The Mutational Robustness of the Genetic Code and Codon Usage in Environmental Context: A Non-Extremophilic Preference?
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ABSTRACT:
SUBMITTER: Radvanyi A
PROVIDER: S-EPMC8398314 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundHow, and the extent to which, evolution acts on DNA and protein sequences to ensure mutational robustness and evolvability is a long-standing open question in the field of molecular evolution. We addressed this issue through the first structurome-scale computational investigation, in which we estimated the change in folding free energy upon all possible single-site mutations introduced in more than 20,000 protein structures, as well as through available experimental stability and fitness data.ResultsAt the amino acid level, we found the protein surface to be more robust against random mutations than the core, this difference being stronger for small proteins. The destabilizing and neutral mutations are more numerous in the core and on the surface, respectively, whereas the stabilizing mutations are about 4% in both regions. At the genetic code level, we observed smallest destabilization for mutations that are due to substitutions of base III in the codon, followed by base I, bases I+III, base II, and other multiple base substitutions. This ranking highly anticorrelates with the codon-anticodon mispairing frequency in the translation process. This suggests that the standard genetic code is optimized to limit the impact of random mutations, but even more so to limit translation errors. At the codon level, both the codon usage and the usage bias appear to optimize mutational robustness and translation accuracy, especially for surface residues.ConclusionOur results highlight the non-universality of mutational robustness and its multiscale dependence on protein features, the structure of the genetic code, and the codon usage. Our analyses and approach are strongly supported by available experimental mutagenesis data.
| S-EPMC7576759 | biostudies-literature
Project description:The mutational robustness of the genetic code is rarely discussed in the context of biological diversity, such as codon usage and related factors, often considered as independent of the actual organism's proteome. Here we put the living beings back to picture and use distortion as a metric of mutational robustness. Distortion estimates the expected severities of non-synonymous mutations measuring it by amino acid physicochemical properties and weighting for codon usage. Using the biological variance of codon frequencies, we interpret the mutational robustness of the standard genetic code with regards to their corresponding environments and genomic compositions (GC-content). Employing phylogenetic analyses, we show that coding fidelity in physicochemical properties can deteriorate with codon usages adapted to extreme environments and these putative effects are not the artefacts of phylogenetic bias. High temperature environments select for codon usages with decreased mutational robustness of hydrophobic, volumetric, and isoelectric properties. Selection at high saline concentrations also leads to reduced fidelity in polar and isoelectric patterns. These show that the genetic code performs best with mesophilic codon usages, strengthening the view that LUCA or its ancestors preferred lower temperature environments. Taxonomic implications, such as rooting the tree of life, are also discussed.
| S-EPMC8154912 | biostudies-literature
Project description:RNA viruses exist as dynamic and diverse populations shaped by constant mutation and selection. Yet little is known about how the mutant spectrum contributes to virus evolvability and pathogenesis. Because several codon choices are available for a given amino acid, a central question concerns whether viral sequences have evolved to optimize not only the protein coding consensus, but also the DNA/RNA sequences accessible through mutation. Here we directly test this hypothesis by comparing wild-type poliovirus to synthetic viruses carrying re-engineered capsid sequences with hundreds of synonymous mutations. Strikingly, such rewiring of the population's mutant network reduced its robustness and attenuated the virus in an animal model of infection. We conclude that the position of a virus in sequence space defines its mutant spectrum, evolutionary trajectory, and pathogenicity. This organizing principle for RNA virus populations confers tolerance to mutations and facilitates replication and spread within the dynamic host environment.
| S-EPMC3504468 | biostudies-literature
Project description:BackgroundSynonymous codons are used differentially in organisms from the three domains of life, a phenomenon referred to as codon usage bias. In addition, codon pair bias, particularly in the 3' codon context, has also been described in several organisms and is associated with the accuracy and rate of translation. An improved understanding of both types of bias is important for the optimization of heterologous protein expression, particularly in biotechnologically important organisms, such as the yeast Xanthophyllomyces dendrorhous, a promising bioresource for the carotenoid astaxanthin. Using genomic and transcriptomic data, the codon usage and codon context biases of X. dendrorhous open reading frames (ORFs) were analyzed to determine their expression levels, GC% and sequence lengths. X. dendrorhous totiviral ORFs were also included in these analyses.ResultsA total of 1,695 X. dendrorhous ORFs were identified through comparison with sequences in multiple databases, and the intron-exon structures of these sequences were determined. Although there were important expression variations among the ORFs under the studied conditions (different phases of growth and available carbon sources), most of these sequences were highly expressed under at least one of the analyzed conditions. Independent of the culture conditions, the highly expressed genes showed a strong bias in both codon usage and the 3' context, with a minor association with the GC% and no relationship to the sequence length. The codon usage and codon-pair bias of the totiviral ORFs were highly variable with no similarities to the host ORFs.ConclusionsThere is a direct relation between the level of gene expression and codon usage and 3' context bias in X. dendrorhous, which is more evident for ORFs that are expressed at the highest levels under the studied conditions. However, there is no direct relation between the totiviral ORF biases and the host ORFs.
| S-EPMC4404019 | biostudies-literature
Project description:The standard genetic code (SGC) is central to molecular biology and its origin and evolution is a fundamental problem in evolutionary biology, the elucidation of which promises to reveal much about the origins of life. In addition, we propose that study of its origin can also reveal some fundamental and generalizable insights into mechanisms of molecular evolution, utilizing concepts from complexity theory. The first is that beneficial traits may arise by non-adaptive processes, via a process of "neutral emergence". The structure of the SGC is optimized for the property of error minimization, which reduces the deleterious impact of point mutations. Via simulation, it can be shown that genetic codes with error minimization superior to the SGC can emerge in a neutral fashion simply by a process of genetic code expansion via tRNA and aminoacyl-tRNA synthetase duplication, whereby similar amino acids are added to codons related to that of the parent amino acid. This process of neutral emergence has implications beyond that of the genetic code, as it suggests that not all beneficial traits have arisen by the direct action of natural selection; we term these "pseudaptations", and discuss a range of potential examples. Secondly, consideration of genetic code deviations (codon reassignments) reveals that these are mostly associated with a reduction in proteome size. This code malleability implies the existence of a proteomic constraint on the genetic code, proportional to the size of the proteome (P), and that its reduction in size leads to an "unfreezing" of the codon - amino acid mapping that defines the genetic code, consistent with Crick's Frozen Accident theory. The concept of a proteomic constraint may be extended to propose a general informational constraint on genetic fidelity, which may be used to explain variously, differences in mutation rates in genomes with differing proteome sizes, differences in DNA repair capacity and genome GC content between organisms, a selective pressure in the evolution of sexual reproduction, and differences in translational fidelity. Lastly, the utility of the concept of an informational constraint to other diverse fields of research is explored.
| S-EPMC4500140 | biostudies-literature
Project description:Alternative synonymous codons are often used at unequal frequencies. Classically, studies of such codon usage bias (CUB) attempted to separate the impact of neutral from selective forces by assuming that deviations from a predicted neutral equilibrium capture selection. However, GC-biased gene conversion (gBGC) can also cause deviation from a neutral null. Alternatively, selection has been inferred from CUB in highly expressed genes, but the accuracy of this approach has not been extensively tested, and gBGC can interfere with such extrapolations (e.g., if expression and gene conversion rates covary). It is therefore critical to examine deviations from a mutational null in a species with no gBGC. To achieve this goal, we implement such an analysis in the highly AT rich genome of Dictyostelium discoideum, where we find no evidence of gBGC. We infer neutral CUB under mutational equilibrium to quantify "adaptive codon preference," a nontautologous genome wide quantitative measure of the relative selection strength driving CUB. We observe signatures of purifying selection consistent with selection favoring adaptive codon preference. Preferred codons are not GC rich, underscoring the independence from gBGC. Expression-associated "preference" largely matches adaptive codon preference but does not wholly capture the influence of selection shaping patterns across all genes, suggesting selective constraints associated specifically with high expression. We observe patterns consistent with effects on mRNA translation and stability shaping adaptive codon preference. Thus, our approach to quantifying adaptive codon preference provides a framework for inferring the sources of selection that shape CUB across different contexts within the genome.
| S-EPMC8321536 | biostudies-literature
Project description:Codon usage bias, where certain codons are used more frequently than their synonymous counterparts, is an interesting phenomenon influenced by three evolutionary forces: mutation, selection, and genetic drift. To better understand how these evolutionary forces affect codon usage bias, an extensive study to detect how codon usage patterns change across species is required. This study investigated 668 single-copy orthologous genes independently in 29 Drosophila species to determine how the codon usage patterns change with phylogenetic distance. We found a strong correlation between phylogenetic distance and codon usage bias and observed striking differences in codon preferences between the two subgenera Drosophila and Sophophora. As compared to the subgenus Sophophora, species of the subgenus Drosophila showed reduced codon usage bias and a reduced preference specifically for codons ending with C, except for codons with G in the second position. We found that codon usage patterns in all species were influenced by the nucleotides in the codon's 2nd and 3rd positions rather than the biochemical properties of the amino acids encoded. We detected a concordance between preferred codons and preferred dinucleotides (at positions 2 and 3 of codons). Furthermore, we observed an association between speciation, codon preferences, and dinucleotide preferences. Our study provides the foundation to understand how selection acts on dinucleotides to influence codon usage bias.
| S-EPMC8496323 | biostudies-literature
Project description:Analysis of genome-wide codon bias shows that only two parameters effectively differentiate the genome-wide codon bias of 100 eubacterial and archaeal organisms. The first parameter correlates with genome GC content, and the second parameter correlates with context-dependent nucleotide bias. Both of these parameters may be calculated from intergenic sequences. Therefore, genome-wide codon bias in eubacteria and archaea may be predicted from intergenic sequences that are not translated. When these two parameters are calculated for genes from nonmammalian eukaryotic organisms, genes from the same organism again have similar values, and genome-wide codon bias may also be predicted from intergenic sequences. In mammals, genes from the same organism are similar only in the second parameter, because GC content varies widely among isochores. Our results suggest that, in general, genome-wide codon bias is determined primarily by mutational processes that act throughout the genome, and only secondarily by selective forces acting on translated sequences.
| S-EPMC373487 | biostudies-literature
Project description:In each genome, synonymous codons are used with different frequencies; this general phenomenon is known as codon usage bias. It has been previously recognised that codon usage bias could affect the cellular fitness and might be associated with the ecology of microbial organisms. In this exploratory study, we investigated the relationship between codon usage bias, lifestyles (thermophiles vs. mesophiles; pathogenic vs. non-pathogenic; halophilic vs. non-halophilic; aerobic vs. anaerobic and facultative) and habitats (aquatic, terrestrial, host-associated, specialised, multiple) of 615 microbial organisms (544 bacteria and 71 archaea). Principal component analysis revealed that species with given phenotypic traits and living in similar environmental conditions have similar codon preferences, as represented by the relative synonymous codon usage (RSCU) index, and similar spectra of tRNA availability, as gauged by the tRNA gene copy number (tGCN). Moreover, by measuring the average tRNA adaptation index (tAI) for each genome, an index that can be associated with translational efficiency, we observed that organisms able to live in multiple habitats, including facultative organisms, mesophiles and pathogenic bacteria, are characterised by a reduced translational efficiency, consistently with their need to adapt to different environments. Our results show that synonymous codon choices might be under strong translational selection, which modulates the choice of the codons to differently match tRNA availability, depending on the organism's lifestyle needs. To our knowledge, this is the first large-scale study that examines the role of codon bias and translational efficiency in the adaptation of microbial organisms to the environment in which they live.
| S-EPMC8144148 | biostudies-literature
Project description:Codon usage bias is a universal feature of all genomes. Although codon usage has been shown to regulate mRNA and protein levels by influencing mRNA decay and transcription in eukaryotes, little or no genome-wide correlations between codon usage and mRNA levels are detected in mammalian cells, raising doubt on the significance of codon usage effect on gene expression. Here we show that gene-specific regulation reduces the genome-wide codon usage and mRNA correlations: Constitutively expressed genes exhibit much higher genome-wide correlations than differentially expressed genes from fungi to human cells. Using Drosophila S2 cells as a model system, we showed that the effect of codon usage on mRNA expression level is promoter-dependent. Regions downstream of the core promoters of differentially expressed genes can repress the codon usage effects on mRNA expression. An element in the Hsp70 promoter was identified to be necessary and sufficient for this inhibitory effect. The promoter-dependent codon usage effects on mRNA levels are regulated at the transcriptional level through modulation of histone modifications, nucleosome densities and premature termination. Together, our results demonstrate that promoters play a major role in determining whether codon usage influences gene expression and further establish the transcription-dependent codon usage effects on gene expression.
| S-EPMC7826287 | biostudies-literature