Species-Specific Codon Context Rules Unveil Non-Neutrality Effects of Synonymous Mutations (original) (raw)

2011, PLOS One

https://doi.org/10.1371/JOURNAL.PONE.0026817

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Abstract

Background: Codon pair usage (codon context) is a species specific gene primary structure feature whose evolutionary and functional roles are poorly understood. The data available show that codon-context has direct impact on both translation accuracy and efficiency, but one does not yet understand how it affects these two translation variables or whether context biases shape gene evolution.

Universal Pattern and Diverse Strengths of Successive Synonymous Codon Bias in Three Domains of Life, Particularly Among Prokaryotic Genomes

There has been significant progress in understanding the process of protein translation in recent years. One of the best examples is the discovery of usage bias in successive synonymous codons and its role in eukaryotic translation efficiency. We observed here a similar type of bias in the other two life domains, bacteria and archaea, although the bias strength was much smaller than in eukaryotes. Among 136 prokaryotic genomes, 98 were found to have significant bias from random use of successive synonymous codons with Z scores larger than three. Furthermore, significantly different bias strengths were found between prokaryotes grouped by various genomic or biochemical characteristics. Interestingly, the bias strength measured by a general Z score could be fitted well (R 5 0.83, P < 10 215 ) by three genomic variables: genome size, G 1 C content, and tRNA gene number based on multiple linear regression. A different distribution of synonymous codon pairs between protein-coding genes and intergenic sequences suggests that bias is caused by translation selection. The present results indicate that protein translation is tuned by codon ( pair) usage, and the intensity of the regulation is associated with genome size, tRNA gene number, and G 1 C content.

Read between the Lines: Diversity of Nontranslational Selection Pressures on Local Codon Usage

Genome Biology and Evolution, 2021

Protein coding genes can contain specific motifs within their nucleotide sequence that function as a signal for various biological pathways. The presence of such sequence motifs within a gene can have beneficial or detrimental effects on the phenotype and fitness of an organism, and this can lead to the enrichment or avoidance of this sequence motif. The degeneracy of the genetic code allows for the existence of alternative synonymous sequences that exclude or include these motifs, while keeping the encoded amino acid sequence intact. This implies that locally, there can be a selective pressure for preferentially using a codon over its synonymous alternative in order to avoid or enrich a specific sequence motif. This selective pressure could—in addition to mutation, drift and selection for translation efficiency and accuracy—contribute to shape the codon usage bias. In this review, we discuss patterns of avoidance of (or enrichment for) the various biological signals contained in sp...

Eukaryotic Evolutionary Transitions Are Associated with Extreme Codon Bias in Functionally-Related Proteins

PLoS ONE, 2011

Codon bias in the genome of an organism influences its phenome by changing the speed and efficiency of mRNA translation and hence protein abundance. We hypothesized that differences in codon bias, either between-species differences in orthologous genes, or within-species differences between genes, may play an evolutionary role. To explore this hypothesis, we compared the genome-wide codon bias in six species that occupy vital positions in the Eukaryotic Tree of Life. We acquired the entire protein coding sequences for these organisms, computed the codon bias for all genes in each organism and explored the output for relationships between codon bias and protein function, both within-and between-lineages. We discovered five notable coordinated patterns, with extreme codon bias most pronounced in traits considered highly characteristic of a given lineage. Firstly, the Homo sapiens genome had stronger codon bias for DNAbinding transcription factors than the Saccharomyces cerevisiae genome, whereas the opposite was true for ribosomal proteins -perhaps underscoring transcriptional regulation in the origin of complexity. Secondly, both mammalian species examined possessed extreme codon bias in genes relating to hair -a tissue unique to mammals. Thirdly, Arabidopsis thaliana showed extreme codon bias in genes implicated in cell wall formation and chloroplast function -which are unique to plants. Fourthly, Gallus gallus possessed strong codon bias in a subset of genes encoding mitochondrial proteinsperhaps reflecting the enhanced bioenergetic efficiency in birds that co-evolved with flight. And lastly, the G. gallus genome had extreme codon bias for the Ciliary Neurotrophic Factor -which may help to explain their spontaneous recovery from deafness. We propose that extreme codon bias in groups of genes that encode functionally related proteins has a pathwaylevel energetic explanation.

Natural selection on gene-specific codon usage bias is common across eukaryotes

SUMMARYAlthough the actual molecular evolutionary forces that shape differences in codon usage across species remain poorly understood, majority of synonymous mutations are assumed to be functionally neutral because they do not affect protein sequences. However, empirical studies suggest that some synonymous mutations can have phenotypic consequences. Here we show that in contrast to the current dogma, natural selection on gene-specific codon usage bias is common across Eukaryota. Furthermore, by using bioinformatic and experimental approaches, we demonstrate that specific combinations of rare codons contribute to the spatial and sex-related regulation of some protein-coding genes in Drosophila melanogaster. Together, these data indicate that natural selection can shape gene-specific codon usage bias, which therefore, represents an overlooked genomic feature that is likely to play an important role in the spatial and temporal regulation of gene functions. Hence, the broadly accepted...

Translational Selection for Speed Is Not Sufficient to Explain Variation in Bacterial Codon Usage Bias

Genome Biology and Evolution, 2018

Increasing growth rate across bacteria strengthens selection for faster translation, concomitantly increasing the total number of tRNA genes and codon usage bias (CUB: enrichment of specific synonymous codons in highly expressed genes). Typically, enriched codons are translated by tRNAs with higher gene copy numbers (GCN). A model of tRNA-CUB coevolution based on fast growth-associated selection on translational speed recapitulates these patterns. A key untested implication of the coevolution model is that translational selection should favor higher tRNA GCN for more frequently used amino acids, potentially weakening the effect of growth-associated selection on CUB. Surprisingly, we find that CUB saturates with increasing growth rate across c-proteobacteria, even as the number of tRNA genes continues to increase. As predicted, amino acid-specific tRNA GCN is positively correlated with the usage of corresponding amino acids, but there is no correlation between growth rate associated changes in CUB and amino acid usage. Instead, we find that some amino acids-cysteine and those in the NNA/G codon family-show weak CUB that does not increase with growth rate, despite large variation in the corresponding tRNA GCN. We suggest that amino acid-specific variation in CUB is not explained by tRNA GCN because GCN does not influence the difference between translation times of synonymous codons as expected. Thus, selection on translational speed alone cannot fully explain quantitative variation in overall or amino acid-specific CUB, suggesting a significant role for other functional constraints and amino acid-specific codon features.

Codon usage bias from tRNA's point of view: Redundancy, specialization, and efficient decoding for translation optimization

Genome Research, 2004

The selection-mutation-drift theory of codon usage plays a major role in the theory of molecular evolution by explaining the co-evolution of codon usage bias and tRNA content in the framework of translation optimization. Because most studies have focused only on codon usage, we analyzed the tRNA gene pool of 102 bacterial species. We show that as minimal generation times get shorter, the genomes contain more tRNA genes, but fewer anticodon species. Surprisingly, despite the wide G+C variation of bacterial genomes these anticodons are the same in most genomes. This suggests an optimization of the translation machinery to use a small subset of optimal codons and anticodons in fast-growing bacteria and in highly expressed genes. As a result, the overrepresented codons in highly expressed genes tend to be the same in very different genomes to match the same most-frequent anticodons. This is particularly important in fast-growing bacteria, which have higher codon usage bias in these genes. Three models were tested to understand the choice of codons recognized by the same anticodons, all providing significant fit, but under different classes of genes and genomes. Thus, co-evolution of tRNA gene composition and codon usage bias in genomes seen from tRNA's point of view agrees with the selection-mutation-drift theory. However, it suggests a much more universal trend in the evolution of anticodon and codon choice than previously thought. It also provides new evidence that a selective force for the optimization of the translation machinery is the maximization of growth.

Switches in species-specific codon preferences: The influence of mutation biases

Journal of Molecular Evolution, 1990

A model of synonymous codon usage is developed in which the most frequent codons are selectively advantageous because of their coadaptation with tRNA abundances. Random drift opposes the progress of this coevolution by pushing codon frequencies in the direction of the frequency that would result from mutation in the absence of selection. It is predicted that, within a certain range, an increased mutation bias away from an advantageous codon has little influence on its usage in highly expressed genes. However, a subsequent small increase in mutation bias over a critical range leads to a large reduction in the frequency of the codon. The switch in preference from one synonym to another is a sharp transition, with no stable intermediate state in which neither codon is advantageous. Codon usage patterns were compared among three related bacterial species of differing genomic G+C contents, Escherichia colt, Serratia marcescens, and Proteus vulgaris. It was found that although changes in mutation biases do not always result in switches in codon preferences, some switches have occurred in the direction of speciesspecific mutation biases. Fluctuating mutation biases may therefore be the main cause of differences between species in their codon preferences.

Synonymous codon usage in Bacillus subtilis reflects both translational selection and mutational biases

Nucleic Acids Research, 1987

Codon usage data for 56 Bacillus subtilis genes show that synonymous codon usage in B. subtilis is less biased than in Escherichia coli, or in Saccharomyces cerevisiae. Nevertheless, certain genes with a high codon bias can be identified by correspondence analysis, and also by various indices of codon bias. These genes are very highly expressed, and a general trend (a decrease) in codon bias across genes seems to correspond to decreasing expression level. This, then, may be a general phenomenon in unicellular organisms. The unusually small effect of translational selection on the pattern of codon usage in lowly expressed genes in B. subtilis yields similar dinucleotide frequencies among different codon positions, and on complementary strands. These patterns could arise through selection on DNA structure, but more probably are largely determined by mutation. This prevalence of mutational bias could lead to difficulties in assessing whether open reading frames encode proteins.

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Synonymous genome recoding: a tool to explore microbial biology and new therapeutic strategies

Nucleic Acids Research

Synthetic genome recoding is a new means of generating designed organisms with altered phenotypes. Synonymous mutations introduced into the protein coding region tolerate modifications in DNA or mRNA without modifying the encoded proteins. Synonymous genome-wide recoding has allowed the synthetic generation of different small-genome viruses with modified phenotypes and biological properties. Recently, a decreased cost of chemically synthesizing DNA and improved methods for assembling DNA fragments (e.g. lambda red recombination and CRISPR-based editing) have enabled the construction of an Escherichia coli variant with a 4-Mb synthetic synonymously recoded genome with a reduced number of sense codons (n = 59) encoding the 20 canonical amino acids. Synonymous genome recoding is increasing our knowledge of microbial interactions with innate immune responses, identifying functional genome structures, and strategically ameliorating cis-inhibitory signaling sequences related to splicing, ...

Attenuation of Viruses by Large-Scale Recoding of their Genomes: the Selection Is Always Biased

Current clinical microbiology reports, 2018

Purpose of Review This review summarizes the current understanding of virus attenuation by large-scale recoding of viral genomes and discusses what would ultimately be necessary for construction of better and safer live modified virus vaccines. Recent Findings It has been shown that codon and codon pair deoptimization are rapid and robust methods that can be used for the development of attenuated vaccine candidates. The viruses attenuated by large-scale recoding have the added value that they are extremely genetically stable. However, the exact mechanisms that lead to viral attenuation by recoding are yet to be determined. Summary While the advantages of large-scale recoding (speed, simplicity, potency, and universal applicability) have been known for more than a decade, this approach has been only inadequately explored and the attention was focused on a limited number of RNA viruses. Attenuation of viruses by large-scale recoding should be explored to combat known and future viral threats. Keywords Codon bias. Codon pair bias. CpG dinucleotides. Live modified virus vaccines. Synthetic attenuation virus engineering. Large-scale recoding This article is part of the Topical Collection on Recent Developments in Anti-viral Vaccines * Dusan Kunec

Codon Pattern and Compositional Constraints Determination of Genes Associated with Chronic Periodontitis

Genes

Genome-wide association studies showed the relationship of NIN, ABHD12B, WHAMM, AP3B2, and SIGLEC5 with chronic periodontitis. The study’s objective was to investigate different molecular patterns and evolutionary forces acting on the mentioned genes. The investigation of molecular patterns encompasses the study of compositional parameters, expression profile, physical properties of genes, codon preferences, degree of codon bias, determination of the most influential codons, and assessment of actions of evolutionary forces, such as mutations and natural selection. The overall compositional analysis revealed the dominance of A and G nucleotides compared to T and C. A relatively low codon usage bias is observed. The CTG codon is the most overused codon, followed by TCC. The genes, AP3B2 and SIGLEC5, preferred GC-ending codons, while NIN, ABHD12B, and WHAMM preferred AT-ending codons. The presence of directional mutational force and natural selection was found to operate codon usage in...

A Survey of Codon and Amino Acid Frequency Bias in Microbial Genomes Focusing on Translational Efficiency

Journal of Molecular Evolution, 2003

Unequal use of synonymous codons has been found in several prokaryotic and eukaryotic genomes. This bias has been associated with translational efficiency. The prevalence of this bias across lineages is currently unknown. Here, a new method (GCB) to measure codon usage bias is presented. It uses an iterative approach for the determination of codon scores and allows the computation of an index of codon bias suitable for interspecies comparison. A server to calculate GCB-values of individual genes as well as a list of compiled results are available at www.g21.bio.uni-goettingen.de. The method was applied to complete bacterial genomes. The relation of codon usage bias with amino acid composition and the choice of stop codons were determined and discussed.

Intragenic Spatial Patterns of Codon Usage Bias in Prokaryotic and Eukaryotic Genomes

Genetics, 2004

To study the roles of translational accuracy, translational efficiency, and the Hill-Robertson effect in codon usage bias, we studied the intragenic spatial distribution of synonymous codon usage bias in four prokaryotic (Escherichia coli, Bacillus subtilis, Sulfolobus tokodaii, and Thermotoga maritima) and two eukaryotic (Saccharomyces cerevisiae and Drosophila melanogaster) genomes. We generated supersequences at each codon position across genes in a genome and computed the overall bias at each codon position. By quantitatively evaluating the trend of spatial patterns using isotonic regression, we show that in yeast and prokaryotic genomes, codon usage bias increases along translational direction, which is consistent with purifying selection against nonsense errors. Fruit fly genes show a nearly symmetric M-shaped spatial pattern of codon usage bias, with less bias in the middle and both ends. The low codon usage bias in the middle region is best explained by interference (the Hil...

The Selective Advantage of Synonymous Codon Usage Bias in Salmonella

PLOS Genetics, 2016

The genetic code in mRNA is redundant, with 61 sense codons translated into 20 different amino acids. Individual amino acids are encoded by up to six different codons but within codon families some are used more frequently than others. This phenomenon is referred to as synonymous codon usage bias. The genomes of free-living unicellular organisms such as bacteria have an extreme codon usage bias and the degree of bias differs between genes within the same genome. The strong positive correlation between codon usage bias and gene expression levels in many microorganisms is attributed to selection for translational efficiency. However, this putative selective advantage has never been measured in bacteria and theoretical estimates vary widely. By systematically exchanging optimal codons for synonymous codons in the tuf genes we quantified the selective advantage of biased codon usage in highly expressed genes to be in the range 0.2-4.2 x 10 −4 per codon per generation. These data quantify for the first time the potential for selection on synonymous codon choice to drive genome-wide sequence evolution in bacteria, and in particular to optimize the sequences of highly expressed genes. This quantification may have predictive applications in the design of synthetic genes and for heterologous gene expression in biotechnology.

Balanced Codon Usage Optimizes Eukaryotic Translational Efficiency

PLoS Genetics, 2012

Cellular efficiency in protein translation is an important fitness determinant in rapidly growing organisms. It is widely believed that synonymous codons are translated with unequal speeds and that translational efficiency is maximized by the exclusive use of rapidly translated codons. Here we estimate the in vivo translational speeds of all sense codons from the budding yeast Saccharomyces cerevisiae. Surprisingly, preferentially used codons are not translated faster than unpreferred ones. We hypothesize that this phenomenon is a result of codon usage in proportion to cognate tRNA concentrations, the optimal strategy in enhancing translational efficiency under tRNA shortage. Our predicted codon-tRNA balance is indeed observed from all model eukaryotes examined, and its impact on translational efficiency is further validated experimentally. Our study reveals a previously unsuspected mechanism by which unequal codon usage increases translational efficiency, demonstrates widespread natural selection for translational efficiency, and offers new strategies to improve synthetic biology.

Efficient translation initiation dictates codon usage at gene start

Molecular Systems Biology, 2014

The genetic code is degenerate; thus, protein evolution does not uniquely determine the coding sequence. One of the puzzles in evolutionary genetics is therefore to uncover evolutionary driving forces that result in specific codon choice. In many bacteria, the first 5-10 codons of protein-coding genes are often codons that are less frequently used in the rest of the genome, an effect that has been argued to arise from selection for slowed early elongation to reduce ribosome traffic jams. However, genome analysis across many species has demonstrated that the region shows reduced mRNA folding consistent with pressure for efficient translation initiation. This raises the possibility that unusual codon usage is a side effect of selection for reduced mRNA structure. Here we discriminate between these two competing hypotheses, and show that in bacteria selection favours codons that reduce mRNA folding around the translation start, regardless of whether these codons are frequent or rare. Experiments confirm that primarily mRNA structure, and not codon usage, at the beginning of genes determines the translation rate.

Codon Usage Heterogeneity in the Multipartite Prokaryote Genome: Selection-Based Coding Bias Associated with Gene Location, Expression Level, and Ancestry

mBio, 2019

Bacterial genomes usually include many thousands of genes which are expressed with diverse spatial-temporal patterns and intensities. A well-known evidence is that highly expressed genes, such as the ribosomal and other translation-related proteins (RTRPs), have accommodated their codon usage to optimize translation efficiency and accuracy. Using a bioinformatic approach, we identify core-genes sets with different ancestries, and demonstrate that selection processes that optimize codon usage are not restricted to RTRPs but extended at a genome-wide scale. Such findings highlight, for the first time, a previously undiscovered adaptation strategy associated with the chromosomal-core information. Contrasted with the translationally more adapted genes, singletons (i.e., exclusive genes, including those of the plasmidome) appear as the gene pool with the less-ameliorated codon usage in the lineage. A comprehensive summary describing the inter- and intra-replicon heterogeneity of codon us...

Inferring biophysical models of evolution from genome-wide patterns of codon usage

2019

Frequencies of synonymous codons are typically non-uniform, despite the fact that such codons correspond to the same amino acid in the genetic code. This phenomenon, known as codon bias, is broadly believed to be due to a combination of factors including genetic drift, mutational biases, and selection for speed and accuracy of codon translation; however, quantitative modeling of codon bias has been elusive. We have developed a biophysical population genetics model which explains genome-wide codon frequencies observed across 20 organisms. We assume that codons evolve independently of each other under the influence of mutation and selection forces, and that the codon population has reached evolutionary steady state. Our model implements codon-level treatment of mutations with transition/transversion biases, and includes two contributions to codon fitness which describe codon translation speed and accuracy. Furthermore, our model includes wobble pairing -the possibility of codon-anticodon base pairing mismatches at the 3' nucleotide position of the codon. We find that the observed patterns of genome-wide codon usage are consistent with a strong selective penalty for mistranslated amino acids. Thus codons undergo purifying selection and their relative frequencies are affected in part by mutational robustness. We find that the dependence of codon fitness on translation speed is weaker on average compared to the strength of selection against mistranslation. Although no constraints on codon-anticodon pairing are imposed a priori, a reasonable hierarchy of pairing rates, which conforms to the wobble hypothesis and is consistent with available structural evidence, emerges spontaneously as a model prediction. Finally, treating the translation process explicitly in the context of a finite ribosomal pool has allowed us to estimate mutation rates per nucleotide directly from the coding sequences. Reminiscent of Drake's observation that mutation rates are inversely correlated with the genome size, we predict that mutation rates are inversely proportional to the number of genes. Overall, our approach offers a unified biophysical and population genetics framework for studying codon bias across all domains of life.

Elucidation of Codon Usage Signatures across the Domains of Life

Molecular Biology and Evolution, 2019

Because of the degeneracy of the genetic code, multiple codons are translated into the same amino acid. Despite being “synonymous,” these codons are not equally used. Selective pressures are thought to drive the choice among synonymous codons within a genome, while GC content, which is typically attributed to mutational drift, is the major determinant of variation across species. Here, we find that in addition to GC content, interspecies codon usage signatures can also be detected. More specifically, we show that a single amino acid, arginine, is the major contributor to codon usage bias differences across domains of life. We then exploit this finding and show that domain-specific codon bias signatures can be used to classify a given sequence into its corresponding domain of life with high accuracy. We then wondered whether the inclusion of codon usage codon autocorrelation patterns, which reflects the nonrandom distribution of codon occurrences throughout a transcript, might improv...

Comparative context analysis of codon pairs on an ORFeome scale

Genome Biology, 2005

Codon context is an important feature of gene primary structure that modulates mRNA decoding accuracy. We have developed an analytical software package and a graphical interface for comparative codon context analysis of all the open reading frames in a genome (the ORFeome). Using the complete ORFeome sequences of Saccharomyces cerevisiae, Schizosaccharomyces pombe, Candida albicans and Escherichia coli, we show that this methodology permits large-scale codon context comparisons and provides new insight on the rules that govern the evolution of codon-pair context.

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