On origin of genetic code and tRNA before translation

Background  

Synthesis of proteins is based on the genetic code - a nearly universal assignment of codons to amino acids (aas). A major challenge to the understanding of the origins of this assignment is the archetypal "key-lock vs. frozen accident" dilemma. Here we re-examine this dilemma in light of 1) the fundamental veto on "foresight evolution", 2) modular structures of tRNAs and aminoacyl-tRNA synthetases, and 3) the updated library of aa-binding sites in RNA aptamers successfully selected in vitro for eight amino acids.     

A four-column theory for the origin of the genetic code: tracing the evolutionary pathways that gave rise to an optimized code

Background  

The arrangement of the amino acids in the genetic code is such that neighbouring codons are assigned to amino acids with similar physical properties. Hence, the effects of translational error are minimized with respect to randomly reshuffled codes. Further inspection reveals that it is amino acids in the same column of the code (i.e. same second base) that are similar, whereas those in the same row show no particular similarity. We propose a 'four-column' theory for the origin of the code that explains how the action of selection during the build-up of the code leads to a final code that has the observed properties.     

Evolution of the genetic code: partial optimization of a random code for robustness to translation error in a rugged fitness landscape

Background  

The standard genetic code table has a distinctly non-random structure, with similar amino acids often encoded by codons series that differ by a single nucleotide substitution, typically, in the third or the first position of the codon. It has been repeatedly argued that this structure of the code results from selective optimization for robustness to translation errors such that translational misreading has the minimal adverse effect. Indeed, it has been shown in several studies that the standard code is more robust than a substantial majority of random codes. However, it remains unclear how much evolution the standard code underwent, what is the level of optimization, and what is the likely starting point.     

Assessment of MIRD data for internal dosimetry using the GATE Monte Carlo code

GATE/GEANT is a Monte Carlo code dedicated to nuclear medicine that allows calculation of the dose to organs of voxel phantoms. On the other hand, MIRD is a well-developed system for estimation of the dose to human organs. In this study, results obtained from GATE/GEANT using Snyder phantom are compared to published MIRD data. For this, the mathematical Snyder phantom was discretized and converted to a digital phantom of 100 × 200 × 360 voxels. The activity was considered uniformly distributed within kidneys, liver, lungs, pancreas, spleen, and adrenals. The GATE/GEANT Monte Carlo code was used to calculate the dose to the organs of the phantom from mono-energetic photons of 10, 15, 20, 30, 50, 100, 200, 500, and 1000 keV. The dose was converted into specific absorbed fraction (SAF) and the results were compared to the corresponding published MIRD data. On average, there was a good correlation (r ²>0.99) between the two series of data. However, the GATE/GEANT data were on average −0.16 ± 6.22% lower than the corresponding MIRD data for self-absorption. Self-absorption in the lungs was considerably higher in the MIRD compared to the GATE/GEANT data, for photon energies of 10–20 keV. As for cross-irradiation to other organs, the GATE/GEANT data were on average +1.5 ± 8.1% higher than the MIRD data, for photon energies of 50–1000 keV. For photon energies of 10–30 keV, the relative difference was +7.5 ± 67%. It turned out that the agreement between the GATE/GEANT and the MIRD data depended upon absolute SAF values and photon energy. For 10–30 keV photons, where the absolute SAF values were small, the uncertainty was high and the effect of cross-section prominent, and there was no agreement between the GATE/GEANT results and the MIRD data. However, for photons of 50–1,000 keV, the bias was negligible and the agreement was acceptable.     

On malleability in the genetic code

To explain now-numerous cases of codon reassignment (departure from the “universal” code), we suggest a pathway in which the transformed codon is temporarily ambiguous. All the unusual tRNA activities required have been demonstrated. In addition, the repetitive use of certain reassignments, the phylogenetic distribution of reassignments, and the properties of present-day reassigned tRNAs are each consistent with evolution of the code via an ambiguous translational intermediate. Correspondence to: M. Yarns     

Simulated evolution applied to study the genetic code optimality using a model of codon reassignments

Background  

As the canonical code is not universal, different theories about its origin and organization have appeared. The optimization or level of adaptation of the canonical genetic code was measured taking into account the harmful consequences resulting from point mutations leading to the replacement of one amino acid for another. There are two basic theories to measure the level of optimization: the statistical approach, which compares the canonical genetic code with many randomly generated alternative ones, and the engineering approach, which compares the canonical code with the best possible alternative.     

Complex phylogenetic distribution of a non-canonical genetic code in green algae

Background  

A non-canonical nuclear genetic code, in which TAG and TAA have been reassigned from stop codons to glutamine, has evolved independently in several eukaryotic lineages, including the ulvophycean green algal orders Dasycladales and Cladophorales. To study the phylogenetic distribution of the standard and non-canonical genetic codes, we generated sequence data of a representative set of ulvophycean green algae and used a robust green algal phylogeny to evaluate different evolutionary scenarios that may account for the origin of the non-canonical code.     

A methanogen hosted the origin of the genetic code

A comparison is made between orthologous proteins from a methanogen (Methanopyrus kandleri) and from a non-methanogen (Pyrococcus abyssi) in order to determine the amino acid substitution pattern. This analysis makes it possible to establish which amino acids are significantly and asymmetrically utilised by these two organisms. A methanophily index (MI) based on this asymmetry makes it possible for any protein to be associated with a numerical value which, when calculated for the same orthologous protein from methanogenic and non-methanogenic organisms, turns out to have the power to discriminate between these two groups of organisms, even if only for about 20% of the analysed proteins. The MI can also be associated to the genetic code under the assumption that the frequency of synonymous codons specifying the amino acids in the genetic code also reflects the frequency with which amino acids appeared in ancestral proteins. Finally a t-test shows that the MI value associated to the genetic code is not different from the mean value of the MI deriving from methanogen proteins, but it differs from the mean MI of non-methanogen proteins. This might indicate that the genetic code evolved in a methanogenic ‘organism’.     

On the molecular mechanism of the evolution of genetic code alterations

Alterations to the standard genetic code have been found in both prokaryotes and eukaryotes. This finding demolished the central dogma of molecular biology, postulated by Crick in 1968, of an immutable and universal genetic code, and raised the question of how organisms survive genetic code alterations. Recent studies suggest that genetic code alterations are driven by selection using a mechanism that requires translational ambiguity. In C. albicans, the leucine CUG codon is decoded as serine through structural alterations of the translational machinery, in particular, of Ser-tRNA_CAG, which has dual identity and novel decoding properties. Here, we review the molecular mechanism of CUG reassignment, focusing on the structural change of the translational machinery and on the impact that such alteration had on the evolution of the Candida albicans genome. Published in Russian in Molekulyarnaya Biologiya, 2006, Vol. 40, No. 4, pp. 634–639. The text was submitted by the authors in English.     

Gene algebra from a genetic code algebraic structure

By considering two important factors involved in the codon-anticodon interactions, the hydrogen bond number and the chemical type of bases, a codon array of the genetic code table as an increasing code scale of interaction energies of amino acids in proteins was obtained. Next, in order to consecutively obtain all codons from the codon AAC, a sum operation has been introduced in the set of codons. The group obtained over the set of codons is isomorphic to the group (Z₆₄, +) of the integer module 64. On the Z₆₄-algebra of the set of 64^N codon sequences of length N, gene mutations are described by means of endomorphisms f:(Z₆₄)^N→(Z₆₄)^N. Endomorphisms and automorphisms helped us describe the gene mutation pathways. For instance, 77.7% mutations in 749 HIV protease gene sequences correspond to unique diagonal endomorphisms of the wild type strain HXB2. In particular, most of the reported mutations that confer drug resistance to the HIV protease gene correspond to diagonal automorphisms of the wild type. What is more, in the human beta-globin gene a similar situation appears where most of the single codon mutations correspond to automorphisms. Hence, in the analyses of molecular evolution process on the DNA sequence set of length N, the Z₆₄-algebra will help us explain the quantitative relationships between genes.     

The fourfold way of the genetic code

We describe a compact representation of the genetic code that factorizes the table in quartets. It represents a “least grammar” for the genetic language. It is justified by the Klein-4 group structure of RNA bases and codon doublets. The matrix of the outer product between the column-vector of bases and the corresponding row-vector V^T = (C G U A), considered as signal vectors, has a block structure consisting of the four cosets of the K × K group of base transformations acting on doublet AA. This matrix, translated into weak/strong (W/S) and purine/pyrimidine (R/Y) nucleotide classes, leads to a code table with mixed and unmixed families in separate regions. A basic difference between them is the non-commuting (R/Y) doublets: AC/CA, GU/UG. We describe the degeneracy in the canonical code and the systematic changes in deviant codes in terms of the divisors of 24, employing modulo multiplication groups. We illustrate binary sub-codes characterizing mutations in the quartets. We introduce a decision-tree to predict the mode of tRNA recognition corresponding to each codon, and compare our result with related findings by Jestin and Soulé [Jestin, J.-L., Soulé, C., 2007. Symmetries by base substitutions in the genetic code predict 2′ or 3′ aminoacylation of tRNAs. J. Theor. Biol. 247, 391–394], and the rearrangements of the table by Delarue [Delarue, M., 2007. An asymmetric underlying rule in the assignment of codons: possible clue to a quick early evolution of the genetic code via successive binary choices. RNA 13, 161–169] and Rodin and Rodin [Rodin, S.N., Rodin, A.S., 2008. On the origin of the genetic code: signatures of its primordial complementarity in tRNAs and aminoacyl-tRNA synthetases. Heredity 100, 341–355], respectively.     

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

Background  

The coevolution theory of the origin of the genetic code suggests that the genetic code is an imprint of the biosynthetic relationships between amino acids. However, this theory does not seem to attribute a role to the biosynthetic relationships between the earliest amino acids that evolved along the pathways of energetic metabolism. As a result, the coevolution theory is unable to clearly define the very earliest phases of genetic code origin. In order to remove this difficulty, I here suggest an extension of the coevolution theory that attributes a crucial role to the first amino acids that evolved along these biosynthetic pathways and to their biosynthetic relationships, even when defined by the non-amino acid molecules that are their precursors.     

Speculations on the evolution of the genetic code II

An evolutionary scheme is postulated in which a primitive code, involving only guanine and cytosine, would code for glycine (GG), alanine (GC), arginine (CG) and proline (CC). From each of these amino acids and their codons, there evolves a family of related amino acids as the code expands. The four families are: (1)alanine valine, leucine, isoleucine, phenylalanine, tyrosine, methionine and tryptophane; (2)proline, threonine and serine; (3)arginine, lysine, and histidine; (4)glycine, serine, cysteine, glutamic acid, glutamine, aspartic acid and asparagine. Except for the glycine relation to glutamic acid and aspartic acid, all amino acids are related by chemical similarities in their side chains. Glycine not having a side chain would permit a more complex set of substitutions.     

Dual-energy contrast-enhanced digital mammography: Glandular dose estimation using a Monte Carlo code and voxel phantom

PurposeTo estimate the mean glandular dose of contrast enhanced digital mammography, using the EGSnrc Monte Carlo code and female adult voxel phantom.MethodsAutomatic exposure control of full field digital mammography system was used for the selection of the X-ray spectrum and the exposure settings for dual energy imaging. Measurements of the air-kerma and of the half value layers were performed and a Monte Carlo simulation of the digital mammography system was used to compute the mean glandular dose, for breast phantoms of various thicknesses, glandularities and for different X-ray spectra (low and high energy).ResultsFor breast phantoms of 2.0–8.0 cm thick and 0.1–100% glandular fraction, CC view acquisition, from AEC settings, can result in a mean glandular dose of 0.450 ± 0.022 mGy −2.575 ± 0.033 mGy for low energy images and 0.061 ± 0.021 mGy – 0.232 ± 0.033 mGy for high energy images. In MLO view acquisition mean glandular dose values ranged between 0.488 ± 0.007 mGy – 2.080 ± 0.021 mGy for low energy images and 0.065 ± 0.012 mGy – 0.215 ± 0.010 mGy for high energy images.ConclusionThe low kV part of contrast enhanced digital mammography is the main contributor to total mean glandular breast dose. The results of this study can be used to provide an estimated mean glandular dose for individual cases.     

Origins of gene, genetic code, protein and life: comprehensive view of life systems from a GNC-SNS primitive genetic code hypothesis

We have investigated the origin of genes, the genetic code, proteins and life using six indices (hydropathy, α-helix, β-sheet and β-turn formabilities, acidic amino acid content and basic amino acid content) necessary for appropriate three-dimensional structure formation of globular proteins. From the analysis of microbial genes, we have concluded that newly-born genes are products of nonstop frames (NSF) on antisense strands of microbial GC-rich genes [GC-NSF(a)] and from SNS repeating sequences [(SNS)_n] similar to the GC-NSF(a) (S and N mean G or C and either of four bases, respectively). We have also proposed that the universal genetic code used by most organisms on the earth presently could be derived from a GNC-SNS primitive genetic code. We have further presented the [GADV]-protein world hypothesis of the origin of life as well as a hypothesis of protein production, suggesting that proteins were originally produced by random peptide formation of amino acids restricted in specific amino acid compositions termed as GNC-, SNS and GC-NSF(a)-0th order structures of proteins. The [GADV]-protein world hypothesis is primarily derived from the GNC-primitive genetic code hypothesis. It is also expected that basic properties of extant genes and proteins could be revealed by considerations based on the scenario with four stages This review is a modified English version of the paper, which was written in Japanese and published inViva Origino 2001 29 66–85.     

In silico aided metabolic engineering of <Emphasis Type="Italic">Streptomyces roseosporus</Emphasis> for daptomycin yield improvement

In silico metabolic network models are valuable tools for strain improvement with desired properties. In this work, based on the comparisons of each pathway flux under two different objective functions for the reconstructed metabolic network of Streptomyces roseosporus, three potential targets of zwf2 (code for glucose-6-phosphate hydrogenase), dptI (code for α-ketoglutarate methyltransferase), and dptJ (code for tryptophan oxygenase) were identified and selected for the genetic modifications. Overexpression of zwf2, dptI, and dptJ genes increased the daptomycin concentration up to 473.2, 452.5, and 489.1 mg/L, respectively. Furthermore, co-overexpression of three genes in series resulted in a 34.4% higher daptomycin concentration compared with the parental strain, which ascribed to the synergistic effect of the enzymes responsible for daptomycin biosynthesis. Finally, the engineered strain enhanced the yield of daptomycin up to 581.5 mg/L in the fed-batch culture, which was approximately 43.2% higher than that of the parental strain. These results demonstrated that the metabolic network based on in silico prediction would be accurate, reasonable, and practical for target gene identification and strain improvement.     

The mitochondrial genome structure of Xenoturbella bocki (phylum Xenoturbellida) is ancestral within the deuterostomes

Background  

Mitochondrial genome comparisons contribute in multiple ways when inferring animal relationships. As well as primary sequence data, rare genomic changes such as gene order, shared gene boundaries and genetic code changes, which are unlikely to have arisen through convergent evolution, are useful tools in resolving deep phylogenies. Xenoturbella bocki is a morphologically simple benthic marine worm recently found to belong among the deuterostomes. Here we present analyses comparing the Xenoturbella bocki mitochondrial gene order, genetic code and control region to those of other metazoan groups.     

An algebraic hypothesis about the primeval genetic code architecture

A plausible architecture of an ancient genetic code is derived from an extended base triplet vector space over the Galois field of the extended base alphabet {D, A, C, G, U}, where symbol D represents one or more hypothetical bases with unspecific pairings. We hypothesized that the high degeneration of a primeval genetic code with five bases and the gradual origin and improvement of a primeval DNA repair system could make possible the transition from ancient to modern genetic codes. Our results suggest that the Watson-Crick base pairing G ≡ C and A = U and the non-specific base pairing of the hypothetical ancestral base D used to define the sum and product operations are enough features to determine the coding constraints of the primeval and the modern genetic code, as well as, the transition from the former to the latter. Geometrical and algebraic properties of this vector space reveal that the present codon assignment of the standard genetic code could be induced from a primeval codon assignment. Besides, the Fourier spectrum of the extended DNA genome sequences derived from the multiple sequence alignment suggests that the called period-3 property of the present coding DNA sequences could also exist in the ancient coding DNA sequences. The phylogenetic analyses achieved with metrics defined in the N-dimensional vector space (B³)^N of DNA sequences and with the new evolutionary model presented here also suggest that an ancient DNA coding sequence with five or more bases does not contradict the expected evolutionary history.     

Development and evaluation of a location-specific wire code

The development of a wire code protocol based on a study of electrical installations in Melbourne, Australia, is described. Because of very significant differences between the Melbourne power distribution system and that used in Denver, Colorado, an approach different from that used by Wertheimer and Leeper was required. A combined practical and theoretical approach was used to determine a continuous exposure index, defined as a measure of the potential for exposure due to external electrical installations. The protocol was tested on a convenient sample of 41 homes in which the field was monitored over a 12 hour overnight period. A correlation of 0.85 (95% CI 0.74–0.92, P < .0001) was obtained between the measured time-weighted average and the wire coding exposure index. To assess the efficacy of the wiring configuration index, a computer simulation of a case-control study was then performed. It was concluded that, using the same basic reasoning of the Wertheimer and Leeper code, it is possible to develop a location-specific code that provides a good correlation with the residential time-weighted average and an acceptable degree of exposure misclassification. © 1994 Wiley-Liss, Inc.