The Case for an Error Minimizing Standard Genetic Code

Since discovering the pattern by which amino acids are assigned to codons within the standard genetic code, investigators have explored the idea that natural selection placed biochemically similar amino acids near to one another in coding space so as to minimize the impact of mutations and/or mistranslations. The analytical evidence to support this theory has grown in sophistication and strength over the years, and counterclaims questioning its plausibility and quantitative support have yet to transcend some significant weaknesses in their approach. These weaknesses are illustrated here by means of a simple simulation model for adaptive genetic code evolution. There remain ill explored facets of the `error minimizing' code hypothesis, however, including the mechanism and pathway by which an adaptive pattern of codon assignments emerged, the extent to which natural selection created synonym redundancy, its role in shaping the amino acid and nucleotide languages, and even the correct interpretation of the adaptive codon assignment pattern: these represent fertile areas for future research.     

Human Males Appear More Prepared Than Females to Resolve Conflicts with Same-Sex Peers

The aim of the study was to investigate sex differences in proximate mechanisms that precede the termination of conflicts. In Study 1, we asked women and men to report their intensity of anger in response to hypothetical, common transgressions involving a same-sex roommate. Direct verbal and physical aggression elicited the highest-intensity anger for both sexes, although overall women reported more intense anger than men to all transgressions. In Study 2, we examined sex differences in subjective and physiological reactions to a conflict using a role-playing scenario. Following recall of a conflict involving direct aggression and role-playing a reaction to it, compared with men, women reported their anger would dissipate less quickly and they would take longer to reconcile. Women also exhibited increased heart rate, but little change in cortisol, whereas men exhibited little change in heart rate but increased cortisol production. We interpret the results as indicating that women are less prepared than men to resolve a conflict with a same-sex peer.     

On Error Minimization in a Sequential Origin of the Standard Genetic Code

Distances between amino acids were derived from the polar requirement measure of amino acid polarity and Benner and co-workers' (1994) 74-100 PAM matrix. These distances were used to examine the average effects of amino acid substitutions due to single-base errors in the standard genetic code and equally degenerate randomized variants of the standard code. Second-position transitions conserved all distances on average, an order of magnitude more than did second-position transversions. In contrast, first-position transitions and transversions were about equally conservative. In comparison with randomized codes, second-position transitions in the standard code significantly conserved mean square differences in polar requirement and mean Benner matrix-based distances, but mean absolute value differences in polar requirement were not significantly conserved. The discrepancy suggests that these commonly used distance measures may be insufficient for strict hypothesis testing without more information. The translational consequences of single-base errors were then examined in different codon contexts, and similarities between these contexts explored with a hierarchical cluster analysis. In one cluster of codon contexts corresponding to the RNY and GNR codons, second-position transversions between C and G and transitions between C and U were most conservative of both polar requirement and the matrix-based distance. In another cluster of codon contexts, second-position transitions between A and G were most conservative. Despite the claims of previous authors to the contrary, it is shown theoretically that the standard code may have been shaped by position-invariant forces such as mutation and base content. These forces may have left heterogeneous signatures in the code because of differences in translational fidelity by codon position. A scenario for the origin of the code is presented wherein selection for error minimization could have occurred multiple times in disjoint parts of the code through a phyletic process of competition between lineages. This process permits error minimization without the disruption of previously useful messages, and does not predict that the code is optimally error-minimizing with respect to modern error. Instead, the code may be a record of genetic process and patterns of mutation before the radiation of modern organisms and organelles. Received: 28 July 1997 / Accepted: 23 January 1998     

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. [Reviewing Editor : Dr. Stephen Freeland]     

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.     

Codon Usage Decreases the Error Minimization Within the Genetic Code

The genetic code is not random but instead is organized in such a way that single nucleotide substitutions are more likely to result in changes between similar amino acids. This fidelity, or error minimization, has been proposed to be an adaptation within the genetic code. Many models have been proposed to measure this adaptation within the genetic code. However, we find that none of these consider codon usage differences between species. Furthermore, use of different indices of amino acid physicochemical characteristics leads to different estimations of this adaptation within the code. In this study, we try to establish a more accurate model to address this problem. In our model, a weighting scheme is established for mistranslation biases of the three different codon positions, transition/transversion biases, and codon usage. Different indices of amino acids physicochemical characteristics are also considered. In contrast to pervious work, our results show that the natural genetic code is not fully optimized for error minimization. The genetic code, therefore, is not the most optimized one for error minimization, but one that balances between flexibility and fidelity for different species.     

On the Origin of Frameshift-Robustness of the Standard Genetic Code

The standard genetic code (SGC) has been extensively analyzed for the biological ramifications of its nonrandom structure. For instance, mismatch errors due to point mutation or mistranslation have an overall smaller effect on the amino acid polar requirement under the SGC than under random genetic codes (RGCs). A similar observation was recently made for frameshift errors, prompting the assertion that the SGC has been shaped by natural selection for frameshift-robustness—conservation of certain amino acid properties upon a frameshift mutation or translational frameshift. However, frameshift-robustness confers no benefit because frameshifts usually create premature stop codons that cause nonsense-mediated mRNA decay or production of nonfunctional truncated proteins. We here propose that the frameshift-robustness of the SGC is a byproduct of its mismatch-robustness. Of 564 amino acid properties considered, the SGC exhibits mismatch-robustness in 93–133 properties and frameshift-robustness in 55 properties, respectively, and that the latter is largely a subset of the former. For each of the 564 real and 564 randomly constructed fake properties of amino acids, there is a positive correlation between mismatch-robustness and frameshift-robustness across one million RGCs; this correlation arises because most amino acid changes resulting from a frameshift are also achievable by a mismatch error. Importantly, the SGC does not show significantly higher frameshift-robustness in any of the 55 properties than RGCs of comparable mismatch-robustness. These findings support that the frameshift-robustness of the SGC need not originate through direct selection and can instead be a site effect of its mismatch-robustness.     

An Extended RNA Code and its Relationship to the Standard Genetic Code: An Algebraic and Geometrical Approach

An algebraic and geometrical approach is used to describe the primaeval RNA code and a proposed Extended RNA code. The former consists of all codons of the type RNY, where R means purines, Y pyrimidines, and N any of them. The latter comprises the 16 codons of the type RNY plus codons obtained by considering the RNA code but in the second (NYR type), and the third, (YRN type) reading frames. In each of these reading frames, there are 16 triplets that altogether complete a set of 48 triplets, which specify 17 out of the 20 amino acids, including AUG, the start codon, and the three known stop codons. The other 16 codons, do not pertain to the Extended RNA code and, constitute the union of the triplets YYY and RRR that we define as the RNA-less code. The codons in each of the three subsets of the Extended RNA code are represented by a four-dimensional hypercube and the set of codons of the RNA-less code is portrayed as a four-dimensional hyperprism. Remarkably, the union of these four symmetrical pairwise disjoint sets comprises precisely the already known six-dimensional hypercube of the Standard Genetic Code (SGC) of 64 triplets. These results suggest a plausible evolutionary path from which the primaeval RNA code could have originated the SGC, via the Extended RNA code plus the RNA-less code. We argue that the life forms that probably obeyed the Extended RNA code were intermediate between the ribo-organisms of the RNA World and the last common ancestor (LCA) of the Prokaryotes, Archaea, and Eucarya, that is, the cenancestor. A general encoding function, E, which maps each codon to its corresponding amino acid or the stop signal is also derived. In 45 out of the 64 cases, this function takes the form of a linear transformation F, which projects the whole six-dimensional hypercube onto a four-dimensional hyperface conformed by all triplets that end in cytosine. In the remaining 19 cases the function E adopts the form of an affine transformation, i.e., the composition of F with a particular translation. Graphical representations of the four local encoding functions and E, are illustrated and discussed. For every amino acid and for the stop signal, a single triplet, among those that specify it, is selected as a canonical representative. From this mapping a graphical representation of the 20 amino acids and the stop signal is also derived. We conclude that the general encoding function E represents the SGC itself.     

Little Evidence the Standard Genetic Code Is Optimized for Resource Conservation

Selection for resource conservation can shape the coding sequences of organisms living in nutrient-limited environments. Recently, it was proposed that selection for resource conservation, specifically for nitrogen and carbon content, has also shaped the structure of the standard genetic code, such that the missense mutations the code allows tend to cause small increases in the number of nitrogen and carbon atoms in amino acids. Moreover, it was proposed that this optimization is not confounded by known optimizations of the standard genetic code, such as for polar requirement or hydropathy. We challenge these claims. We show the proposed optimization for nitrogen conservation is highly sensitive to choice of null model and the proposed optimization for carbon conservation is confounded by the known conservative nature of the standard genetic code with respect to the molecular volume of amino acids. There is therefore little evidence the standard genetic code is optimized for resource conservation. We discuss our findings in the context of null models of the standard genetic code.     

The Robust Statistical Bases of the Coevolution Theory of Genetic Code Origin

A paper (Amirnovin R, J Mol Evol 44:473–476, 1997) seems to undermine the validity of the coevolution theory of genetic code origin by shedding doubt on the connection between the biosynthetic relationships between amino acids and the organization of the genetic code, at a time when the literature on the topic takes this for granted. However, as a few papers cite this paper as evidence against the coevolution theory, and to cast aside all doubt on the subject, we have decided to reanalyze the statistical bases on which this theory is founded. We come to the following conclusions: (1) the methods used in the above referred paper contain certain mistakes, and (2) the statistical foundations on which the coevolution theory is based are extremely robust. We have done this by critically appraising Amirnovin's paper and suggesting an alternative method based on the generation of random codes which, along with the method reported in the literature, allows us to evaluate the significance, in the genetic code, of different sets of amino acid pairs in biosynthetic relationships. In particular, by using this method and after building up a certain set of amino acid pairs reflecting the expectations of the coevolution theory, we show that the presence of this set in the genetic code would be obtained, purely by chance, with a probability of 6 × 10⁻⁵. This observation seems to provide particularly strong support to the coevolution theory. Received: 28 June 1999 / Accepted: 23 October 1999     

Factors in Protobiomonomer Selection for the Origin of the Standard Genetic Code

Acta Biotheoretica - Natural selection of specific protobiomonomers during abiogenic development of the prototype genetic code is hindered by the diversity of structural, spatial, and rotational...     

Phenotypic Graphs and Evolution Unfold the Standard Genetic Code as the Optimal

In this work, we explicitly consider the evolution of the Standard Genetic Code (SGC) by assuming two evolutionary stages, to wit, the primeval RNY code and two intermediate codes in between. We used network theory and graph theory to measure the connectivity of each phenotypic graph. The connectivity values are compared to the values of the codes under different randomization scenarios. An error-correcting optimal code is one in which the algebraic connectivity is minimized. We show that the SGC is optimal in regard to its robustness and error-tolerance when compared to all random codes under different assumptions.     

Genetic Hotels for the Standard Genetic Code: Evolutionary Analysis Based upon Novel Three-Dimensional Algebraic Models

Herein, we rigorously develop novel 3-dimensional algebraic models called Genetic Hotels of the Standard Genetic Code (SGC). We start by considering the primeval RNA genetic code which consists of the 16 codons of type RNY (purine-any base-pyrimidine). Using simple algebraic operations, we show how the RNA code could have evolved toward the current SGC via two different intermediate evolutionary stages called Extended RNA code type I and II. By rotations or translations of the subset RNY, we arrive at the SGC via the former (type I) or via the latter (type II), respectively. Biologically, the Extended RNA code type I, consists of all codons of the type RNY plus codons obtained by considering the RNA code but in the second (NYR type) and third (YRN type) reading frames. The Extended RNA code type II, comprises all codons of the type RNY plus codons that arise from transversions of the RNA code in the first (YNY type) and third (RNR) nucleotide bases. Since the dimensions of remarkable subsets of the Genetic Hotels are not necessarily integer numbers, we also introduce the concept of algebraic fractal dimension. A general decoding function which maps each codon to its corresponding amino acid or the stop signals is also derived. The Phenotypic Hotel of amino acids is also illustrated. The proposed evolutionary paths are discussed in terms of the existing theories of the evolution of the SGC. The adoption of 3-dimensional models of the Genetic and Phenotypic Hotels will facilitate the understanding of the biological properties of the SGC.     

A Robust Alternative to the Schemper–Henderson Estimator of Prediction Error

Summary In clinical applications, the prediction error of survival models has to be taken into consideration to assess the practical suitability of conclusions drawn from these models. Different approaches to evaluate the predictive performance of survival models have been suggested in the literature. In this article, we analyze the properties of the estimator of prediction error developed by Schemper and Henderson (2000 , Biometrics 56, 249–255), which quantifies the absolute distance between predicted and observed survival functions. We provide a formal proof that the estimator proposed by Schemper and Henderson is not robust against misspecification of the survival model, that is, the estimator will only be meaningful if the model family used for deriving predictions has been specified correctly. To remedy this problem, we construct a new estimator of the absolute distance between predicted and observed survival functions. We show that this modified Schemper–Henderson estimator is robust against model misspecification, allowing its practical application to a wide class of survival models. The properties of the Schemper–Henderson estimator and its new modification are illustrated by means of a simulation study and the analysis of two clinical data sets.     

The Contributions of Wobbling and Superwobbling to the Reading of the Genetic Code

Reduced bacterial genomes and most genomes of cell organelles (chloroplasts and mitochondria) do not encode the full set of 32 tRNA species required to read all triplets of the genetic code according to the conventional wobble rules. Superwobbling, in which a single tRNA species that contains a uridine in the wobble position of the anticodon reads an entire four-fold degenerate codon box, has been suggested as a possible mechanism for how tRNA sets can be reduced. However, the general feasibility of superwobbling and its efficiency in the various codon boxes have remained unknown. Here we report a complete experimental assessment of the decoding rules in a typical prokaryotic genetic system, the plastid genome. By constructing a large set of transplastomic knock-out mutants for pairs of isoaccepting tRNA species, we show that superwobbling occurs in all codon boxes where it is theoretically possible. Phenotypic characterization of the transplastomic mutant plants revealed that the efficiency of superwobbling varies in a codon box-dependent manner, but—contrary to previous suggestions—it is independent of the number of hydrogen bonds engaged in codon-anticodon interaction. Finally, our data provide experimental evidence of the minimum tRNA set comprising 25 tRNA species, a number lower than previously suggested. Our results demonstrate that all triplets with pyrimidines in third codon position are dually decoded: by a tRNA species utilizing standard base pairing or wobbling and by a second tRNA species employing superwobbling. This has important implications for the interpretation of the genetic code and will aid the construction of synthetic genomes with a minimum-size translational apparatus.