonomic information) that best explain the use of each of the two alternative genetic codes.     

Potential automata. Application to the genetic code III

In previous notes, we have described both mathematical properties of potential (n-switches) and potential-Hamiltonian (Liénard systems) continuous differential systems, and also biological applications, especially those concerning primitive cyclic RNAs related to the genetic code. In the present note, we give a general definition of a potential automaton, and we show that a discrete Hopfield-like system already introduced by Goles et al. is a good candidate for such a potential automaton: it has a Lyapunov functional that decreases on its trajectories and whose time derivative is just its discrete velocity. Then we apply this new notion of potential automaton to the genetic code. We show in particular that the consideration of only physicochemical properties of amino-acids, like their molecular weight, hydrophobicity and ability to create hydrogen bonds suffices to build a potential decreasing on trajectories corresponding to the synonymy classes of the genetic code. Such an 'a minima' construction reinforces the classical stereochemical hypothesis about the origin of the genetic code and authorizes new views about the optimality of its synonymy classes.     

Selection, history and chemistry: the three faces of the genetic code.

The genetic code might be a historical accident that was fixed in the last common ancestor of modern organisms. 'Adaptive', 'historical' and 'chemical' arguments, however, challenge such a 'frozen accident' model. These arguments propose that the current code is somehow optimal, reflects the expansion of a more primitive code to include more amino acids, or is a consequence of direct chemical interactions between RNA and amino acids, respectively. Such models are not mutually exclusive, however. They can be reconciled by an evolutionary model whereby stereochemical interactions shaped the initial code, which subsequently expanded through biosynthetic modification of encoded amino acids and, finally, was optimized through codon reassignment. Alternatively, all three forces might have acted in concert to assign the 20 'natural' amino acids to their present positions in the genetic code.