Codon usage bias creates a ramp of hydrogen bonding at the 5′-end in prokaryotic ORFeomes

Codon usage bias exerts control over a wide variety of molecular processes. The positioning of synonymous codons within coding sequences (CDSs) dictates protein expression by mechanisms such as local translation efficiency, mRNA Gibbs free energy, and protein co-translational folding. In this work, we explore how codon variants affect the position-dependent content of hydrogen bonding, which in turn influences energy requirements for unwinding double-stranded DNA. By analyzing over 14,000 bacterial, archaeal, and fungal ORFeomes, we found that Bacteria and Archaea exhibit an exponential ramp of hydrogen bonding at the 5′-end of CDSs, while a similar ramp was not found in Fungi. The ramp develops within the first 20 codon positions in prokaryotes, eventually reaching a steady carrying capacity of hydrogen bonding that does not differ from Fungi. Selection against uniformity tests proved that selection acts against synonymous codons with high content of hydrogen bonding at the 5′-end of prokaryotic ORFeomes. Overall, this study provides novel insights into the molecular feature of hydrogen bonding that is governed by the genetic code at the 5′-end of CDSs. A web-based application to analyze the position-dependent hydrogen bonding of ORFeomes has been developed and is publicly available (https://juanvillada.shinyapps.io/hbonds/).

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Interplay between Position-Dependent Codon Usage Bias and Hydrogen Bonding at the 5ʹ End of ORFeomes

mSystems ◽

10.1128/msystems.00613-20 ◽

2020 ◽

Vol 5 (4) ◽

Cited By ~ 1

Author(s):

Juan C. Villada ◽

Maria F. Duran ◽

Patrick K. H. Lee

Keyword(s):

Hydrogen Bonding ◽

Hydrogen Bonds ◽

Codon Usage ◽

Codon Usage Bias ◽

Synonymous Codon ◽

Protein Biosynthesis ◽

Translation Efficiency ◽

Content Type ◽

Synonymous Codons ◽

Double Stranded Dna

ABSTRACT Codon usage bias exerts control over a wide variety of molecular processes. The positioning of synonymous codons within coding sequences (CDSs) dictates protein expression by mechanisms such as local translation efficiency, mRNA Gibbs free energy, and protein cotranslational folding. In this work, we explore how codon usage affects the position-dependent content of hydrogen bonding, which in turn influences energy requirements for unwinding double-stranded DNA (dsDNA). We categorized codons according to their hydrogen bond content and found differential effects on hydrogen bonding encoded by codon variants. The specific positional disposition of codon variants within CDSs creates a ramp of hydrogen bonding at the 5ʹ end of the ORFeome in Escherichia coli. CDSs occupying the first position of operons are subjected to selective pressure that reduces their hydrogen bonding compared to internal CDSs, and highly transcribed CDSs demand a lower maximum capacity of hydrogen bonds per codon, suggesting that the energetic requirement for unwinding the dsDNA in highly transcribed CDSs has evolved to be minimized in E. coli. Subsequent analysis of over 14,000 ORFeomes showed a pervasive ramp of hydrogen bonding at the 5ʹ end in Bacteria and Archaea that positively correlates with the probability of mRNA secondary structure formation. Both the ramp and the correlation were not found in Fungi. The position-dependent hydrogen bonding might be part of the mechanism that contributes to the coordination between transcription and translation in Bacteria and Archaea. A Web-based application to analyze the position-dependent hydrogen bonding of ORFeomes has been developed and is publicly available (https://juanvillada.shinyapps.io/hbonds/). IMPORTANCE Redundancy of the genetic code creates a vast space of alternatives to encode a protein. Synonymous codons exert control over a variety of molecular and physiological processes of cells mainly through influencing protein biosynthesis. Recent findings have shown that synonymous codon choice affects transcription by controlling mRNA abundance, mRNA stability, transcription termination, and transcript biosynthesis cost. In this work, by analyzing thousands of Bacteria, Archaea, and Fungi genomes, we extend recent findings by showing that synonymous codon choice, corresponding to the number of hydrogen bonds in a codon, can also have an effect on the energetic requirements for unwinding double-stranded DNA in a position-dependent fashion. This report offers new perspectives on the mechanism behind the transcription-translation coordination and complements previous hypotheses on the resource allocation strategies used by Bacteria and Archaea to manage energy efficiency in gene expression.

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Codon usage of highly expressed genes affects proteome-wide translation efficiency

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1719375115 ◽

2018 ◽

Vol 115 (21) ◽

pp. E4940-E4949 ◽

Cited By ~ 57

Author(s):

Idan Frumkin ◽

Marc J. Lajoie ◽

Christopher J. Gregg ◽

Gil Hornung ◽

George M. Church ◽

...

Keyword(s):

Escherichia Coli ◽

Amino Acid ◽

Codon Usage ◽

Codon Usage Bias ◽

Protein Translation ◽

Translation Efficiency ◽

Synonymous Codons ◽

Codon Composition ◽

Theoretical Predictions ◽

Highly Expressed Genes

Although the genetic code is redundant, synonymous codons for the same amino acid are not used with equal frequencies in genomes, a phenomenon termed “codon usage bias.” Previous studies have demonstrated that synonymous changes in a coding sequence can exert significantciseffects on the gene’s expression level. However, whether the codon composition of a gene can also affect the translation efficiency of other genes has not been thoroughly explored. To study how codon usage bias influences the cellular economy of translation, we massively converted abundant codons to their rare synonymous counterpart in several highly expressed genes inEscherichia coli. This perturbation reduces both the cellular fitness and the translation efficiency of genes that have high initiation rates and are naturally enriched with the manipulated codon, in agreement with theoretical predictions. Interestingly, we could alleviate the observed phenotypes by increasing the supply of the tRNA for the highly demanded codon, thus demonstrating that the codon usage of highly expressed genes was selected in evolution to maintain the efficiency of global protein translation.

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Comparative analysis of codon usage bias in Crenarchaea and Euryarchaea genome reveals differential preference of synonymous codons to encode highly expressed ribosomal and RNA polymerase proteins

Journal of Genetics ◽

10.1007/s12041-016-0667-5 ◽

2016 ◽

Vol 95 (3) ◽

pp. 537-549 ◽

Cited By ~ 2

Author(s):

VISHWA JYOTI BARUAH ◽

SIDDHARTHA SANKAR SATAPATHY ◽

BHESH RAJ POWDEL ◽

ROCKTOTPAL KONWARH ◽

ALAK KUMAR BURAGOHAIN ◽

...

Keyword(s):

Comparative Analysis ◽

Rna Polymerase ◽

Codon Usage ◽

Codon Usage Bias ◽

Synonymous Codons

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Codon usage and protein sequence pattern dependency in different organisms: A Bioinformatics approach

Journal of Bioinformatics and Computational Biology ◽

10.1142/s021972001550002x ◽

2015 ◽

Vol 13 (02) ◽

pp. 1550002

Author(s):

Mohammad-Hadi Foroughmand-Araabi ◽

Bahram Goliaei ◽

Kasra Alishahi ◽

Mehdi Sadeghi ◽

Sama Goliaei

Keyword(s):

Gene Regulation ◽

Codon Usage ◽

Protein Sequence ◽

Multinomial Logistic Regression ◽

Translation Efficiency ◽

Translation Rate ◽

Protein Levels ◽

Synonymous Codons ◽

First Time

Although it is known that synonymous codons are not chosen randomly, the role of the codon usage in gene regulation is not clearly understood, yet. Researchers have investigated the relation between the codon usage and various properties, such as gene regulation, translation rate, translation efficiency, mRNA stability, splicing, and protein domains. Recently, a universal codon usage based mechanism for gene regulation is proposed. We studied the role of protein sequence patterns on the codons usage by related genes. Considering a subsequence of a protein that matches to a pattern or motif, we showed that, parts of the genes, which are translated to this subsequence, use specific ratios of synonymous codons. Also, we built a multinomial logistic regression statistical model for codon usage, which considers the effect of patterns on codon usage. This model justifies the observed codon usage preference better than the classic organism dependent codon usage. Our results showed that the codon usage plays a role in controlling protein levels, for genes that participate in a specific biological function. This is the first time that this phenomenon is reported.

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Codon Usage in the Iflaviridae Family Is Not Diverse Though the Family Members Are Isolated from Diverse Host Taxa

Viruses ◽

10.3390/v11121087 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1087 ◽

Cited By ~ 2

Author(s):

Sheng-Lin Shi ◽

Run-Xi Xia

Keyword(s):

Codon Usage ◽

Codon Usage Bias ◽

Synonymous Codon ◽

Nucleotide Composition ◽

Effective Number ◽

Bias Analysis ◽

The Family ◽

Usage Patterns ◽

Codon Positions ◽

Effective Number Of Codons

All iflavirus members belong to the unique genus, Iflavirus, of the family, Iflaviridae. The host taxa and sequence identities of these viruses are diverse. A codon usage bias, maintained by a balance between selection, mutation, and genetic drift, exists in a wide variety of organisms. We characterized the codon usage patterns of 44 iflavirus genomes that were isolated from the classes, Insecta, Arachnida, Mammalia, and Malacostraca. Iflaviruses lack a strong codon usage bias when they are evaluated using an effective number of codons. The odds ratios of the majority of dinucleotides are within the normal range. However, the dinucleotides at the 1st–2nd codon positions are more biased than those at the 2nd–3rd codon positions. Plots of effective numbers of codons, relative neutrality analysis, and PR2 bias analysis all indicate that selection pressure dominates mutations in shaping codon usage patterns in the family, Iflaviridae. When these viruses were grouped into their host taxa, we found that the indices, including the nucleotide composition, effective number of codons, relative synonymous codon usage, and the influencing factors behind the codon usage patterns, all show that there are non-significant differences between the six host-taxa-groups. Our results disagree with our assumption that diverse viruses should possess diverse codon usage patterns, suggesting that the nucleotide composition and codon usage in the family, Iflaviridae, are not host taxa-specific signatures.

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Codon Usage Bias of the Wheat Flower Development Gene WAG-2 and Other AGAMOUS Group Genes

Journal of Agricultural Science ◽

10.5539/jas.v9n9p56 ◽

2017 ◽

Vol 9 (9) ◽

pp. 56

Author(s):

Wenhan Hu ◽

Shuhong Wei

Keyword(s):

Codon Usage ◽

Codon Usage Bias ◽

Codon Bias ◽

Target Genes ◽

Expression System ◽

Functional Studies ◽

Codon Preference ◽

Synonymous Codons ◽

The Difference ◽

Relationship Of

Analyzing codon usage bias of WAG-2 gene in wheat three-pistil (TP) mutant may provide a basis for selecting the appropriate host expression systems to improve the expression of target genes. In the present study, we analyzed the codon bias of the complete coding sequence (CDS) of the WAG-2 gene in TP using Codon W program, and compared the results with AGAMOUS (AG) group genes of other plant species. Results showed that the WAG-2 gene in TP and other monocot AG group genes preferably used codons ending with G/C bases, but Arabidopsis thaliana, Nicotiana tabacum, and other dicot crops were biased toward the synonymous codons with A/T. The clustering results based on codon bias were consistent with those based on CDS of the AG group genes, indicating that the difference in codon preference of AG group genes sequences was closely associated with the genetic relationship of the species. The Euclidean distance coefficients of WAG-2 with A. thaliana and N. tabacum were 9.255 and 5.730, respectively, indicating that N. tabacum may be more suitable for the expression of WAG-2. There were 37 codons showing distinct usage differences between WAG-2 and genome of yeast, 23 between WAG-2 and Escherichia coli. Therefore, the E. coli was the superior protein expression system. These results may improve our understanding of codon usage bias and functional studies of WAG-2.

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

Cell Communication and Signaling ◽

10.1186/s12964-020-00642-6 ◽

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.

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Characterization of Codon Usage Bias in UL13 Gene of the Duck Plague Virus

Advanced Materials Research ◽

10.4028/www.scientific.net/amr.393-395.641 ◽

2011 ◽

Vol 393-395 ◽

pp. 641-650

Author(s):

Xi Xia Hu ◽

An Chun Cheng ◽

Ming Shu Wang

Keyword(s):

Codon Usage ◽

Codon Usage Bias ◽

Codon Position ◽

Expression System ◽

Expression Systems ◽

Yeast Expression System ◽

E Coli ◽

Synonymous Codons ◽

Suitable Expression

A comprehensive analysis of codon usage bias of DPV UL13 gene (GenBank Accession No. EU195098) was performed to provide a basis for understanding the relevant mechanism for its biased usage of synonymous codons and for selecting suitable expression systems to improve the expression of UL13 genes. Our study showed that codon usage bias of DPV UL13 gene strongly prefered to the synonymous with A and T at the third codon position. And ENC value and GC3s contents of the codon usage bias of UL13 gene in DPV were significantly different compared with those in other 21 reference herpesviruses. The phylogentic analysis about the putative protein of DPV UL13 and the 21 reference herpesviruses revealed that DPV was evolutionarily closer to the AnHV-1. In addition, the codon usage bias of DPV UL13 gene was compared with those of E. coli, yeast and human. There are 23 codons showing distinct usage differences between DPV and E. coli, 12 codons between DPV and yeast, 21 codons between DPV and human. Therefore, the yeast expression system is more appropriate for heterologous expression of the DPV UL13 gene.

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Comparisons of Coding and Noncoding Sequences to infer the Origin of Codon usage Bias

10.1101/174359 ◽

2017 ◽

Author(s):

Prashant Mainali ◽

Sobita Pathak

Keyword(s):

Codon Usage ◽

Codon Usage Bias ◽

Gc Content ◽

Mutation Bias ◽

Translation Process ◽

Noncoding Regions ◽

Coding Regions ◽

Synonymous Codons ◽

Shed Light

ABSTRACTCodon usage bias is the preferential use of the subset of synonymous codons during translation. In this paper, the comparisons of normalized entropy and GC content between the sequence of coding regions of Escherichia coli k12 and noncoding regions (ncRNA, rRNA) of various organisms were done to shed light on the origin of the codon usage bias.The normalized entropy of the coding regions was found significantly higher than the noncoding regions, suggesting the role of the translation process in shaping codon usage bias. Further, when the position specific GC content of both coding and noncoding regions was analyzed, the GC2 content in coding regions was lower than GC1 and GC2 while in noncoding regions, the GC1, GC2, GC3 contents were approximately equal. This discrepancy is explained by the biased mutation coupled with the presence and absence of selection pressure. The accumulation of CG content occurs in the sequences due to mutation bias in DNA repair and recombination process. In noncoding regions, the mutation is harmful and thus, selected against while due to the degeneracy of codons in coding regions, a mutation in GC3 is neutral and hence, not selected. Thus, the accumulation of GC content occurs in coding regions, and thus codon usage bias occurs.

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Hidden patterns of codon usage bias across kingdoms

10.1101/478016 ◽

2018 ◽

Author(s):

Yun Deng ◽

Fabio de Lima Hedayioglu ◽

Jeremie Kalfon ◽

Dominique Chu ◽

Tobias von der Haar

Keyword(s):

Amino Acids ◽

Codon Usage ◽

Codon Usage Bias ◽

Large Scale ◽

Model Organisms ◽

Stochastic Thermodynamics ◽

Synonymous Codons ◽

Genome Wide ◽

Taxonomic Class ◽

Taxonomic Groups

AbstractThe genetic code is necessarily degenerate with 64 possible nucleotide triplets being translated into 20 amino acids. 18 out of the 20 amino acids are encoded by multiple synonymous codons. While synonymous codons are clearly equivalent in terms of the information they carry, it is now well established that they are used in a biased fashion. There is currently no consensus as to the origin of this bias. Drawing on ideas from stochastic thermodynamics we derive from first principles a mathematical model describing the statistics of codon usage bias. We show that the model accurately describes the distribution of codon usage bias of genomes in the fungal and bacterial kingdoms. Based on it, we derive a new computational measure of codon usage bias — the distance capturing two aspects of codon usage bias: (i) Differences in the genome-wide frequency of codons and (ii) apparent non-random distributions of codons across mRNAs. By means of large scale computational analysis of over 900 species across 2 kingdoms of life, we demonstrate that our measure provides novel biological insights. Specifically, we show that while codon usage bias is clearly based on heritable traits and closely related species show similar degrees of bias, there is considerable variation in the magnitude of within taxonomic classes suggesting that the contribution of sequence-level selection to codon bias varies substantially within relatively confined taxonomic groups. Interestingly, commonly used model organisms are near the median for values of for their taxonomic class, suggesting that they may not be good representative models for species with more extreme , which comprise organisms of medical an agricultural interest. We also demonstrate that amino acid specific patterns of codon usage are themselves quite variable between branches of the tree of life, and that some of this variability correlates with organismal tRNA content.

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