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The genetic code is nearly universal, and the arrangement of the codons in the standard codon table is highly non-random. The three main concepts on origin and evolution of the code are the stereochemical theory; the coevolution theory; and the error minimization theory. These theories are not mutually exclusive and are also compatible with the frozen accident hypothesis. Mathematical analysis of the structure and possible evolutionary trajectories of the code shows that it is highly robust to translational error but there is a huge number of more robust codes, so that the standard code potentially could evolve from a random code via a short sequence of codon series reassignments. Thus, much of the evolution that led to the standard code can be interpreted as a combination of frozen accident with selection for translational error minimization although contributions from coevolution of the code with metabolic pathways and/or weak affinities between amino acids and nucleotide triplets cannot be ruled out. However, such scenarios for the code evolution are based on formal schemes whose relevance to the actual primordial evolution is uncertain, so much caution in interpretation is necessary. A real understanding of the code's origin and evolution is likely to be attainable only in conjunction with a credible scenario for the evolution of the coding principle itself and the translation system.

Abstract The genetic code is based on an alphabet of four bases (A, U, C, G), organized into triplets called codons. By systematically analyzing the combinations at the levels of nucleotides, theoretical doublets, and triplets, and then applying a simple numerical transformation — —, I identified the recurrent emergence of specific constants (1, ≈96, 128). These values also appear at the atomic level for the constituent elements of DNA (C, H, O, N), suggesting that they do not result from chance, but from fundamental combinatorial constraints linked to the quaternary alphabet and the chemical composition of the bases. This points to the existence of multi-scale numerical invariants comparable to fractal patterns, without implying any direct biological function. The scientific interest of this discovery therefore does not lie in a new biological application, but in the perspective it opens: to consider the genetic code not only as a sequence of biochemical information, but also as a mathematical object. The poetic analogy is illuminating: a poem is generally studied for its meaning and emotions, but it also obeys formal rules (syllables, rhymes, meters). My approach seeks to unveil these invisible rules in the genome. As in a Sierpinski triangle, where a pattern repeats infinitely, the same constants (1, ≈96, 128) manifest at different scales, from the atom to the codon. This organization shows that the genetic code is not random: it is structured by universal arithmetic constraints. These invariants may represent the fundamental building blocks that guided its emergence and evolution. The multi-scale numerical invariants identified (1, ≈96, 128) suggest that the structure of the genetic code is not a purely contingent product of terrestrial evolution, but the result of combinatorial constraints imposed by the chemistry of the four main constituent elements of DNA (C, H, O, N). These elements possess fixed numbers of protons, neutrons, and electrons, which, when combined in nucleotide bases and then codons, generate universal arithmetic regularities. Thus, DNA can be interpreted not only as a biochemical support for information, but also as the logical consequence of the atomic combinatorics of CHON. This perspective opens a theoretical framework in which the genetic code appears as a quasi-necessary structure, whose organization derives directly from the fundamental properties of organic chemistry. It suggests that the emergence of DNA, or of a functionally analogous molecule, could be inevitable whenever life based on CHON appears, regardless of the geological or evolutionary context. In this sense, my work belongs to the field of theoretical biomathematics and bioinformatics: it does not aim to explain a new function, but to highlight the hidden elegance of the structure of life. This study extends a previous work ( The Mirror-Twin Paradox: A New Approach to DNA ), in which I proposed an inversion transformation (A↔G, C↔T) generating a “mirror genome” — a symmetry — tested on genetic databases. In both cases, the goal remains the same: to apply a systematic mathematical transformation to DNA in order to reveal structures invisible to a classical biological reading. Together, these approaches reinforce the idea that the genome possesses a universal internal organization, which can be revealed through operations of symmetry or numerical transformation. Exobiology and astrobiology: towards a numerical framework for the recognition of life One of the major contributions of this approach lies in its exobiological potential. Until now, the search for extraterrestrial life has relied mainly on two criteria: the detection of organic molecules (CHON) and the identification of metabolic signatures. Yet these criteria remain closely tied to terrestrial chemistry and risk missing forms of life based on other substrates. The identification of multi-scale numerical invariants (1, ≈96, 128), independent of biological function but emerging from simple atomic combinatorics, suggests the existence of a universal mathematical grammar intrinsic to the structuring of living information. These invariants, embedded in the logic of the quaternary alphabet and combinatorial rules, could thus serve as numerical markers of life, transcending local chemical contingencies. A remarkable point is that the codon table, when analyzed arithmetically before translation into amino acids, remains identical for the 33 genetic codes on Earth recorded by the NCBI. In other words, whatever biological variations are observed (codon reassignments), the underlying numerical structure does not change. This invariant character reinforces the idea that the genetic code can be interpreted as a stable mathematical matrix, independent of local evolutionary contingencies. In other words, even if a form of life did not rely strictly on DNA or on the known nucleotide bases, an organization based on comparable numerical invariants could reveal its biological nature. In this framework, the proposed approach provides a novel conceptual tool for thinking about the detection of living systems elsewhere in the universe: not only through the analysis of molecules, but through the search for recurrent and fractal numerical structures that would testify to an internal logic of life. In this sense, terrestrial DNA no longer appears as a historical contingency but as a particular realization of a more general principle: life, wherever it emerges, could be recognizable by its mathematical invariants, beyond its material substrate.

Requiring stability of genetic code against translation errors, modelised by suitable mathematical operators in the crystal basis model of the genetic code, the main features of the organisation in multiplets of the mitochondrial and of the standard genetic code are explained.

The importance of the notion of symmetry in physics is well established: could it also be the case for the genetic code? In this spirit, a model for the Genetic Code based on continuous symmetries and entitled the "Crystal Basis Model" has been proposed a few years ago. The present paper is a review of the model, of some of its first applications as well as of its recent developments. Indeed, after a motivated presentation of our mathematical model, we illustrate its pertinence by applying it for the elaboration and verification of sum rules for codon usage probabilities, as well as for establishing relations and some predictions between physical-chemical properties of amino-acids. Then, defining in this context a "bio-spin" structure for the nucleotides and codons, the interaction between a couple of codon-anticodon can simply be represented by a (bio) spin-spin potential. This approach will constitute the second part of the paper where, imposing the minimum energy principle, an analysis of the evolution of the genetic code can be performed with good agreement with the generally accepted scheme. A more precise study of this interaction model provides informations on codon bias, consistent with data.

Analysis of the conserved trace of tRNA molecules attributed to the last common ancestor, by phylogenetic techniques adapted to pre-divergence evolution, revealed that the genetic code contains domains of nearest-neighbor base triplets read by tRNA adaptors, descended from a common ancestor, that convey amino acids synthesized from a common precursor. This finding provides compelling evidence that tRNA molecules were cofactors in amino acid synthesis, in the era preceding the last common ancestor. This help make sense of the structure of the genetic code, especially regarding the source of its coding domains.

General Biology Lecture

The nature of the quantitative distribution of the 64 DNA codons in the human genome has been an issue of debate for over a decade. Some groups have proposed that the quantitative distribution of the DNA codons ordered as a rank-frequency plot follows a well-known power law called Zipf's law. Others have shown that the DNA codon distribution is best fitted to an exponential function. However, the reason for such scaling behavior has not yet been addressed. In the present study, we demonstrate that the nonlinearity of the DNA codon distribution is a direct consequence of the frequency recurrence of the codon usage (i.e., the repetitiveness of codon usage frequencies at the whole genome level). We discover that if frequency recurrence is absent from the human genome, the frequency of occurrence of codons scales linearly with the codon rank. We also show that DNA codons of both low and high frequency of occurrence in the genome are best fitted by an exponential function and provide strong evidence to suggest that the coding region of the human genome does not follow Zipf's law. Information-theoretic methods and entropy calculations are applied to the DNA codon distribution and a new approach, called the lariat method, is proposed to quantitatively analyze the DNA codon distribution in Homo sapiens.

New developments are presented in the framework of the model introduced by the authors in refs. [1,2] and in which nucleotides as well as codons are classified in crystal bases of the quantum group U_q(sl(2)+sl(2)) in the limit q -> 0. An operator which gives the correspondence between the amino-acids and the codons is now obtained for any known genetic code. The free energy released by base pairing of dinucleotides as well as the relative hydrophilicity and hydrophobicity of the dinucleosides are also computed. For the vertebrate series, a universal behaviour in the ratios of codon usage frequencies is put in evidence and is shown to fit nicely in our model. Then a first attempt to represent the mutations relative to the deletion of a pyrimidine by action of a suitable crystal spinor operator is proposed. Finally recent theoretical descriptions are reviewed and compared with our model.

A dynamical theory for the evolution of the genetic code is presented, which accounts for its universality and optimality. The central concept is that a variety of collective, but non-Darwinian, mechanisms likely to be present in early communal life generically lead to refinement and selection of innovation-sharing protocols, such as the genetic code. Our proposal is illustrated using a simplified computer model, and placed within the context of a sequence of transitions that early life may have made, prior to the emergence of vertical descent.

A dynamical theory for the evolution of the genetic code is presented, which accounts for its universality and optimality. The central concept is that a variety of collective, but non-Darwinian, mechanisms likely to be present in early communal life generically lead to refinement and selection of innovation-sharing protocols, such as the genetic code. Our proposal is illustrated using a simplified computer model, and placed within the context of a sequence of transitions that early life may have made, prior to the emergence of vertical descent.

General Biology Lecture

Dr. Frank Bryan will begin by defending an assertion: Vermont is unique, profoundly unique, in its status as a civil society.  Given this, he will seek to explore one causal sequence of variables that might explain why this is so. In so doing, he will present some new evidence of his own and comment on some of the literature that has proffered explanations of Vermont’s socio/political development such as Paul Searls’s impressive new interpretation of Vermont history,  Two Vermonts: Geography and Identity, 1865–1910  (2006). Dr. Bryan will end the seminar with a brief normative recommendation. Research-in-Progress Seminar #227

This article is from Frontiers in Genetics , volume 5 . Abstract The codon redundancy (“degeneracy”) found in protein-coding regions of mRNA also prescribes Translational Pausing (TP). When coupled with the appropriate interpreters, multiple meanings and functions are programmed into the same sequence of configurable switch-settings. This additional layer of Ontological Prescriptive Information (PIo) purposely slows or speeds up the translation-decoding process within the ribosome. Variable translation rates help prescribe functional folding of the nascent protein. Redundancy of the codon to amino acid mapping, therefore, is anything but superfluous or degenerate. Redundancy programming allows for simultaneous dual prescriptions of TP and amino acid assignments without cross-talk. This allows both functions to be coincident and realizable. We will demonstrate that the TP schema is a bona fide rule-based code, conforming to logical code-like properties. Second, we will demonstrate that this TP code is programmed into the supposedly degenerate redundancy of the codon table. We will show that algorithmic processes play a dominant role in the realization of this multi-dimensional code.

Chapter 12-3 The Genetic Code by MrBiology360

Degeneracy of the genetic code is a biological way to minimize effects of the undesirable mutation changes. Degeneration has a natural description on the 5-adic space of 64 codons $\mathcal{C}_5 (64) = \{n_0 + n_1 5 + n_2 5^2 : n_i = 1, 2, 3, 4 \} ,$ where $n_i$ are digits related to nucleotides as follows: C = 1, A = 2, T = U = 3, G = 4. The smallest 5-adic distance between codons joins them into 16 quadruplets, which under 2-adic distance decay into 32 doublets. p-Adically close codons are assigned to one of 20 amino acids, which are building blocks of proteins, or code termination of protein synthesis. We shown that genetic code multiplets are made of the p-adic nearest codons.

A model for the origin of protein synthesis. The essential features of the model are that 5'-AMP and perhaps other monoribonucleotides can serve as catalysts for the selective synthesis of L-based peptides. A unique set of characteristics of 5'-AMP is responsible for the selective catalysts and these characteristics are described in detail. The model involves the formation of diesters as intermediates and selectivity for use of the L-isomer occurs principally at the step of forming the diester. However, in the formation of acetyl phenylalanine-AMP monoester there is a selectivity for esterification by the D-isomer. Data showing this selectivity is presented. This selectivity for D-isomer disappears after the first step. The identity was confirmed of all four of possible diesters of acetyl-D- and -L phenylaline with 5'-AMP by nuclear magnetic resonance (NMR). The data using flourescence and NMR show the Trp ring can associate with the adenine ring more strongly when the D-isomer is in the 2' position than it can when in the 3' position. These same data also suggest a molecular mechanisim for the faster esterificaton of 5'-AMP by acetyl-D-phenylaline. Some new data is also presented on the possible structure of the 2' isomer of acetyl-D-tryptophan-AMP monoester. The HPLC elution times of all four possible acetyl diphenylalanine esters of 5'-AMP were studied, these peptidyl esters will be products in the studies of peptide formation on the ribose of 5'-AMP. Other studies were on the rate of synthesis and the identity of the product when producing 3'Ac-Phe-2'tBOC-Phe-AMP diester. HPLC purification and identification of this product were accomplished.

This article is from Genome Biology and Evolution , volume 6 . Abstract The 20 canonical amino acids of the genetic code have been invariant over 3 billion years of biological evolution. Although various aminoacyl-tRNA synthetases can charge their cognate tRNAs with amino acid analogs, there has been no known displacement of any canonical amino acid from the code. Experimental departure from this universal protein alphabet comprising the canonical amino acids was first achieved in the mutants of the Bacillus subtilis QB928 strain, which after serial selection and mutagenesis led to the HR23 strain that could use 4-fluorotryptophan (4FTrp) but not canonical tryptophan (Trp) for propagation. To gain insight into this displacement of Trp from the genetic code by 4FTrp, genome sequencing was performed on LC33 (a precursor strain of HR23), HR23, and TR7 (a revertant of HR23 that regained the capacity to propagate on Trp). Compared with QB928, the negative regulator mtrB of Trp transport was found to be knocked out in LC33, HR23, and TR7, and sigma factor sigB was mutated in HR23 and TR7. Moreover, rpoBC encoding RNA polymerase subunits were mutated in three independent isolates of TR7 relative to HR23. Increased expression of sigB was also observed in HR23 and in TR7 growing under 4FTrp. These findings indicated that stabilization of the genetic code can be provided by just a small number of analog-sensitive proteins, forming an oligogenic barrier that safeguards the canonical amino acids throughout biological evolution.

Although several synonymous codons can encode the same aminoacid, this symmetry is generally broken in natural genetic systems. In this article, we show that the symmetry breaking can result from selective pressures due to the violation of the synonym symmetry by mutation and recombination. We conjecture that this enhances the probability to produce mutants that are well-adapted to the current environment. Evidence is found in the codon frequencies of the HIV {\it env} protein: the codons most likely to mutate and lead to new viruses resistant to the current immunological attack, are found with a greater frequency than their less mutable synonyms.

The discovery of distinct domains within the genetic code established that the growth of tRNA-dependent amino acid synthesis pathways was central to code formation. This finding helped explain many seemingly unrelated features of code structure and provided an insight into how amino acids were identified in the RNA code, before appearance of amino acid recognizing proteins.

This article is from Nucleic Acids Research , volume 41 . Abstract An important goal of evolutionary biology is to understand the constraints that shape the dynamics and outcomes of evolution. Here, we address the extent to which the structure of the standard genetic code constrains evolution by analyzing adaptive mutations of the antibiotic resistance gene TEM-1 β-lactamase and the fitness distribution of codon substitutions in two influenza hemagglutinin inhibitor genes. We find that the architecture of the genetic code significantly constrains the adaptive exploration of sequence space. However, the constraints endow the code with two advantages: the ability to restrict access to amino acid mutations with a strong negative effect and, most remarkably, the ability to enrich for adaptive mutations. Our findings support the hypothesis that the standard genetic code was shaped by selective pressure to minimize the deleterious effects of mutation yet facilitate the evolution of proteins through imposing an adaptive mutation bias.

We propose a physical model to describe the mechanisms of two major scenarios of the genetic code evolution, the codon capture and ambiguous intermediate scenarios, in a consistent manner. We sketch the lowest dimensional version of our model, a minimal model, by introducing a physical quantity, codon level. On the basis of the hierarchical structure of the codon levels two scenarios are classified into two different routes of the evolutional process. In the case of the ambiguous intermediate scenario we perform a simulation implemented cost selection of amino acids and confirm a rapid transition of the code change. Such rapidness reduces uncomfortableness of the non-unique translation of the code at intermediate state that is the weakness of the scenario.

We propose a physical model to describe the mechanisms of two major scenarios of the genetic code evolution, the codon capture and ambiguous intermediate scenarios, in a consistent manner. We sketch the lowest dimensional version of our model, a minimal model, by introducing a physical quantity, codon level. On the basis of the hierarchical structure of the codon levels two scenarios are classified into two different routes of the evolutional process. In the case of the ambiguous intermediate scenario we perform a simulation implemented cost selection of amino acids and confirm a rapid transition of the code change. Such rapidness reduces uncomfortableness of the non-unique translation of the code at intermediate state that is the weakness of the scenario.

The Forbidden Genetic Code Combinations

Recent advances in genome editing have quickly turned ideas thought restricted to science fiction into reality such as custom synthetic organisms and designer babies. These technologies rely on the fidelity of the genetic code, which translates nucleotides into proteins. The underlying mechanism of translation is well understood where triplets of nucleotides, known as codons, are recognized by transfer RNAs with complementally nucleotide triplets. These transfer RNAs carry one of twenty amino acids which are then added to the growing protein chain by the ribosome. However, relatively little work has examined how a transfer RNA that recognizes a certain codon always carries the correct amino acid. The rules that determine which amino acid a transfer RNA carries have been termed the second genetic code. I have developed a computational method based on information theory that can elucidate the second genetic code from genomic sequences. Interestingly, the second genetic code is highly variable between organisms unlike the genetic code which is relatively static. I will present how my method cracks the second genetic code and how the variability of the second genetic code can be exploited to develop new treatments to combat bacterial infections and parasites, create targeted bio-controls to combat invasive species, and expand the genetic code to incorporate exotic amino acids. Source: https://www.youtube.com/watch?v=HgsY1yvoRdQ Uploader: DEFCONConference

Recent advances in genome editing have quickly turned ideas thought restricted to science fiction into reality such as custom synthetic organisms and designer babies. These technologies rely on the fidelity of the genetic code, which translates nucleotides into proteins. The underlying mechanism of translation is well understood where triplets of nucleotides, known as codons, are recognized by transfer RNAs with complementally nucleotide triplets. These transfer RNAs carry one of twenty amino acids which are then added to the growing protein chain by the ribosome. However, relatively little work has examined how a transfer RNA that recognizes a certain codon always carries the correct amino acid. The rules that determine which amino acid a transfer RNA carries have been termed the second genetic code. I have developed a computational method based on information theory that can elucidate the second genetic code from genomic sequences. Interestingly, the second genetic code is highly variable between organisms unlike the genetic code which is relatively static. I will present how my method cracks the second genetic code and how the variability of the second genetic code can be exploited to develop new treatments to combat bacterial infections and parasites, create targeted bio-controls to combat invasive species, and expand the genetic code to incorporate exotic amino acids. Source: https://www.youtube.com/watch?v=HgsY1yvoRdQ Uploader: DEFCONConference

The genetic code underlying protein synthesis is a canonical example of a degenerate biological system. Degeneracies in physical and biological systems can be lifted by external perturbations thus allowing degenerate systems to exhibit a wide range of behaviors. Here we show that the degeneracy of the genetic code is lifted by environmental perturbations to regulate protein levels in living cells. By measuring protein synthesis rates from a synthetic reporter library in Escherichia coli, we find that environmental perturbations, such as reduction of cognate amino acid supply, lift the degeneracy of the genetic code by splitting codon families into a hierarchy of robust and sensitive synonymous codons. Rates of protein synthesis associated with robust codons are up to hundred-fold higher than those associated with sensitive codons under these conditions. We find that the observed hierarchy between synonymous codons is not determined by usual rules associated with tRNA abundance and codon usage. Rather, competition among tRNA isoacceptors for aminoacylation underlies the robustness of protein synthesis. Remarkably, the hierarchy established using the synthetic library also explains the measured robustness of synthesis for endogenous proteins in E. coli. We further found that the same hierarchy is reflected in the fitness cost of synonymous mutations in amino acid biosynthesis genes and in the transcriptional control of sigma factor genes. Our study reveals that the degeneracy of the genetic code can be lifted by environmental perturbations, and it suggests that organisms can exploit degeneracy lifting as a general strategy to adapt protein synthesis to their environment.

We introduce the simple parametrization for the space of codons (triples of nucleotides) by 8\times 8 table. This table (which we call the dyadic plane) possesses the natural 2-adic ultrametric. We show that after this parametrization the genetic code will be a locally constant map of the simple form. The local constancy of this map will describe degeneracy of the genetic code. The map of the genetic code defines 2-adic ultrametric on the space of amino acids. We show that hydrophobic amino acids will be clustered in two balls with respect to this ultrametric. Therefore the introduced parametrization of space of codons exhibits the hidden regularity of the genetic code.

We introduce the simple parametrization for the space of codons (triples of nucleotides) by 8\times 8 table. This table (which we call the dyadic plane) possesses the natural 2-adic ultrametric. We show that after this parametrization the genetic code will be a locally constant map of the simple form. The local constancy of this map will describe degeneracy of the genetic code. The map of the genetic code defines 2-adic ultrametric on the space of amino acids. We show that hydrophobic amino acids will be clustered in two balls with respect to this ultrametric. Therefore the introduced parametrization of space of codons exhibits the hidden regularity of the genetic code.

We introduce the simple parametrization for the space of codons (triples of nucleotides) by 8\times 8 table. This table (which we call the dyadic plane) possesses the natural 2-adic ultrametric. We show that after this parametrization the genetic code will be a locally constant map of the simple form. The local constancy of this map will describe degeneracy of the genetic code. The map of the genetic code defines 2-adic ultrametric on the space of amino acids. We show that hydrophobic amino acids will be clustered in two balls with respect to this ultrametric. Therefore the introduced parametrization of space of codons exhibits the hidden regularity of the genetic code.

We introduce the simple parametrization for the space of codons (triples of nucleotides) by 8\times 8 table. This table (which we call the dyadic plane) possesses the natural 2-adic ultrametric. We show that after this parametrization the genetic code will be a locally constant map of the simple form. The local constancy of this map will describe degeneracy of the genetic code. The map of the genetic code defines 2-adic ultrametric on the space of amino acids. We show that hydrophobic amino acids will be clustered in two balls with respect to this ultrametric. Therefore the introduced parametrization of space of codons exhibits the hidden regularity of the genetic code.

Continuing our attempt to explain the degeneracy of the genetic code using basic classical Lie superalgebras, we present the branching schemes for the typical codon representations (typical 64-dimensional irreducible representations) of basic classical Lie superalgebras and find three schemes that do reproduce the degeneracies of the standard code, based on the orthosymplectic algebra osp(5|2) and differing only in details of the symmetry breaking pattern during the last step.

This article is from Computational and Structural Biotechnology Journal , volume 1 . Abstract The genetic code is said to be redundant in that the same amino acid residue can be encoded by multiple, so-called synonymous, codons. If all properties of synonymous codons were entirely equivalent, one would expect that they would be equally distributed along protein coding sequences. However, many studies over the last three decades have demonstrated that their distribution is not entirely random. It has been postulated that certain codons may be translated by the ribosome faster than others and thus their non-random distribution dictates how fast the ribosome moves along particular segments of the mRNA. The reasons behind such segmental variability in the rates of protein synthesis, and thus polypeptide emergence from the ribosome, have been explored by theoretical and experimental approaches. Predictions of the relative rates at which particular codons are translated and their impact on the nascent chain have not arrived at unequivocal conclusions. This is probably due, at least in part, to variation in the basis for classification of codons as “fast” or “slow”, as well as variability in the number and types of genes and proteins analyzed. Recent methodological advances have allowed nucleotide-resolution studies of ribosome residency times in entire transcriptomes, which confirm the non-uniform movement of ribosomes along mRNAs and shed light on the actual determinants of rate control. Moreover, experiments have begun to emerge that systematically examine the influence of variations in ribosomal movement and the fate of the emerging polypeptide chain.

This article is from Frontiers in Genetics , volume 5 . Abstract With rapid advances in sequencing technologies, we are undergoing a paradigm shift from hypothesis- to data-driven research. Genome-wide profiling efforts have given informative insights into biological processes; however, considering the wealth of variation, the major challenge still remains in their meaningful interpretation. In particular sequence variation in non-coding contexts is often challenging to interpret. Here, data integration approaches for the identification of functional genetic variability represent a possible solution. Exemplary, functional linkage analysis integrating genotype and expression data determined regulatory quantitative trait loci and proposed causal relationships. In addition to gene expression, epigenetic regulation and specifically DNA methylation was established as highly valuable surrogate mark for functional variance of the genetic code. Epigenetic modification has served as powerful mediator trait to elucidate mechanisms forming phenotypes in health and disease. Particularly, integrative studies of genetic and DNA methylation data have been able to guide interpretation strategies of risk genotypes, but also proved their value for physiological traits, such as natural human variation and aging. This Review seeks to illustrate the power of data integration in the genomic era exemplified by DNA methylation quantitative trait loci. However, the model is further extendable to virtually all traceable molecular traits.

This episode is also available as a blog post: https://aboriginalcreationlore.com/2021/06/25/earth-holds-the-genetic-code/

The ratios of the codon usage in the quartets and sextets for the vertebrate series exhibit a correlated behaviour which fits naturally in the framework of the crystal basis model of the genetic code. Moreover the observed universal behaviour of these suitably normalized ratios can be easily explained.

Modelising the translation errors by suitable mathematical operators in the crystal basis model of the genetic code and requiring that codons prone to be misread encode the same amino-acid, the main features of the organisation in multiplets of the genetic code are described.

A model for the origin of protein synthesis. The essential features of the model are that 5'-AMP and perhaps other monoribonucleotides can serve as catalysts for the selective synthesis of L-based peptides. A unique set of characteristics of 5'-AMP is responsible for the selective catalysts and these characteristics are described in detail. The model involves the formation of diesters as intermediates and selectivity for use of the L-isomer occurs principally at the step of forming the diester. However, in the formation of acetyl phenylalanine-AMP monoester there is a selectivity for esterification by the D-isomer. Data showing this selectivity is presented. This selectivity for D-isomer disappears after the first step. The identity was confirmed of all four of possible diesters of acetyl-D- and -L phenylaline with 5'-AMP by nuclear magnetic resonance (NMR). The data using flourescence and NMR show the Trp ring can associate with the adenine ring more strongly when the D-isomer is in the 2' position than it can when in the 3' position. These same data also suggest a molecular mechanisim for the faster esterificaton of 5'-AMP by acetyl-D-phenylaline. Some new data is also presented on the possible structure of the 2' isomer of acetyl-D-tryptophan-AMP monoester. The HPLC elution times of all four possible acetyl diphenylalanine esters of 5'-AMP were studied, these peptidyl esters will be products in the studies of peptide formation on the ribose of 5'-AMP. Other studies were on the rate of synthesis and the identity of the product when producing 3'Ac-Phe-2'tBOC-Phe-AMP diester. HPLC purification and identification of this product were accomplished.

Free α-carboxyl distribution in amino acid biosynthesis, genetic code domains,and pre-divergence tRNA phylogenetics conserve the imprint of tRNA-dependent amino acid synthesis pathways during code formation. Their dicarboxyl distribution is linked here to tRNA cofactor exchange credited with anomalies apparent in tRNA(leucine) and tRNA(arginine)coding specificity. Pre-species-divergence tRNA specific for amino acids synthesized from pyruvate, phosphoenolpyruvate, and phospho-glycerate exhibit elevated identity with tRNA(asparagine), consistent with oxaloacetate being an upstream precursor before the protein takeover of these pathways.

This article is from RNA Biology , volume 10 . Abstract Despite more than 50 years of effort, the origin of the genetic code remains enigmatic. Among different theories, the stereochemical hypothesis suggests that the code evolved as a consequence of direct interactions between amino acids and appropriate bases. If indeed true, such physicochemical foundation of the mRNA/protein relationship could also potentially lead to novel principles of protein-mRNA interactions in general. Inspired by this promise, we have recently explored the connection between the physicochemical properties of mRNAs and their cognate proteins at the proteome level. Using experimentally and computationally derived measures of solubility of amino acids in aqueous solutions of pyrimidine analogs together with knowledge-based interaction preferences of amino acids for different nucleobases, we have revealed a statistically significant matching between the composition of mRNA coding sequences and the base-binding preferences of their cognate protein sequences. Our findings provide strong support for the stereochemical hypothesis of genetic code’s origin and suggest the possibility of direct complementary interactions between mRNAs and cognate proteins even in present-day cells.

Listen to the full interview at the Solari Report - solari.com.

Amino acids from the same synthesis family are conveyed by related tRNA, cognate with nearest-neighbor codons, within a contiguous region of the genetic code, termed a domain. Its domain structure links genetic code formation with the growth of nascent tRNA-dependent amino acid synthesis pathways. Path-identity elements in these cofactor/adaptor tRNA molecules furnish a pre-synthetase RNA based mechanism for specifically pairing amino acids and their codons.

Amino acids from the same synthesis family are conveyed by related tRNA, cognate with nearest-neighbor codons, within a contiguous region of the genetic code, termed a domain. Its domain structure links genetic code formation with the growth of nascent tRNA-dependent amino acid synthesis pathways. Path-identity elements in these cofactor/adaptor tRNA molecules furnish a pre-synthetase RNA based mechanism for specifically pairing amino acids and their codons.

Replication of DNA and synthesis of proteins are studied from the view-point of quantum database search. Identification of a base-pairing with a quantum query gives a natural (and first ever) explanation of why living organisms have 4 nucleotide bases and 20 amino acids. It is amazing that these numbers arise as solutions to an optimisation problem. Components of the DNA structure which implement Grover's algorithm are identified, and a physical scenario is presented for the execution of the quantum algorithm. It is proposed that enzymes play a crucial role in maintaining quantum coherence of the process. Experimental tests that can verify this scenario are pointed out.

Broadening the versatility of lentiviral vectors as a tool in nucleic acid research via genetic code expansion 作者： Zheng, Yongxiang 1 Yu, Fei 1 Wu, Yiming 1 Si, Longlong 1 Xu, Huan 1 Zhang, Chuanling 1 Xia, Qing 1 Xiao, Sulong 1 Wang, Qi 1 He, Qiuchen 1 Taira, Kazunari 1 Zhang, Lihe 1 Zhou, Demin 1 Wang, Qi 2 Chen, Peng 3 Wang, Jiangyun 4 作者单位： 1. Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China. 2. Peking Univ, Dept Mol & Cellular Pharmacol, Sch Pharmaceut Sci, Beijing 100191, Peoples R China. 3. Peking Univ, Coll Chem & Mol Engn, Beijing 100871, Peoples R China. 4. Chinese Acad Sci, Inst Biophys, Beijing 100101, Peoples R China. 提交时间： 2016-05-12 摘要: With the aim of broadening the versatility of lentiviral vectors as a tool in nucleic acid research, we expanded the genetic code in the propagation of lentiviral vectors for site-specific incorporation of chemical moieties with unique properties. Through systematic exploration of the structure-function relationship of lentiviral VSVg envelope by site-specific mutagenesis and incorporation of residues displaying azide- and diazirine-moieties, the modifiable sites on the vector surface were identified, with most at the PH domain that neither affects the expression of envelope protein nor propagation or infectivity of the progeny virus. Furthermore, via the incorporation of such chemical moieties, a variety of fluorescence probes, ligands, PEG and other functional molecules are conjugated, orthogonally and stoichiometrically, to the lentiviral vector. Using this methodology, a facile platform is established that is useful for tracking virus movement, targeting gene delivery and detecting virus-host interactions. This study may provide a new direction for rational design of lentiviral vectors, with significant impact on both basic research and therapeutic applications. STOMATITIS-VIRUS GLYCOPROTEIN IMMUNODEFICIENCY-VIRUS INTEGRIN ALPHA(V)BETA(3) CELL-ADHESION THERAPY TRANSDUCTION RNAI PERSPECTIVES EXPRESSION TRACKING 期刊： NUCLEIC ACIDS RESEARCH 分类： 生物学 >> 生物物理学 >> 生物物理、生物化学与分子生物学 引用： ChinaXiv:201605.01533 (或此版本 ChinaXiv:201605.01533V1 ) doi:10.12074/201605.01533 CSTR:32003.36.ChinaXiv.201605.01533.V1 推荐引用方式： Zheng, Yongxiang,Yu, Fei,Wu, Yiming,Si, Longlong,Xu, Huan,Zhang, Chuanling,Xia, Qing,Xiao, Sulong,Wang, Qi,He, Qiuchen,Taira, Kazunari,Zhang, Lihe,Zhou, Demin,Wang, Qi,Chen, Peng,Wang, Jiangyun.(2016).Broadening the versatility of lentiviral vectors as a tool in nucleic acid research via genetic code expansion.NUCLEIC ACIDS RESEARCH.[ChinaXiv:201605.01533] 版本历史 [V1] 2016-05-12 08:40:41 ChinaXiv:201605.01533V1 下载全文

Abstract    The present discussion serves the emergence and explanation of significant theoretical novelties, which are related to the presence of the Wuhan virus. A search for fundamental and intangible relations has been enhanced through the explicitness of the functional state ˗ termini relations of the dimensions of Intention and Orientation . Their common causal determination has been treated as efficient definition of adaptation and consequently transformational fitness. Essential to fitness is the provision that the resulting energy landscapes take into account the deeply ingrained structural cores of the involved kinetic forces. Their autonomous treatment allows for the generative processing of sophisticated modifications. Besides alteration of kinematic differences, the capacity of the corresponding workspaces provide the ground for fusion and unification at the states were the forces converge into the global state attractors. However, the structural aspects of this change must be captured mentally through the naming of the resulting final states. Hence, what the critical meaning of the resulting energy landscapes exactly is has been made visible and communicated through the designation of the final and all-inclusive state termini, namely Samples destruction by Wuhan’s demand and the corresponding Virus tracking . Both are carrying the deep commonalty that biological mechanisms produce in their pattern evolution.

A quaternionic representation of the genetic code, previously reported by the authors, is updated in order to incorporate chirality of nucleotide bases and amino acids. The original representation assigns to each nucleotide base a prime integer quaternion of norm 7 and involves a function that associates with each codon, represented by three of these quaternions, another integer quaternion (amino acid type quaternion) in such a way that the essentials of the standard genetic code (particulaty its degeneration) are preserved. To show the advantages of such a quaternionic representation we have, in turn, associated with each amino acid of a given protein, besides of the type quaternion, another real one according to its order along the protein (order quaternion) and have designed an algorithm to go from the primary to the tertiary structure of the protein by using type and order quaternions. In this context, we incorporate chirality in our representation by observing that the set of eight integer quaternions of norm 7 can be partitioned into a pair of subsets of cardinality four each with their elements mutually conjugates and by putting they in correspondence one to one with the two sets of enantiomers (D and L) of the four nucleotide bases adenine, cytosine, guanine and uracil, respectively. Thus, guided by two diagrams proposed for the codes evolution, we define functions that in each case assign a L- (D-) amino acid type integer quaternion to the triplets of D- (L-) bases. The assignation is such that for a given D-amino acid, the associated integer quaternion is the conjugate of that one corresponding to the enantiomer L. The chiral type quaternions obtained for the amino acids are used, together with a common set of order quaternions, to describe the folding of the two classes, L and D, of homochiral proteins.

A representation of the genetic code as a six-dimensional Boolean hypercube is proposed. It is assumed here that this structure is the result of the hierarchical order of the interaction energies of the bases in codon-anticodon recognition. The proposed structure demonstrates that in the genetic code there is a balance between conservatism and innovation. Comparing aligned positions in homologous protein sequences two different behaviors are found: a) There are sites in which the different amino acids present may be explained by one or two "attractor nodes" (coding for the dominating amino acid(s)) and their one-bit neighbors in the codon hypercube, and b) There are sites in which the amino acids present correspond to codons located in closed paths in the hypercube. The structure of the code facilitates evolution: the variation found at the variable positions of proteins do not corresponds to random jumps at the codon level, but to well defined regions of the hypercube.

The previously formulated model for the evolution of the genetic code was shown to clarify why base triplets of some precursor amino acids differ by a single base from product amino acid codons, while others show less homology. First, the model indicated that the direction of code evolution changed on expansion from the N-fixers code (stage 2). Growth of the code from 16 codons in the NAN column (N, any standard nucleotide) proceeded by assignment of codons in the GNN, ANN, CNN and UNN rows. Expansion phase (stage 4 to 7) precursor/product pairs that spanned this shift included aspartate/threonine, aspartate/methionine and glutamate/proline. Both 5' and mid-base differ in the codons of each of these pairs. Second, post-expansion additions (stage 9 to 14) required codon reassignment, eliminating initial correlations. Codons for the post-expansion pair, aspartate (glutamate)/arginine, also differ at both 5' and mid-base sites. Third, the distribution of core structure groups among acceptors indicated that variant tRNA specific for a sibling, rather than precursor, commonly participated as cofactors in early amino acid synthesis. Sibling pairs, rather than precursor/product pairs, then exhibit codon correlations. On removing these sources of variation, highly significant correlations emerged between codons assigned to biosynthetically related amino acids.

How robust is the natural genetic code with respect to mistranslation errors? It has long been known that the genetic code is very efficient in limiting the effect of point mutation. A misread codon will commonly code either for the same amino acid or for a similar one in terms of its biochemical properties, so the structure and function of the coded protein remain relatively unaltered. Previous studies have attempted to address this question more quantitatively, namely by statistically estimating the fraction of randomly generated codes that do better than the genetic code regarding its overall robustness. In this paper, we extend these results by investigating the role of amino acid frequencies in the optimality of the genetic code. When measuring the relative fitness of the natural code with respect to a random code, it is indeed natural to assume that a translation error affecting a frequent amino acid is less favorable than that of a rare one, at equal mutation cost. We find that taking the amino acid frequency into account accordingly decreases the fraction of random codes that beat the natural code, making the latter comparatively even more robust. This effect is particularly pronounced when more refined measures of the amino acid substitution cost are used than hydrophobicity. To show this, we devise a new cost function by evaluating with computer experiments the change in folding free energy caused by all possible single-site mutations in a set of known protein structures. With this cost function, we estimate that of the order of one random code out of 100 millions is more fit than the natural code when taking amino acid frequencies into account. The genetic code seems therefore structured so as to minimize the consequences of translation errors on the 3D structure and stability of proteins.

How robust is the natural genetic code with respect to mistranslation errors? It has long been known that the genetic code is very efficient in limiting the effect of point mutation. A misread codon will commonly code either for the same amino acid or for a similar one in terms of its biochemical properties, so the structure and function of the coded protein remain relatively unaltered. Previous studies have attempted to address this question more quantitatively, namely by statistically estimating the fraction of randomly generated codes that do better than the genetic code regarding its overall robustness. In this paper, we extend these results by investigating the role of amino acid frequencies in the optimality of the genetic code. When measuring the relative fitness of the natural code with respect to a random code, it is indeed natural to assume that a translation error affecting a frequent amino acid is less favorable than that of a rare one, at equal mutation cost. We find that taking the amino acid frequency into account accordingly decreases the fraction of random codes that beat the natural code, making the latter comparatively even more robust. This effect is particularly pronounced when more refined measures of the amino acid substitution cost are used than hydrophobicity. To show this, we devise a new cost function by evaluating with computer experiments the change in folding free energy caused by all possible single-site mutations in a set of known protein structures. With this cost function, we estimate that of the order of one random code out of 100 millions is more fit than the natural code when taking amino acid frequencies into account. The genetic code seems therefore structured so as to minimize the consequences of translation errors on the 3D structure and stability of proteins.