Search

Hypothesizing that CpG codon dyads, formed by consecutive codons containing a cytosine-guanine pair (NNC-GNN), may play a crucial role in gene function, we conducted an extensive analysis to investigate their distribution and conservation within mammalian genes. Our findings reveal that genes characterized by a high density of CpG codon dyads are notably associated with homeobox domains and RNA polymerase II transcription factors. Conversely, genes exhibiting low CpG codon dyad density have links to DNA damage repair and mitosis. Importantly, our study identifies a re-markable increase in expressed genes that harbor CpG during embryonic development, suggesting their potential involvement in gene regulation at these developmental stages. These results under-score the functional significance of CpG codon dyads in DNA methylation and gene expression, fur-ther demonstrating the coevolution of consecutive codons and their contribution to codon usage bias. [ABSTRACT FROM AUTHOR]

Protein-coding DNA sequences can be translated into completely different amino acid sequences if the nucleotide triplets used are shifted by a non-triplet amount on the same DNA strand or by translating codons from the opposite strand. Such "alternative reading frames" of protein-coding genes are a major contributor to the evolution of novel protein products. Recent studies demonstrating this include examples across the three domains of cellular life and in viruses. These sequences increase the number of trials potentially available for the evolutionary invention of new genes and also have unusual properties which may facilitate gene origin. There is evidence that the structure of the standard genetic code contributes to the features and gene-likeness of some alternative frame sequences. These findings have important implications across diverse areas of molecular biology, including for genome annotation, structural biology, and evolutionary genomics. [ABSTRACT FROM AUTHOR]

The standard genetic code determines that in most species, including viruses, there are 20 amino acids that are coded by 61 codons, while the other three codons are stop triplets. Considering the whole proteome each species features its own amino acid frequencies, given the slow rate of change, closely related species display similar GC content and amino acids usage. In contrast, distantly related species display different amino acid frequencies. Furthermore, within certain multicellular species, as mammals, intragenomic differences in the usage of amino acids are evident. In this communication, we shall summarize some of the most prominent and well-established factors that determine the differences found in the amino acid usage, both across evolution and intragenomically. [ABSTRACT FROM AUTHOR]

The structure and function of human leucocyte antigen (HLA-A) is well known and is an extremely variable protein. From the public HLA-A database, we chose 26 high frequency HLA-A alleles (45% of sequenced alleles). Using five arbitrary references from these alleles, we analyzed synonymous mutations at the third codon position (sSNP3) and non-synonymous mutations (NSM). Both mutation types showed non-random locations of 29 sSNP3 codons and 71 NSM codons in the five reference lists. Most sSNP3 codons show identical mutation types with many mutations resulting from cytosine deamination. We proposed 23 ancestral parents of sSNP3 in five reference sequences using conserved parents in five unidirectional codons and 18 majority parents in reciprocal codons. These 23 proposed ancestral parents show exclusive codon usage of G3 or C3 parents located on both DNA strands that mutate to A3 or T3 variants mostly (76%) by cytosine deamination The sSNP3 and NSM show clear separation of the two variant types with most sSNP3 located in conserved areas in exons 2, 3 and 4, compared to most NSM appearing in two Variable Areas with no sSNP3 in the latter parts of exons 2 (α1) and 3 (α2). The Variable Areas contain NSM (polymorphic) residues at the center of the groove that bind the foreign peptide. We find distinctly different mutation patterns in NSM codons from those of sSNP3. Namely, G-C to A-T mutation frequency was much smaller, suggesting that evolutional pressures of deamination and other mechanisms applied to the two areas are significantly different. [ABSTRACT FROM AUTHOR]

Codon usage is the outcome of different evolutionary processes and can inform us about the conditions in which organisms live and evolve. Here, we present R_ENC', which is an improvement to the original S index developed by dos Reis et al. (2004). Our index is less sensitive to G+C content, which greatly affects synonymous codon usage in prokaryotes, making it better suited to detect selection acting on codon usage. We used R_ENC' to estimate the extent of selected codon usage bias in 1800 genomes representing 26 prokaryotic phyla. We found that Gammaproteobacteria, Betaproteobacteria, Actinobacteria, and Firmicutes are the phyla/subphyla showing more genomes with selected codon usage bias. In particular, we found that several lineages within Gammaproteobacteria and Firmicutes show a similar set of functional terms enriched in genes under selected codon usage bias, indicating convergent evolution. We also show that selected codon usage bias tends to evolve in genes coding for the translation machinery before other functional GO terms. Finally, we discuss the possibility to use R_ENC' to predict whether lineages evolved in copiotrophic or oligotrophic environments. [ABSTRACT FROM AUTHOR]

The Last Common Ancestor (LCA) is understood as a hypothetical population of organisms from which all extant living creatures are thought to have descended. Its biology and environment have been and continue to be the subject of discussions within the scientific community. Since the first bacterial genomes were obtained, multiple attempts to reconstruct the genetic content of the LCA have been made. In this review, we compare 10 of the most extensive reconstructions of the gene content possessed by the LCA as they relate to aspects of the translation machinery. Although each reconstruction has its own methodological biases and many disagree in the metabolic nature of the LCA all, to some extent, indicate that several components of the translation machinery are among the most conserved genetic elements. The datasets from each reconstruction clearly show that the LCA already had a largely complete translational system with a genetic code already in place and therefore was not a progenote. Among these features several ribosomal proteins, transcription factors like IF2, EF-G, and EF-Tu and both class I and class II aminoacyl tRNA synthetases were found in essentially all reconstructions. Due to the limitations of the various methodologies, some features such as the occurrence of rRNA posttranscriptional modified bases are not fully addressed. However, conserved as it is, non-universal ribosomal features found in various reconstructions indicate that LCA's translation machinery was still evolving, thereby acquiring the domain specific features in the process. Although progenotes from the pre-LCA likely no longer exist recent results obtained by unraveling the early history of the ribosome and other genetic processes can provide insight to the nature of the pre-LCA world., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Recent findings, in vitro and in silico, are strengthening the idea of a simpler, earlier stage of genetically encoded proteins which used amino acids produced by prebiotic chemistry. These findings motivate a re-examination of prior work which has identified unusual properties of the set of twenty amino acids found within the full genetic code, while leaving it unclear whether similar patterns also characterize the subset of prebiotically plausible amino acids. We have suggested previously that this ambiguity may result from the low number of amino acids recognized by the definition of prebiotic plausibility used for the analysis. Here, we test this hypothesis using significantly updated data for organic material detected within meteorites, which contain several coded and non-coded amino acids absent from prior studies. In addition to confirming the well-established idea that "late" arriving amino acids expanded the chemistry space encoded by genetic material, we find that a prebiotically plausible subset of coded amino acids generally emulates the patterns found in the full set of 20, namely an exceptionally broad and even distribution of volumes and an exceptionally even distribution of hydrophobicities (quantified as logP) over a narrow range. However, the strength of this pattern varies depending on both the size and composition the library used to create a background (null model) for a random alphabet, and the precise definition of exactly which amino acids were present in a simpler, earlier code. Findings support the idea that a small sample size of amino acids caused previous ambiguous results, and further improvements in meteorite analysis, and/or prebiotic simulations will further clarify the nature and extent of unusual properties. We discuss the case of sulfur-containing amino acids as a specific and clear example and conclude by reviewing the potential impact of better understanding the chemical "logic" of a smaller forerunner to the standard amino acid alphabet. [ABSTRACT FROM AUTHOR]

The evolutionary history of Class I aminoacyl-tRNA synthetases (aaRS) through the reconstruction of ancestral sequences is presented. From structural molecular modeling, we sought to understand its relationship with the acceptor arms and the tRNA anticodon loop, how this relationship was established, and the possible implications in determining the genetic code and the translation system. The results of the molecular docking showed that in 7 out 9 aaRS, the acceptor arm and the anticodon loop bond practically in the same region. Domain accretion process in aaRS and repositioning of interactions between tRNAs and aaRS are illustrated. Based on these results, we propose that the operational code and the anticodon code coexisted, competing for the aaRS catalytic region, while consequently contributed to the stabilization of these proteins. [ABSTRACT FROM AUTHOR]

Since the genetic code is degenerate, several codons are translated to the same amino acid. Although these triplets were historically considered to be "synonymous" and therefore expected to be used at rather equal frequencies in all genomes, we now know that this is not the case. Indeed, since several coding sequences were obtained in the late '70s and early '80s in the last century, coming from either the same or different species, it was evident that (a) each genome, taken globally, displayed different codon usage patterns, which means that different genomes display a particular global codon usage table when all genes are considered together, and (b) there is a strong intragenomic diversity: in other words, within a given species the codon usage pattern can (and usually do) differ greatly among genes in the same genome. These different patterns were attributed to two main factors: first, the mutational bias characteristic of each genome, which determines that GC− poor species display a general bias towards A/T codons while the reverse is true for GC− rich species. Second, the differences in codon usage among genes from the same species are due to natural selection acting at the level of translation, in such a way that highly expressed genes tend to use codons that match with the most abundant isoacceptor tRNAs. Thus, these genes are translated at a highest rate, which in turn leads to avoid the limiting factor in translation which is the number of available ribosomes per cell. Although these explanations are still valid, new factors are almost constantly postulated to affect codon usage. In this mini review, we shall try to summarize them. [ABSTRACT FROM AUTHOR]

We use large-scale mutagenesis data and computer simulations to quantify the mutational robustness of protein-coding genes by taking into account constraints arising from protein function and the genetic code. Analyses of the distribution of amino acid substitutions from 18 mutagenesis studies revealed an average of 45% of neutral variants; while mutagenesis data of 12 proteins artificially designed under no other constraints but stability, reach an average of 60%. Simulations using a lattice protein model allow us to contrast these estimates to the expected mutational robustness of protein families by generating unbiased samples of foldable sequences, which we find to have 30% of neutral variants. In agreement with mutagenesis data of designed proteins, the model shows that maximally robust protein families might access up to twice the amount of neutral variants observed in the unbiased samples (i.e. 60%). A biophysical model of protein-ligand binding suggests that constraints associated to molecular function have only a moderate impact on robustness of approximately 5 to 10% of neutral variants; and that the direction of this effect depends on the relation between functional performance and thermodynamic stability. Although the genetic code constraints the access of a gene's nucleotide sequence to only 30% of the full distribution of amino acid mutations, it provides an extra 15 to 20% of neutral variants to the estimations above, such that the expected, observed, and maximal robustness of protein-coding genes are approximately 50, 65, and 75%, respectively. We discuss our results in the light of three main hypothesis put forward to explain the existence of mutationally robust genes. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that concatemers of ancestral tRNAs gave rise to the 16S ribosomal RNA. We built an ancestral sequence of proto-tRNAs that showed a significant identity of 51.69% and a percentage of structural identity of 0.941 with the 3′ upper domain of 16S ribosomal molecule. We also propose a hypothesis in which the small ribosomal subunit emerged by proto-tRNA fusion and worked as a point to bind RNAs in an open structure configuration. In this context, the two ribosomal subunits initially worked independently, and that the subunit junction, with consequent primitive ribosome formation, was mediated by interactions with tRNA molecules during the primordial genetic code formation. [ABSTRACT FROM AUTHOR]

Wobble coding is inevitable during evolution of the Standard Genetic Code (SGC). It ultimately splits half of NN U/C/A/G coding boxes with different assignments. Further, it contributes to pervasive SGC order by reinforcing close spacing for identical SGC assignments. But wobble cannot appear too soon, or it will inhibit encoding and more decisively, obstruct evolution of full coding tables. However, these prior results assumed Crick wobble, NN U/C and NN A/G, read by a single adaptor RNA. Superwobble translates NN U/C/A/G codons, using one adaptor RNA with an unmodified 5′ anticodon U (appropriate to earliest coding) in modern mitochondria, plastids, and mycoplasma. Assuming the SGC was selected when evolving codes most resembled it, characteristics of the critical selection events can be calculated. For example, continuous superwobble infrequently evolves SGC-like coding tables. So, continuous superwobble is a very improbable origin hypothesis. In contrast, late-arising superwobble shares late Crick wobble's frequent resemblance to SGC order. Thus late superwobble is possible, but yields SGC-like assignments less frequently than late Crick wobble. Ancient coding ambiguity, most simply, arose from Crick wobble alone. This is consistent with SGC assignments to NAN codons. [ABSTRACT FROM AUTHOR]

The Standard Genetic Code (SGC) exists in every known organism on Earth. SGC evolution via early unique codon assignment, then later wobble, yields coding resembling the near-universal code. Below, later wobble is shown to also create an optimal route to accurate codon assignment. Time of optimal codon assignment matches the previously defined mean time for ordered coding, exhibiting ≥ 90% of SGC order. Accurate evolution is also accessible, sufficiently frequent to appear in populations of 103 to 104 codes. SGC-like coding capacity, code order, and accurate assignments therefore arise together, in one attainable evolutionary intermediate. Examples, which plausibly resemble coding at evolutionary domain separation, are characterized. [ABSTRACT FROM AUTHOR]

A near-universal Standard Genetic Code (SGC) implies a single origin for present Earth life. To study this unique event, I compute paths to the SGC, comparing different plausible histories. Notably, SGC-like coding emerges from traditional evolutionary mechanisms, and a superior route can be identified. To objectively measure evolution, progress values from 0 (random coding) to 1 (SGC-like) are defined: these measure fractions of random-code-to-SGC distance. Progress types are spacing/distance/delta Polar Requirement, detecting space between identical assignments/mutational distance to the SGC/chemical order, respectively. The coding system is based on selected RNAs performing aminoacyl-RNA synthetase reactions. Acceptor RNAs exhibit SGC-like Crick wobble; alternatively, non-wobbling triplets uniquely encode 20 amino acids/start/stop. Triplets acquire 22 functions by stereochemistry, selection, coevolution, or at random. Assignments also propagate to an assigned triplet's neighborhood via single mutations, but can also decay. A vast code universe makes futile evolutionary paths plentiful. Thus, SGC evolution is critically sensitive to disorder from random assignments. Evolution also inevitably slows near coding completion. The SGC likely avoided these difficulties, and two suitable paths are compared. In late wobble, a majority of non-wobble assignments are made before wobble is adopted. In continuous wobble, a uniquely advantageous early intermediate yields an ordered SGC. Revised coding evolution (limited randomness, late wobble, concentration on amino acid encoding, chemically conservative coevolution with a chemically ordered elite) produces varied full codes with excellent joint progress values. A population of only 600 independent coding tables includes SGC-like members; a Bayesian path toward more accurate SGC evolution is available. [ABSTRACT FROM AUTHOR]

The natural circular code consists of 20 codons (X0) overrepresented in the coding frame of protein-coding genes as compared to remaining noncoding frames, and X1 and X2 (N1N2N3 → N3N1N2 and N1N2N3 → N2N3N1 permutations of X0, overrepresented in + 1 and − 1 frames of protein-coding genes, not self-complementary). X0, X1 and X2 detect ribosomal, + 1 and − 1 frames. X0 spontaneously emerges in the 25 theoretical minimal RNA rings, 22-nucleotide-long circular RNAs designed to code once for each of the genetic code's coding signals (a start, a stop and each of the 20 amino acids) by three overlapping frames. RNA rings presumed ancient are biased for X1, and bias for X0 increases in presumed recent RNA rings, indicating an evolutionary X1-to-X0 switch. Here, analyses explore biases for X0, X1 and X2 in non-redundant nucleotide tetra- and pentamers, for different genetic codes. Biases for X0 occur in non-redundant nucleotide pentamers and seem stronger in nuclear than mitochondrial genetic codes; tendencies are opposite for X1. Strand-asymmetric replication presumably causes mitogenomes to escape Chargaff's rule which expects ratios A/T = G/C = 1 in single-stranded sequences. Hence, presumably X1 emerged in ancient genetic codes used in single-stranded protogenomes/coding RNAs; the self-complementary X0 presumably evolved secondarily with double-stranded genomes and strand-symmetric replication. Results indicate that selection for non-redundant overlap coding in short nucleotide sequences produced the natural circular code. [ABSTRACT FROM AUTHOR]

The underlying structure of the canonical amino acid substitution matrix (aaSM) is examined by considering stepwise improvements in the differential recognition of amino acids according to their chemical properties during the branching history of the two aminoacyl-tRNA synthetase (aaRS) superfamilies. The evolutionary expansion of the genetic code is described by a simple parameterization of the aaSM, in which (i) the number of distinguishable amino acid types, (ii) the matrix dimension and (iii) the number of parameters, each increases by one for each bifurcation in an aaRS phylogeny. Parameterized matrices corresponding to trees in which the size of an amino acid sidechain is the only discernible property behind its categorization as a substrate, exclusively for a Class I or II aaRS, provide a significantly better fit to empirically determined aaSM than trees with random bifurcation patterns. A second split between polar and nonpolar amino acids in each Class effects a vastly greater further improvement. The earliest Class-separated epochs in the phylogenies of the aaRS reflect these enzymes' capability to distinguish tRNAs through the recognition of acceptor stem identity elements via the minor (Class I) and major (Class II) helical grooves, which is how the ancient operational code functioned. The advent of tRNA recognition using the anticodon loop supports the evolution of the optimal map of amino acid chemistry found in the later genetic code, an essentially digital categorization, in which polarity is the major functional property, compensating for the unrefined, haphazard differentiation of amino acids achieved by the operational code. [ABSTRACT FROM AUTHOR]

Theoretical minimal RNA rings were designed to mimick life's primordial RNAs by forming stem-loop hairpins and coding once for each of the 20 amino acids, a start and a stop codon. At most 25 22-nucleotide long RNA rings follow these criteria. These align well with a consensus tRNA sequence, predicting for each RNA ring an anticodon and an associated cognate amino acid. Hypotheses on cognate amino acid order of inclusion in the genetic code produce evolutionary ranks for theoretical RNA rings. This evolutionary hypothesis predicts that pieces of RNA rings with more ancient cognate amino acid should be more frequent in modern genes than those from RNA rings with late cognate amino acids. Analyses of genes for tRNA synthetases, among the most ancient proteins, from archaeal, bacterial, eukaryote and viral superkingdoms overall confirm these predictions, least for tRNA synthetases with early cognate amino acids and for the neogene-enriched genome of the giant virus Tupanvirus. Hence early tRNA synthetase genes and late RNA rings evolved separately. Results indicate that RNA rings and tRNA synthetases with the same cognate amino acid are less separated for relatively recent cognate amino acids, suggesting that over evolutionary time the components of the molecular apparatus became more integrated, perhaps in cell-like membrane-bound systems. Results confirm that theoretical considerations in the design of minimal RNA rings recreated RNAs close to the actual primordial RNA population that produce genes by accretion, and confirm the hypothesis of homology of minimal RNA rings with tRNAs and their proto-tRNA status. [ABSTRACT FROM AUTHOR]

The definition of a genomic signature (GS) is "the total net response to selective pressure". Recent isolation and sequencing of naturally occurring organisms, hereby named entoorganisms, within Acanthamoeba polyphaga, raised the hypothesis of a common genomic signature despite their diverse and unrelated evolutionary origin. Widely accepted and implemented tests for GS detection are oligonucleotide relative frequencies (OnRF) and relative codon usage (RCU) surveys. A common pattern and strong correlations were unveiled from OnRFs among A. polyphaga's Mimivirus and virophage Sputnik. RCU showed a common A-T bias at third codon position. We expanded tests to the amoebal mitochondrial genome and amoeba-resistant bacteria, achieving strikingly coherent results to the aforementioned viral analyses. The GSs in these entoorganisms of diverse evolutionary origin are coevolutionarily conserved within an intracellular environment that provides sanctuary for species of ecological and biomedical relevance. [ABSTRACT FROM AUTHOR]

Massey (J Mol Evol 67:510-516, 2008; J Theor Biol 408:237-242, 2016; Nat Comput. https://doi.org/10.1007/s11047-017-9669-3, 2018) claims that the error minimization of the genetic code is derived by means of a neutral process and was not due to the action of natural selection. Here, I argue that this neutralist hypothesis of the origin of error minimization is not based directly on any neutral process but it could be only indirectly. On the contrary, it has been natural selection that has acted during the origin of the genetic code determining the property that similar amino acids are coded by similar codons within the genetic code table. [ABSTRACT FROM AUTHOR]

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

The AdpA protein from a streptomycin producer Streptomyces griseus is a founding member of the AdpA family of pleiotropic regulators, known to be ubiquitously present in streptomycetes. Functional genomic approaches revealed a huge number of AdpA targets, leading to the claim that the AdpA regulon is the largest one in bacteria. The expression of adpA is limited at the level of translation of the rare leucyl UUA codon. All known properties of AdpA regulators were discovered on a few streptomycete strains. There are open questions about the true abundance and diversity of AdpA across actinobacterial taxa (and beyond) and about the possible evolutionary forces that shape the AdpA orthologous group in Streptomyces. Here we show that, with respect to the TTA codon, streptomycete adpA is more diverse than has been previously thought, as the genes differ in presence/position of this codon. Reciprocal best hits to AdpA can be found in many actinobacterial orders, with a domain organization resembling that of the prototypical AdpA, but other configurations also exist. Diversifying positive selection was detected within the DNA-binding (AraC) domain in adpA of Streptomyces origin, most likely affecting residues enabling AdpA to recognize a degenerate operator. Sequence coding for putative glutamine amidotransferase (GATase-1) domain also shows signs of positive selection. The two-domain organization of AdpA most likely arose from a fusion of genes encoding separate GATase-1 and AraC domains. Indeed, we show that the AraC domain retains a biological function in the absence of the GATase-1 part. We suggest that acquisition of the regulatory role by TTA codon is a relatively recent event in the evolution of AdpA, which coincided with the rise of the Streptomycetales clade and, at present, is under relaxed selective constraints. Further experimental scrutiny of our findings is invited, which should provide new insights into the evolution and prospects for engineering of an AdpA-centered regulatory network. [ABSTRACT FROM AUTHOR]

Since the elucidation of the genetic code almost 50 years ago, many nonrandom aspects of its codon organization remain only partly resolved. Here, we investigate the recent hypothesis of 'dual-use' codons which proposes that in addition to allowing adjustment of codon optimization to tRNA abundance, the degeneracy in the triplet-based genetic code also multiplexes information regarding DNA's helical shape and protein-binding dynamics while avoiding interference with other proteinlevel characteristics determined by amino acid properties. How such structural optimization of the code within eukaryotic chromatin could have arisen from an RNA world is a mystery, but would imply some preadaptation in an RNA context. We analyzed synonymous (protein-silent) and nonsynonymous (protein-altering) mutational impacts on molecular dynamics in 13823 identically degenerate alternative codon reorganizations, defined by codon transitions in 7680 GPU-accelerated molecular dynamic simulations of implicitly and explicitly solvated double-stranded aRNA and bDNA structures. When compared to all possible alternative codon assignments, the standard genetic code minimized the impact of synonymous mutations on the random atomic fluctuations and correlations of carbon backbone vector trajectories while facilitating the specific movements that contribute to DNA polymer flexibility. This trend was notably stronger in the context of RNA supporting the idea that dual-use codon optimization and informational multiplexing in DNA resulted from the preadaptation of the RNA duplex to resist changes to thermostability. The nonrandom and divergent molecular dynamics of synonymous mutations also imply that the triplet-based code may have resulted from adaptive functional expansion enabling a primordial doublet code to multiplex gene regulatory information via the shape and charge of the minor groove. [ABSTRACT FROM AUTHOR]

In a recent Letter, Di Giulio questions the use of the term 'neutral' when describing the process by which error minimization may have arisen as a side-product of genetic code expansion, resulting from the addition of similar amino acids to similar codons (Di Giulio, in J Mol Evol 86(9):593-597, 2018). However, I point out that in this scenario error minimization is non-adaptive, and so 'neutral' is an appropriate term to describe its imperviousness to direct selection. Error minimization is a form of mutational robustness, and so commonly viewed as beneficial. This in turn implies that not all beneficial traits may be adaptations generated by direct selection for that trait. [ABSTRACT FROM AUTHOR]

The coevolution theory of the origin of the genetic code maintains that the biosynthetic relationships between amino acids co-evolved with the genetic code organization. In other words, the metabolism of amino acids co-evolved with the organization of the genetic code because the biosynthetic pathways of amino acids occurred on tRNA-like molecules. Thus, a heterotrophic origin of amino acids-also only of those involved in the early phase of the structuring of the genetic code-would seem to contradict the main postulate of the coevolution theory. As a matter of fact, this origin not being linked to the metabolism of amino acids in any way-being taken from a physical setting-would seem to remove the possibility that this metabolism had instead heavily contributed to the structuring of the genetic code. Therefore, I have analyzed the structure of the genetic code and mechanisms that brought to its structuring for understanding if the coevolution theory is compatible with autotrophic or heterotrophic conditions. One of the arguments was that an autotrophic origin of amino acids would have the advantage to be able to directly link their metabolism to the structure of the genetic code if-as hypothesized by the coevolution theory-the biosyntheses of amino acids occurred on tRNA-like molecules. Simultaneously, a heterotrophic origin would not have been able to link the metabolism of amino acids to the structure of the genetic code for the absence of a precise determinism of allocation of amino acids, that is to say of a clear mechanism-linked to tRNA-like molecules, for example-that would have determined the specific pattern observed in the genetic code of the biosynthetic relationships between amino acids. The conclusion is that an autotrophic origin of coded amino acids would seem to be the condition under which the genetic code originated. [ABSTRACT FROM AUTHOR]

In Drosophila, many studies have examined the short- or long-term evolution occurring across synonymous sites. Few, however, have examined both the recent and long-term evolution to gain a complete view of this selection. Here we have analyzed Drosophila ananassae DNA polymorphism and divergence data using several different methods, and have identified evidence of positive selection favoring preferred codons in both recent and long-term evolutionary time scale. Further in D. ananassae, the strength of selection for preferred codons was stronger on the X chromosome compared to the autosomes. We show that this stronger selection is not due to higher gene expression of X-linked genes. Analysis of the selectively neutral introns indicated that the X chromosome also had a preference for GC over AT nucleotides, potentially from GC-biased gene conversions (gcBGCs) that can also affect the base composition of synonymous sites. Thus selection for preferred codons and gcBGC both seem to be partially responsible for shaping the D. ananassae synonymous site evolution. [ABSTRACT FROM AUTHOR]

Allopolyploidization induces a multiple processes of genomic reorganization, including the structurally functional diversification of the homoeologous genes. An example of such diversification is the appearance of the Lr34 gene on chromosome 7D of bread wheat T. aestivum (BAD), the gene conferring durable, race non-specific protection against three fungal pathogens. In this study, we focused on the variability of a functionally critical region between exons 10-12 of Lr34 among diploid progenitors of wheat genomes and their respective polyploids. In the diploid A-genome species, two basic forms of the studied region have been revealed: (1) non-functional forms containing stop codons, or/and frameshifts ( T. monococcum/T. urartu) and (2) forms with no such a mutations ( T. boeoticum). The Lr34 sequence of T. urartu containing a TGA stop codon was inherited by the first tetraploid T. dicoccoides (BA), and then reorganized in some accessions of this species due to the insertion of an LTR retroelement in exon 10. Besides T. boeoticum, the second form of the Lr34 sequence is also characteristic of A. speltoides, which presumably donated this form to all polyploid descendants bearing B-genome. No differences were found between the D-genome-specific Lr34 sequences studied here and downloaded from databases, implying the highest level of conservation of the Lr34 predecessor throughout evolution. The sequence data were later used to construct phylograms, and apparent peculiarities in the evolution of the studied region of Lr34 genes discussed. [ABSTRACT FROM AUTHOR]

The hypothesis of direct coding, assuming the direct contact of pairs of coding molecules with amino acid side chains in hollow unit cells (cellules) of a regular crystal-structure mineral is proposed. The coding nucleobase-containing molecules in each cellule (named ' lithocodon') partially shield each other; the remaining free space determines the stereochemical character of the filling side chain. Apatite-group minerals are considered as the most preferable for this type of coding (named ' lithocoding'). A scheme of the cellule with certain stereometric parameters, providing for the isomeric selection of contacting molecules is proposed. We modelled the filling of cellules with molecules involved in direct coding, with the possibility of coding by their single combination for a group of stereochemically similar amino acids. The regular ordered arrangement of cellules enables the polymerization of amino acids and nucleobase-containing molecules in the same direction (named ' lithotranslation') preventing the shift of coding. A table of the presumed ' LithoCode' (possible and optimal lithocodon assignments for abiogenically synthesized α-amino acids involved in lithocoding and lithotranslation) is proposed. The magmatic nature of the mineral, abiogenic synthesis of organic molecules and polymerization events are considered within the framework of the proposed 'volcanic scenario'. [ABSTRACT FROM AUTHOR]

Some mutations in gene coding regions exchange one synonymous codon for another, and thus do not alter the amino acid sequence of the encoded protein. Even though they are often called 'silent,' these mutations may exhibit a plethora of effects on the living cell. Therefore, they are often selected during evolution, causing synonymous codon usage biases in genomes. Comparative analyses of bacterial, archaeal, fungal, and human cancer genomes have found many links between a gene's biological role and the accrual of synonymous mutations during evolution. In particular, highly expressed genes in certain functional categories are enriched with optimal codons, which are decoded by the abundant tRNAs, thus enhancing the speed and accuracy of the translating ribosome. The set of genes exhibiting codon adaptation differs between genomes, and these differences show robust associations to organismal phenotypes. In addition to selection for translation efficiency, other distinct codon bias patterns have been found in: amino acid starvation genes, cyclically expressed genes, tissue-specific genes in animals and plants, oxidative stress response genes, cellular differentiation genes, and oncogenes. In addition, genomes of organisms harboring tRNA modifications exhibit particular codon preferences. The evolutionary trace of codon bias patterns across orthologous genes may be examined to learn about a gene's relevance to various phenotypes, or, more generally, its function in the cell. [ABSTRACT FROM AUTHOR]

I present a model for the evolution of the genetic code that seems to predict, in a totally natural way, the origin of the first mRNAs. In particular, the model-bestowing to peptidated-RNAs the major catalytic role in the phase that triggered the genetic code origin-suggests that interactions between peptidated-RNAs led to the synthesis of these ancestral catalysts. Within every group of these interactions, a pre-mRNA molecule evolved that was able to direct all interactions between peptidated-RNAs of that particular group. This represented an improvement in the coding of these interactions compared to the interaction groups that did not evolve these pre-mRNAs. This would represent a natural and intrinsic tendency. Therefore, these molecules of pre-mRNAs were positively selected because they improved the synthesis of the catalysts through this first form of coding of interactions among peptidated-RNAs. Thus, according to the model were the pairings-involving a base number greater than three (ennuplet code)-between peptidated-RNAs and pre-mRNAs that would represent the first form of the genetic code. The evolution of this ennuplet code to the triplet code might have been simply triggered by the natural tendency to make the reading module-that is the interactions between peptidated-RNAs and pre-mRNAs-of the different ennuplets to the triplet uniform, because in this way the heterogeneity existing in interactions between the aminoacylated or peptidated-RNAs and pre-mRNAs was eliminated. That is to say, there might have been the natural tendency toward the triplets because these would have made these interactions more efficient, given that the ennuplets were at least more cumbersome and therefore less economic and with an inferior adaptive value; and also because the triplets would represent the simpler choice among that available given that the doublets would have codified too few meanings and quartets instead too many. Therefore, the genetic code would result from a very long era of interactions among peptidated-RNAs under the continuous and fundamental selective pressure for improving catalysts' syntheses and thus catalysis. The model is strongly corroborated by the explanation that the tmRNA molecule (transfer-messenger RNA) would seem to be the very molecule of pre-mRNAs that the model predicts. In other words, the tmRNA would be the molecular fossil of the evolutionary stages that led to the appearance of the first mRNAs. [ABSTRACT FROM AUTHOR]

In the early 1970s, Manfred Eigen and colleagues developed the quasispecies model (qs) for the population-based origin of RNAs representing the early genetic code. The Eigen idea is basically that a halo of mutants is generated by error-prone replication around the master fittest type which will behave similarly as a biological population. But almost from the start, very interesting and unexpected observations were made regarding competition versus co-operation which suggested more complex interactions. It thus became increasingly clear that although viruses functioned similar to biological species, their behavior was much more complex than the original theory could explain, especially adaptation without changing the consensus involving minority populations. With respect to the origin of natural codes, meaning, and code-use in interactions (communication), it also became clear that individual fittest type-based mechanisms were likewise unable to explain the origin of natural codes such as the genetic code with their context- and consortia-dependence (pragmatic nature). This, instead, required the participation of groups of agents competent in the code and able to edit code because natural codes do not code themselves. Three lines of inquiry, experimental virology, quasispecies theory, and the study of natural codes converged to indicate that consortia of co-operative RNA agents such as viruses must be involved in the fitness of RNA and its involvement in communication, i.e., code-competent interactions. We called this co-operative form quasispecies consortia (qs-c). They are the essential agents that constitute the possibility of evolution of biological group identity. Finally, the basic interactional motifs for the emergence of group identity, communication, and co-operation-together with its opposing functions-are explained by the 'Gangen' hypothesis. [ABSTRACT FROM AUTHOR]

There have been two distinct phases of evolution of the genetic code: an ancient phase-prior to the divergence of the three domains of life, during which the standard genetic code was established-and a modern phase, in which many alternative codes have arisen in specific groups of genomes that differ only slightly from the standard code. Here we discuss the factors that are most important in these two phases, and we argue that these are substantially different. In the modern phase, changes are driven by chance events such as tRNA gene deletions and codon disappearance events. Selection acts as a barrier to prevent changes in the code. In contrast, in the ancient phase, selection for increased diversity of amino acids in the code can be a driving force for addition of new amino acids. The pathway of code evolution is constrained by avoiding disruption of genes that are already encoded by earlier versions of the code. The current arrangement of the standard code suggests that it evolved from a four-column code in which Gly, Ala, Asp, and Val were the earliest encoded amino acids. [ABSTRACT FROM AUTHOR]

The genetic code was likely complete in its current form by the time of the last universal common ancestor (LUCA). Several scenarios have been proposed for explaining the code's pre-LUCA emergence and expansion, and the relative order of the appearance of amino acids used in translation. One co-evolutionary model of genetic code expansion proposes that at least some amino acids were added to the code by the ancient divergence of aminoacyl-tRNA synthetase (aaRS) families. Of all the amino acids used within the genetic code, Trp is most frequently claimed as a relatively recent addition. We observe that, since TrpRS and TyrRS are paralogous protein families retaining significant sequence similarity, the inferred sequence composition of their ancestor can be used to evaluate this co-evolutionary model of genetic code expansion. We show that ancestral sequence reconstructions of the pre-LUCA paralog ancestor of TyrRS and TrpRS have several sites containing Tyr, yet a complete absence of sites containing Trp. This is consistent with the paralog ancestor being specific for the utilization of Tyr, with Trp being a subsequent addition to the genetic code facilitated by a process of aaRS divergence and neofunctionalization. Only after this divergence could Trp be specifically encoded and incorporated into proteins, including the TyrRS and TrpRS descendant lineages themselves. This early absence of Trp is observed under both homogeneous and non-homogeneous models of ancestral sequence reconstruction. Simulations support that this observed absence of Trp is unlikely to be due to chance or model bias. These results support that the final stages of genetic code evolution occurred well within the 'protein world,' and that the presence-absence of Trp within conserved sites of ancient protein domains is a likely measure of their relative antiquity, permitting the relative timing of extremely early events within protein evolution before LUCA. [ABSTRACT FROM AUTHOR]

An RNA World that predated the modern world of polypeptide and polynucleotide is one of the most widely accepted models in origin of life research. In this model, the translation system shepherded the RNA World into the extant biology of DNA, RNA, and protein. Here, we examine the RNA World Hypothesis in the context of increasingly detailed information available about the origins, evolution, functions, and mechanisms of the translation system. We conclude that the translation system presents critical challenges to RNA World Hypotheses. Firstly, a timeline of the RNA World is problematic when the ribosome is incorporated. The mechanism of peptidyl transfer of the ribosome appears distinct from evolved enzymes, signaling origins in a chemical rather than biological milieu. Secondly, we have no evidence that the basic biochemical toolset of life is subject to substantive change by Darwinian evolution, as required for the transition from the RNA world to extant biology. Thirdly, we do not see specific evidence for biological takeover of ribozyme function by protein enzymes. Finally, we can find no basis for preservation of the ribosome as ribozyme or the universality of translation, if it were the case that other information transducing ribozymes, such as ribozyme polymerases, were replaced by protein analogs and erased from the phylogenetic record. We suggest that an updated model of the RNA World should address the current state of knowledge of the translation system. [ABSTRACT FROM AUTHOR]

For most amino acids, more than one codon can be used. Many hypotheses have been put forward to account for patterns of uneven use of synonymous codons (codon usage bias) that most often have been indirectly tested primarily by analyses of patterns. Direct experimental tests of effects of synonymous codon usage are available for unicellular organisms, however empirical data addressing this problem in multicellular eukaryotes are sparse. We have developed a flexible transfecting plasmid that allows us to empirically test the effects of different codons on transcription and translation and present data from Drosophila. We could detect no significant effects of codon usage on transcription. With regard to translation, optimal codons (most used) produce higher levels of protein expression compared to non-optimal codons if the effect of difference in thermodynamic stability of secondary structure of the 5′ mRNA ribosome-binding site is controlled for. These results are consistent with what has been found in bacteria and thus expand the generality of these principles to multicellular eukaryotes. [ABSTRACT FROM AUTHOR]

Since the advent of rapid techniques for sequencing DNA in the mid 70's, it became clear that all codons coding for the same amino acid are not used according to neutral expectations. In the last 30 years, several theories were proposed for explaining this fact. However, the most important concepts were the result of analyses carried out in Bacteria, and unicellular and multicellular eukaryotes like mammals (in other words, in two of the three Domains of life). In this communication, we study the main forces that shape codon usage in Archaeae under an evolutionary perspective. This is important because, as known, the orthologous genes related with the informational system in this Domain (replication, transcription and translation) are more similar to eukaryotes than to Bacteria. Our results show that the effect of selection acting at the level of translation is present in the Domain but mainly restricted to only a phylum (Euryarchaeota) and therefore is not as extended as in Bacteria. Besides, we describe the phylogenetic distribution of translational optimal codons and estimate the effect of selection acting at the level of accuracy. Finally, we discuss these results under some peculiarities that characterize this Domain. [ABSTRACT FROM AUTHOR]

The phylogenetic analyses as far as the identification of the number of domains of life is concerned have not reached a clear conclusion. In the attempt to improve this circumstance, I introduce the concept that the amino acids codified in the genetic code might be of markers with outstanding phylogenetic power. In particular, I hypothesise the existence of a biosphere populated, for instance, by three groups of organisms having different genetic codes because codifying at least a different amino acid. Evidently, these amino acids would mark the proteins that are present in the three groups of organisms in an unambiguous way. Therefore, in essence, this mark would not be other than the one that we usually try to make in the phylogenetic analyses in which we transform the protein sequences in phylogenetic trees, for the purpose to identify, for example, the domains of life. Indeed, this mark would allow to classify proteins without performing phylogenetic analyses because proteins belonging to a group of organisms would be recognisable as marked in a natural way by at least a different amino acid among the diverse groups of organisms. This conceptualisation answers the question of how many fundamental kinds of cells have evolved from the Last Universal Common Ancestor (LUCA), as the genetic code has unique proprieties that make the codified amino acids excellent phylogenetic markers. The presence of the formyl-methionine only in proteins of bacteria would mark them and would identify these as domain of life. On the other hand, the presence of pyrrolysine in the genetic code of the euryarchaeota would identify them such as another fundamental kind of cell evolved from the LUCA. Overall, the phylogenetic distribution of formyl-methionine and pyrrolysine would identify at least two domains of life-Bacteria and Archaea-but their number might be actually four; that is to say, Bacteria, Euryarchaeota, archeobacteria that are not euryarchaeota and Eukarya. The usually accepted domains of life represented by Bacteria, Archaea and Eukarya are not compatible with the phylogenetic distribution of these two amino acids and therefore this last classification might be mistaken. [ABSTRACT FROM AUTHOR]

Proteins are elaborate biopolymers balancing between contradicting intrinsic propensities to fold, aggregate, or remain disordered. Assessing their primary structural preferences observable without evolutionary optimization has been reinforced by the recent identification of de novo proteins that have emerged from previously non-coding sequences. In this paper we investigate structural preferences of hypothetical proteins translated from random DNA segments using the standard genetic code and three of its proposed evolutionarily predecessor models encoding 10, 6, and 4 amino acids, respectively. Our only main assumption is that the disorder, aggregation, and transmembrane helix predictions used are able to reflect the differences in the trends of the protein sets investigated. We found that the 10-residue code encodes proteins that resemble modern proteins in their predicted structural properties. All of the investigated early genetic codes give rise to proteins with enhanced disorder and diminished aggregation propensities. Our results suggest that an ancestral genetic code similar to the proposed 10-residue one is capable of encoding functionally diverse proteins but these might have existed under conditions different from today's common physiological ones. The existence of a protein functional repertoire for the investigated earlier stages which is quite distinct as it is today can be deduced from the presented results. [ABSTRACT FROM AUTHOR]

The metallothionein (MT) gene superfamily consists of metal-binding proteins involved in various metal detoxification and storage mechanisms. The evolution of this gene family in vertebrates has mostly been studied in mammals using sparse taxon or gene sampling. Genomic databases and available data on MT protein function and expression allow a better understanding of the evolution and functional divergence of the different MT types. We recovered 77 MT coding sequences from 20 representative vertebrates with annotated complete genomes. We found multiple MT genes, also in reptiles, which were thought to have only one MT type. Phylogenetic and synteny analyses indicate the existence of a eutherian MT1 and MT2, a tetrapod MT3, an amniote MT4, and fish MT. The optimal gene-tree/species-tree reconciliation analyses identified the best root in the fish clade. Functional analyses reveal variation in hydropathic index among protein domains, likely correlated with their distinct flexibility and metal affinity. Analyses of functional divergence identified amino acid sites correlated with functional divergence among MT types. Uncovering the number of genes and sites possibly correlated with functional divergence will help to design cost-effective MT functional and gene expression studies. This will permit further understanding of the distinct roles and specificity of these proteins and to properly target specific MT for different types of functional studies. Therefore, this work presents a critical background on the molecular evolution and functional divergence of vertebrate MTs to carry out further detailed studies on the relationship between heavy metal metabolism and tolerances among vertebrates. [ABSTRACT FROM AUTHOR]

The fourfold degenerate site (FDS) in coding sequences is important for studying the effect of any selection pressure on codon usage bias (CUB) because nucleotide substitution per se is not under any such pressure at the site due to the unaltered amino acid sequence in a protein. We estimated the frequency variation of nucleotides at the FDS across the eight family boxes (FBs) defined as Um( g), the unevenness measure of a gene g. The study was made in 545 species of bacteria. In many bacteria, the Um( g) correlated strongly with Nc′-a measure of the CUB. Analysis of the strongly correlated bacteria revealed that the U-ending codons (GGU, CGU) were preferred to the G-ending codons (GGG, CGG) in Gly and Arg FBs even in the genomes with G+C % higher than 65.0. Further evidence suggested that these codons can be used as a good indicator of selection pressure on CUB in genomes with higher G+C %. [ABSTRACT FROM AUTHOR]

Similarities and differences between amino acids define the rates at which they substitute for one another within protein sequences and the patterns by which these sequences form protein structures. However, there exist many ways to measure similarity, whether one considers the molecular attributes of individual amino acids, the roles that they play within proteins, or some nuanced contribution of each. One popular approach to representing these relationships is to divide the 20 amino acids of the standard genetic code into groups, thereby forming a simplified amino acid alphabet. Here, we develop a method to compare or combine different simplified alphabets, and apply it to 34 simplified alphabets from the scientific literature. We use this method to show that while different suggestions vary and agree in non-intuitive ways, they combine to reveal a consensus view of amino acid similarity that is clearly rooted in physico-chemistry. [ABSTRACT FROM AUTHOR]