In Vivo Introduction of Unpreferred Synonymous Codons Into the Drosophila Adh Gene Results in Reduced Levels of ADH Protein

Genetics ◽  
2003 ◽  
Vol 163 (1) ◽  
pp. 239-243 ◽  
Author(s):  
David B Carlini ◽  
Wolfgang Stephan
Keyword(s):  
Natural Selection ◽  
Codon Bias ◽  
Protein Production ◽  
Empirical Relationship ◽  
Abundant Species ◽  
Translational Efficiency ◽  
Synonymous Mutations ◽  
Synonymous Codons ◽  
Synonymous Sites

Abstract The evolution of codon bias, the unequal usage of synonymous codons, is thought to be due to natural selection for the use of preferred codons that match the most abundant species of isoaccepting tRNA, resulting in increased translational efficiency and accuracy. We examined this hypothesis by introducing 1, 6, and 10 unpreferred codons into the Drosophila alcohol dehydrogenase gene (Adh). We observed a significant decrease in ADH protein production with number of unpreferred codons, confirming the importance of natural selection as a mechanism leading to codon bias. We then used this empirical relationship to estimate the selection coefficient (s) against unpreferred synonymous mutations and found the value (s ≥ 10-5) to be approximately one order of magnitude greater than previous estimates from population genetics theory. The observed differences in protein production appear to be too large to be consistent with current estimates of the strength of selection on synonymous sites in D. melanogaster.

scholarly journals Natural Selection on Synonymous Sites Is Correlated With Gene Length and Recombination in Drosophila

Genetics ◽  
1999 ◽  
Vol 151 (1) ◽  
pp. 239-249 ◽  
Author(s):  
Josep M Comeron ◽  
Martin Kreitman ◽  
Montserrat Aguadé
Keyword(s):  
Natural Selection ◽  
Codon Bias ◽  
Synonymous Substitution ◽  
Small Scale ◽  
Evolutionary Analysis ◽  
Coding Region ◽  
Weak Selection ◽  
Recombination Rates ◽  
Synonymous Mutations ◽  
Synonymous Sites

AbstractEvolutionary analysis of codon bias in Drosophila indicates that synonymous mutations are not neutral, but rather are subject to weak selection at the translation level. Here we show that the effectiveness of natural selection on synonymous sites is strongly correlated with the rate of recombination, in accord with the nearly neutral hypothesis. This correlation, however, is apparent only in genes encoding short proteins. Long coding regions have both a lower codon bias and higher synonymous substitution rates, suggesting that they are affected less efficiently by selection. Therefore, both the length of the coding region and the recombination rate modulate codon bias. In addition, the data indicate that selection coefficients for synonymous mutations must vary by a minimum of one or two orders of magnitude. Two hypotheses are proposed to explain the relationship among the coding region length, the codon bias, and the synonymous divergence and polymorphism levels across the range of recombination rates in Drosophila. The first hypothesis is that selection coefficients on synonymous mutations are inversely related to the total length of the coding region. The second hypothesis proposes that interference among synonymous mutations reduces the efficacy of selection on these mutations. We investigated this second hypothesis by carrying out forward simulations of weakly selected mutations in model populations. These simulations show that even with realistic recombination rates, this interference, which we call the “small-scale” Hill-Robertson effect, can have a moderately strong influence on codon bias.

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 Visualization of Differential Gene Expression by Improved Cyan Fluorescent Protein and Yellow Fluorescent Protein Production in Bacillus subtilis

2004 ◽  
Vol 70 (11) ◽  
pp. 6809-6815 ◽  
Author(s):  
Jan-Willem Veening ◽  
Wiep Klaas Smits ◽  
Leendert W. Hamoen ◽  
Jan D. H. Jongbloed ◽  
Oscar P. Kuipers
Keyword(s):  
Bacillus Subtilis ◽  
Codon Bias ◽  
Protein Production ◽  
Fluorescent Protein ◽  
Fluorescent Proteins ◽  
Yellow Fluorescent Protein ◽  
Terminal Part ◽  
Cloning Vectors ◽  
Differential Gene

ABSTRACT The distinguishable cyan and yellow fluorescent proteins (CFP and YFP) enable the simultaneous in vivo visualization of different promoter activities. Here, we report new cloning vectors for the construction of cfp and yfp fusions in Bacillus subtilis. By extending the N-terminal portions of previously described CFP and YFP variants, 20- to 70-fold-improved fluorescent-protein production was achieved. Probably, the addition of sequences encoding the first eight amino acids of the N-terminal part of ComGA of B. subtilis overcomes the slow translation initiation that is provoked by the eukaryotic codon bias present in the original cfp and yfp genes. Using these new vectors, we demonstrate that, within an isogenic population of sporulating B. subtilis cells, expression of the abrB and spoIIA genes is distinct in individual cells.

scholarly journals Codon usage influences fitness through RNA toxicity

2018 ◽  
Vol 115 (34) ◽  
pp. 8639-8644 ◽  
Author(s):  
Pragya Mittal ◽  
James Brindle ◽  
Julie Stephen ◽  
Joshua B. Plotkin ◽  
Grzegorz Kudla
Keyword(s):  
Mrna Levels ◽  
Bacterial Gene ◽  
E Coli ◽  
Rna Toxicity ◽  
Synonymous Mutations ◽  
Bacterial Gene Expression ◽  
Synonymous Codons ◽  
Synonymous Sites ◽  
Bacterial Fitness ◽  
Promoter Mutations

Many organisms are subject to selective pressure that gives rise to unequal usage of synonymous codons, known as codon bias. To experimentally dissect the mechanisms of selection on synonymous sites, we expressed several hundred synonymous variants of the GFP gene inEscherichia coli, and used quantitative growth and viability assays to estimate bacterial fitness. Unexpectedly, we found many synonymous variants whose expression was toxic toE. coli. Unlike previously studied effects of synonymous mutations, the effect that we discovered is independent of translation, but it depends on the production of toxic mRNA molecules. We identified RNA sequence determinants of toxicity and evolved suppressor strains that can tolerate the expression of toxic GFP variants. Genome sequencing of these suppressor strains revealed a cluster of promoter mutations that prevented toxicity by reducing mRNA levels. We conclude that translation-independent RNA toxicity is a previously unrecognized obstacle in bacterial gene expression.

scholarly journals Natural selection shapes codon usage in the human genome

2019 ◽  
Author(s):  
Ryan S Dhindsa ◽  
Brett R Copeland ◽  
Anthony M Mustoe ◽  
David B Goldstein
Keyword(s):  
Natural Selection ◽  
Codon Usage ◽  
Human Genome ◽  
Synonymous Codon ◽  
Model Organisms ◽  
Translational Efficiency ◽  
Evolutionary Constraint ◽  
Sequencing Data ◽  
Genetic Sequencing ◽  
Synonymous Mutations

AbstractSynonymous codon usage has been identified as an important determinant of translational efficiency and mRNA stability in model organisms and human cell lines. However, to date, population genetics studies have failed to observe evolutionary constraint on human codon usage, and synonymous variation has been largely overlooked as a component of human genetic diversity. Using genetic sequencing data from nearly 200,000 individuals, we uncover clear evidence that natural selection optimizes codon content in the human genome. We derive intolerance metrics to quantify gene-level constraint on synonymous variation and demonstrate that dosage-sensitive, DNA damage response, and cell cycle regulated genes are more intolerant to synonymous variation than other genes in the genome. Notably, we illustrate that reductions in codon optimality can attenuate the function of BRCA1. Our results reveal that synonymous mutations likely play an important and underappreciated role in human variation.

scholarly journals Inferring weak selection from patterns of polymorphism and divergence at "silent" sites in Drosophila DNA.

Genetics ◽  
1995 ◽  
Vol 139 (2) ◽  
pp. 1067-1076 ◽  
Author(s):  
H Akashi
Keyword(s):  
Population Genetics ◽  
Drosophila Melanogaster ◽  
Natural Selection ◽  
Evolutionary Dynamics ◽  
Effective Population ◽  
Weak Selection ◽  
Fitness Effect ◽  
Synonymous Mutations ◽  
Synonymous Codons ◽  
Dna Mutations

Abstract Patterns of codon usage and "silent" DNA divergence suggest that natural selection discriminates among synonymous codons in Drosophila. "Preferred" codons are consistently found in higher frequencies within their synonymous families in Drosophila melanogaster genes. This suggests a simple model of silent DNA evolution where natural selection favors mutations from unpreferred to preferred codons (preferred changes). Changes in the opposite direction, from preferred to unpreferred synonymous codons (unpreferred changes), are selected against. Here, selection on synonymous DNA mutations is investigated by comparing the evolutionary dynamics of these two categories of silent DNA changes. Sequences from outgroups are used to determine the direction of synonymous DNA changes within and between D. melanogaster and Drosophila simulans for five genes. Population genetics theory shows that differences in the fitness effect of mutations can be inferred from the comparison of ratios of polymorphism to divergence. Unpreferred changes show a significantly higher ratio of polymorphism to divergence than preferred changes in the D. simulans lineage, confirming the action of selection at silent sites. An excess of unpreferred fixations in 28 genes suggests a relaxation of selection on synonymous mutations in D. melanogaster. Estimates of selection coefficients for synonymous mutations (3.6 < magnitude of Nes < 1.3) in D. simulans are consistent with the reduced efficacy of natural selection (magnitude of Nes < 1) in the three- to sixfold smaller effective population size of D. melanogaster. Synonymous DNA changes appear to be a prevalent class of weakly selected mutations in Drosophila.

scholarly journals Accounting for programmed ribosomal frameshifting in the computation of codon

2018 ◽  
Author(s):  
Victor Garcia ◽  
Stefan Zoller ◽  
Maria Anisimova
Keyword(s):  
Protein Expression ◽  
Translational Efficiency ◽  
Translation Efficiency ◽  
Ribosomal Frameshifting ◽  
Synonymous Mutations ◽  
Synonymous Codons ◽  
Distinct Frequency ◽  
Selection For ◽  
Accuracy Constraints ◽  
Genetic Fitness

Experimental evidence shows that synonymous mutations can have important consequences on genetic fitness. Many organisms display codon usage bias (CUB), where synonymous codons that are translated into the same amino acid appear with distinct frequency. CUB is thought to arise from selection for translational efficiency and accuracy, termed the translational efficiency hypothesis (TEH). Indeed, CUB indices correlate with protein expression levels, which is widely interpreted as evidence for translational selection. However, these tests neglect −1 programmed ribosomal frameshifting (−1 PRF), an important translational disruption effect found across all organisms of the tree of life. Genes that contain −1 PRF signals should cost more to express than genes without. Thus, CUB indices that do not consider −1 PRF may overestimate genes’ true adaptation to translational efficiency and accuracy constraints. Here, we first investigate whether −1 PRF signals do indeed carry such translational cost. We then propose two corrections for CUB indices for genes containing −1 PRF signals. We retest the TEH under these corrections. We find that the correlation between corrected CUB index and protein expression remains intact for most levels of uniform −1 PRF efficiencies, and tends to increase when these efficiencies decline with protein expression. We conclude that the TEH is strengthened and that −1 PRF events constitute a promising and useful tool to examine the relationships between CUB and selection for translation efficiency and accuracy.

Interactions Between Natural Selection, Recombination and Gene Density in the Genes of Drosophila

Genetics ◽  
2002 ◽  
Vol 160 (2) ◽  
pp. 595-608 ◽  
Author(s):  
Jody Hey ◽  
Richard M Kliman
Keyword(s):  
Gene Expression ◽  
Natural Selection ◽  
Recombination Rate ◽  
Codon Bias ◽  
Gene Density ◽  
Drosophila Genome ◽  
Functional Variation ◽  
Subtle Effect ◽  
Efficiency Of Selection ◽  
The Impact

AbstractIn Drosophila, as in many organisms, natural selection leads to high levels of codon bias in genes that are highly expressed. Thus codon bias is an indicator of the intensity of one kind of selection that is experienced by genes and can be used to assess the impact of other genomic factors on natural selection. Among 13,000 genes in the Drosophila genome, codon bias has a slight positive, and strongly significant, association with recombination—as expected if recombination allows natural selection to act more efficiently when multiple linked sites segregate functional variation. The same reasoning leads to the expectation that the efficiency of selection, and thus average codon bias, should decline with gene density. However, this prediction is not confirmed. Levels of codon bias and gene expression are highest for those genes in an intermediate range of gene density, a pattern that may be the result of a tradeoff between the advantages for gene expression of close gene spacing and disadvantages arising from regulatory conflicts among tightly packed genes. These factors appear to overlay the more subtle effect of linkage among selected sites that gives rise to the association between recombination rate and codon bias.

The effect of expression levels on codon usage inPlasmodium falciparum

Parasitology ◽  
2004 ◽  
Vol 128 (3) ◽  
pp. 245-251 ◽  
Author(s):  
L. PEIXOTO ◽  
V. FERNÁNDEZ ◽  
H. MUSTO
Keyword(s):  
Amino Acids ◽  
Plasmodium Falciparum ◽  
Natural Selection ◽  
Codon Usage ◽  
Complete Sequence ◽  
Expression Data ◽  
Expression Levels ◽  
Synonymous Codons ◽  
Translational Selection ◽  
Highly Expressed Genes

The usage of alternative synonymous codons in the completely sequenced, extremely A+T-rich parasitePlasmodium falciparumwas studied. Confirming previous studies obtained with less than 3% of the total genes recently described, we found that A- and U-ending triplets predominate but translational selection increases the frequency of a subset of codons in highly expressed genes. However, some new results come from the analysis of the complete sequence. First, there is more variation in GC3 than previously described; second, the effect of natural selection acting at the level of translation has been analysed with real expression data at 4 different stages and third, we found that highly expressed proteins increment the frequency of energetically less expensive amino acids. The implications of these results are discussed.

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