Are synonymous codons indeed synonymous?

2012 ◽  
Vol 3 (1) ◽  
pp. 21-28 ◽  
Author(s):  
Pál Venetianer
Keyword(s):  
Protein Synthesis ◽  
Synonymous Codon ◽  
Synonymous Mutations ◽  
Synonymous Codons ◽  
Two Factors ◽  
Trna Species ◽  
Frequency Of Occurence

AbstractIt has long been known that the distribution and frequency of occurence of synonymous codons can vary greatly among different species, and that the abundance of isoaccepting tRNA species could also be very different. The interaction of these two factors may influence the rate and efficiency of protein synthesis and therefore synonymous mutations might influence the fitness of the organism and cannot be treated generally as ‘neutral’ in an evolutionary sense. These general effects of synonymous mutations, and their possible role in evolution, have been discussed in several recent papers. This review, however, will only deal with the influence of synonymous codon replacements on the expression of individual genes. It will describe the possible mechanisms of such effects and will present examples demonstrating the existence and effects of each of these mechanisms.

scholarly journals Human Retrovirus Codon Usage from tRNA Point of View: Therapeutic Insights

2013 ◽  
Vol 7 ◽  
pp. BBI.S12093 ◽  
Author(s):  
Diego Frias ◽  
Joana P. Monteiro-Cunha ◽  
Aline C. Mota-Miranda ◽  
Vagner S. Fonseca ◽  
Tulio De Oliveira ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Codon Usage ◽  
Supply And Demand ◽  
Mrna Translation ◽  
Protein Translation ◽  
Point Of View ◽  
T Score ◽  
Synonymous Codons ◽  
Trna Species ◽  
Gene Data

The purpose of this study was to investigate the balance between transfer ribonucleic acid (tRNA) supply and demand in retrovirus-infected cells, seeking the best targets for antiretroviral therapy based on the hypothetical tRNA Inhibition Therapy (TRIT). Codon usage and tRNA gene data were retrieved from public databases. Based on logistic principles, a therapeutic score (T-score) was calculated for all sense codons, in each retrovirus-host system. Codons that are critical for viral protein translation, but not as critical for the host, have the highest T-score values. Theoretically, inactivating the cognate tRNA species should imply a severe reduction of the elongation rate during viral mRNA translation. We developed a method to predict tRNA species critical for retroviral protein synthesis. Four of the best TRIT targets in HIV-1 and HIV-2 encode Large Hydrophobic Residues (LHR), which have a central role in protein folding. One of them, codon CUA, is also a TRIT target in both HTLV-1 and HTLV-2. Therefore, a drug designed for inactivating or reducing the cytoplasmatic concentration of tRNA species with anticodon TAG could attenuate significantly both HIV and HTLV protein synthesis rates. Inversely, replacing codons ending in UA by synonymous codons should increase the expression, which is relevant for DNA vaccine design.

scholarly journals Presyncodon, a Web Server for Gene Design with the Evolutionary Information of the Expression Hosts

2018 ◽  
Vol 19 (12) ◽  
pp. 3872 ◽  
Author(s):  
Jian Tian ◽  
Qingbin Li ◽  
Xiaoyu Chu ◽  
Ningfeng Wu
Keyword(s):  
High Frequency ◽  
Synonymous Codon ◽  
Low Frequency ◽  
Synonymous Codon Usage ◽  
Codon Usage Pattern ◽  
Evolutionary Information ◽  
Specific Expression ◽  
Synonymous Codons ◽  
New Genes ◽  
And Function

In the natural host, most of the synonymous codons of a gene have been evolutionarily selected and related to protein expression and function. However, for the design of a new gene, most of the existing codon optimization tools select the high-frequency-usage codons and neglect the contribution of the low-frequency-usage codons (rare codons) to the expression of the target gene in the host. In this study, we developed the method Presyncodon, available in a web version, to predict the gene code from a protein sequence, using built-in evolutionary information on a specific expression host. The synonymous codon-usage pattern of a peptide was studied from three genomic datasets (Escherichia coli, Bacillus subtilis, and Saccharomyces cerevisiae). Machine-learning models were constructed to predict a selection of synonymous codons (low- or high-frequency-usage codon) in a gene. This method could be easily and efficiently used to design new genes from protein sequences for optimal expression in three expression hosts (E. coli, B. subtilis, and S. cerevisiae). Presyncodon is free to academic and noncommercial users; accessible at http://www.mobioinfor.cn/presyncodon_www/index.html.

scholarly journals Analysis of computational codon usage models and their association with translationally slow codons

2020 ◽  
Author(s):  
Gabriel Wright ◽  
Anabel Rodriguez ◽  
Jun Li ◽  
Patricia L. Clark ◽  
Tijana Milenković ◽  
...  
Keyword(s):  
Codon Usage ◽  
Computational Models ◽  
Selective Pressure ◽  
Synonymous Codon ◽  
Ground Truth ◽  
Protein Translation ◽  
Weak Correlation ◽  
Experimental Conditions ◽  
Synonymous Codons ◽  
Genome Wide

AbstractImproved computational modeling of protein translation rates, including better prediction of where translational slowdowns along an mRNA sequence may occur, is critical for understanding co-translational folding. Because codons within a synonymous codon group are translated at different rates, many computational translation models rely on analyzing synonymous codons. Some models rely on genome-wide codon usage bias (CUB), believing that globally rare and common codons are the most informative of slow and fast translation, respectively. Others use the CUB observed only in highly expressed genes, which should be under selective pressure to be translated efficiently (and whose CUB may therefore be more indicative of translation rates). No prior work has analyzed these models for their ability to predict translational slowdowns. Here, we evaluate five models for their association with slowly translated positions as denoted by two independent ribosome footprint (RFP) count experiments from S. cerevisiae, because RFP data is often considered as a “ground truth” for translation rates across mRNA sequences. We show that all five considered models strongly associate with the RFP data and therefore have potential for estimating translational slowdowns. However, we also show that there is a weak correlation between RFP counts for the same genes originating from independent experiments, even when their experimental conditions are similar. This raises concerns about the efficacy of using current RFP experimental data for estimating translation rates and highlights a potential advantage of using computational models to understand translation rates instead.

scholarly journals Parsing the synonymous mutations in the maize genome: isoaccepting mutations are more advantageous in regions with codon co-occurrence bias

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Duan Chu ◽  
Lai Wei
Keyword(s):  
Amino Acids ◽  
Natural Selection ◽  
Codon Bias ◽  
Synonymous Codon ◽  
Translation Efficiency ◽  
Maize Genome ◽  
Rna Seq ◽  
Synonymous Mutations ◽  
Coding Regions ◽  
The Relationship

Abstract Background Synonymous mutations do not change amino acids but do sometimes change the tRNAs (anticodons) that decode a particular codon. An isoaccepting codon is a synonymous codon that shares the same tRNA. If a mutated codon could base pair with the same anticodon as the original, the mutation is termed an isoaccepting mutation. An interesting but less-studied type of codon bias is codon co-occurrence bias. There is a trend to cluster the isoaccepting codons in the genome. The proposed advantage of codon co-occurrence bias is that the tRNA released from the ribosome E site could be quickly recharged and subsequently decode the following isoaccepting codons. This advantage would enhance translation efficiency. In plant species, whether there are signals of positive selection on isoaccepting mutations in the codon co-occurred regions has not been studied. Results We termed polymorphic mutations in coding regions using publicly available RNA-seq data in maize (Zea mays). Next, we classified all synonymous mutations into three categories according to the context, i.e., the relationship between the focal codon and the previous codon, as follows: isoaccepting, nonisoaccepting and nonsynonymous. We observed higher fractions of isoaccepting mutations in the isoaccepting context. If we looked at the minor allele frequency (MAF) spectrum, the isoaccepting mutations have a higher MAF in the isoaccepting context than that in other regions, and accordingly, the nonisoaccepting mutations have a higher MAF in the nonisoaccepting context. Conclusion Our results indicate that in regions with codon co-occurrence bias, natural selection maintains this pattern by suppressing the nonisoaccepting mutations. However, if the consecutive codons are nonisoaccepting, mutations tend to switch these codons to become isoaccepting. Our study demonstrates that the codon co-occurrence bias in the maize genome is selectively maintained by natural selection and that the advantage of this trend could potentially be the rapid recharging and reuse of tRNAs to increase translation efficiency.

scholarly journals The selection-mutation-drift theory of synonymous codon usage.

Genetics ◽  
1991 ◽  
Vol 129 (3) ◽  
pp. 897-907 ◽  
Author(s):  
M Bulmer
Keyword(s):  
Codon Usage ◽  
Genetic Model ◽  
Synonymous Codon ◽  
Growth Yield ◽  
Synonymous Codon Usage ◽  
Synonymous Codons ◽  
Drift Theory ◽  
Highly Expressed Genes ◽  
Unicellular Organisms ◽  
Selection For

Abstract It is argued that the bias in synonymous codon usage observed in unicellular organisms is due to a balance between the forces of selection and mutation in a finite population, with greater bias in highly expressed genes reflecting stronger selection for efficiency of translation. A population genetic model is developed taking into account population size and selective differences between synonymous codons. A biochemical model is then developed to predict the magnitude of selective differences between synonymous codons in unicellular organisms in which growth rate (or possibly growth yield) can be equated with fitness. Selection can arise from differences in either the speed or the accuracy of translation. A model for the effect of speed of translation on fitness is considered in detail, a similar model for accuracy more briefly. The model is successful in predicting a difference in the degree of bias at the beginning than in the rest of the gene under some circumstances, as observed in Escherichia coli, but grossly overestimates the amount of bias expected. Possible reasons for this discrepancy are discussed.

scholarly journals Selection on silent sites in the rodent H3 histone gene family.

Genetics ◽  
1994 ◽  
Vol 138 (1) ◽  
pp. 191-202
Author(s):  
R W DeBry ◽  
W F Marzluff
Keyword(s):  
Codon Usage ◽  
Gene Conversion ◽  
Base Composition ◽  
Large Scale ◽  
Synonymous Codon ◽  
Histone Genes ◽  
Flanking Sequence ◽  
Effective Population ◽  
Mutation Pressure ◽  
Synonymous Codons

Abstract Selection promoting differential use of synonymous codons has been shown for several unicellular organisms and for Drosophila, but not for mammals. Selection coefficients operating on synonymous codons are likely to be extremely small, so that a very large effective population size is required for selection to overcome the effects of drift. In mammals, codon-usage bias is believed to be determined exclusively by mutation pressure, with differences between genes due to large-scale variation in base composition around the genome. The replication-dependent histone genes are expressed at extremely high levels during periods of DNA synthesis, and thus are among the most likely mammalian genes to be affected by selection on synonymous codon usage. We suggest that the extremely biased pattern of codon usage in the H3 genes is determined in part by selection. Silent site G + C content is much higher than expected based on flanking sequence G + C content, compared to other rodent genes with similar silent site base composition but lower levels of expression. Dinucleotide-mediated mutation bias does affect codon usage, but the affect is limited to the choice between G and C in some fourfold degenerate codons. Gene conversion between the two clusters of histone genes has not been an important force in the evolution of the H3 genes, but gene conversion appears to have had some effect within the cluster on chromosome 13.

scholarly journals The evolutionary impacts of synonymous mutations

2021 ◽  
Author(s):  
Deepa Agashe
Keyword(s):  
Synonymous Codon ◽  
Analytical Framework ◽  
Synonymous Mutations ◽  
Fitness Effects ◽  
Distinct Category ◽  
Dramatic Shift ◽  
Evolutionary Consequences ◽  
New Mutations

During the 50 years since the genetic code was cracked, our understanding of the evolutionary consequences of synonymous mutations has undergone a dramatic shift. Synonymous codon changes were initially considered selectively neutral, and as such, exemplars of evolution via genetic drift. However, the pervasive and non-negligible fitness impacts of synonymous mutations are now clear across organisms. Despite the accumulated evidence, it remains challenging to incorporate the effects of synonymous changes in studies of selection, because the existing analytical framework was built with a focus on the fitness effects of nonsynonymous mutations. In this chapter, I trace the development of this topic and discuss the evidence that gradually transformed our thinking about the role of synonymous mutations in evolution. I suggest that our evolutionary framework should encompass the impacts of all mutations on various forms of information transmission. Folding synonymous mutations into a common distribution – rather than setting them apart as a distinct category – will allow a more complete and cohesive picture of the evolutionary consequences of new mutations.

scholarly journals A code within the genetic code: codon usage regulates co-translational protein folding

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Yi Liu
Keyword(s):  
Protein Folding ◽  
Codon Usage ◽  
Genetic Code ◽  
Synonymous Codon ◽  
Protein Structures ◽  
Translation Efficiency ◽  
Intrinsically Disordered ◽  
Synonymous Codons ◽  
Eukaryotic Organisms ◽  
And Function

Abstract The genetic code is degenerate, and most amino acids are encoded by two to six synonymous codons. Codon usage bias, the preference for certain synonymous codons, is a universal feature of all genomes examined. Synonymous codon mutations were previously thought to be silent; however, a growing body evidence now shows that codon usage regulates protein structure and gene expression through effects on co-translational protein folding, translation efficiency and accuracy, mRNA stability, and transcription. Codon usage regulates the speed of translation elongation, resulting in non-uniform ribosome decoding rates on mRNAs during translation that is adapted to co-translational protein folding process. Biochemical and genetic evidence demonstrate that codon usage plays an important role in regulating protein folding and function in both prokaryotic and eukaryotic organisms. Certain protein structural types are more sensitive than others to the effects of codon usage on protein folding, and predicted intrinsically disordered domains are more prone to misfolding caused by codon usage changes than other domain types. Bioinformatic analyses revealed that gene codon usage correlates with different protein structures in diverse organisms, indicating the existence of a codon usage code for co-translational protein folding. This review focuses on recent literature on the role and mechanism of codon usage in regulating translation kinetics and co-translational protein folding.

scholarly journals Three tRNAs on the ribosome slow translation elongation

2017 ◽  
Vol 114 (52) ◽  
pp. 13691-13696 ◽  
Author(s):  
Junhong Choi ◽  
Joseph D. Puglisi
Keyword(s):  
Protein Synthesis ◽  
Ionic Strength ◽  
Binding Sites ◽  
Elongation Factor ◽  
Transfer Rna ◽  
Dissociation Kinetics ◽  
Translation Elongation ◽  
Trna Species ◽  
Trna Binding

During protein synthesis, the ribosome simultaneously binds up to three different transfer RNA (tRNA) molecules. Among the three tRNA binding sites, the regulatory role of the exit (E) site, where deacylated tRNA spontaneously dissociates from the translational complex, has remained elusive. Here we use two donor–quencher pairs to observe and correlate both the conformation of ribosomes and tRNAs as well as tRNA occupancy. Our results reveal a partially rotated state of the ribosome wherein all three tRNA sites are occupied during translation elongation. The appearance and lifetime of this state depend on the E-site tRNA dissociation kinetics, which may vary among tRNA species and depends on temperature and ionic strength. The 3-tRNA partially rotated state is not a proper substrate for elongation factor G (EF-G), thus inhibiting translocation until the E-site tRNA dissociates. Our result presents two parallel kinetic pathways during translation elongation, underscoring the ability of E-site codons to modulate the dynamics of protein synthesis.

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