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

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.

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A flexible ChIP-sequencing simulation toolkit

BMC Bioinformatics ◽

10.1186/s12859-021-04097-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

An Zheng ◽

Michael Lamkin ◽

Yutong Qiu ◽

Kevin Ren ◽

Alon Goren ◽

...

Keyword(s):

Ground Truth ◽

Peak Calling ◽

Simulation Framework ◽

Experimental Conditions ◽

Ground Truth Data ◽

Chip Sequencing ◽

Genome Wide ◽

Experimental Parameters ◽

Differential Binding ◽

The Impact

Abstract Background A major challenge in evaluating quantitative ChIP-seq analyses, such as peak calling and differential binding, is a lack of reliable ground truth data. Accurate simulation of ChIP-seq data can mitigate this challenge, but existing frameworks are either too cumbersome to apply genome-wide or unable to model a number of important experimental conditions in ChIP-seq. Results We present ChIPs, a toolkit for rapidly simulating ChIP-seq data using statistical models of key experimental steps. We demonstrate how ChIPs can be used for a range of applications, including benchmarking analysis tools and evaluating the impact of various experimental parameters. ChIPs is implemented as a standalone command-line program written in C++ and is available from https://github.com/gymreklab/chips. Conclusions ChIPs is an efficient ChIP-seq simulation framework that generates realistic datasets over a flexible range of experimental conditions. It can serve as an important component in various ChIP-seq analyses where ground truth data are needed.

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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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Synonymous variants in holoprosencephaly alter codon usage and impact the Sonic Hedgehog protein

Brain ◽

10.1093/brain/awaa152 ◽

2020 ◽

Vol 143 (7) ◽

pp. 2027-2038

Author(s):

Artem Kim ◽

Jérôme Le Douce ◽

Farah Diab ◽

Monika Ferovova ◽

Christèle Dubourg ◽

...

Keyword(s):

Codon Usage ◽

Sonic Hedgehog ◽

In Silico ◽

Synonymous Codon ◽

Critical Role ◽

Protein Translation ◽

Mirna Regulation ◽

Single Nucleotide Variants ◽

Mrna Structure ◽

The Impact

Abstract Synonymous single nucleotide variants (sSNVs) have been implicated in various genetic disorders through alterations of pre-mRNA splicing, mRNA structure and miRNA regulation. However, their impact on synonymous codon usage and protein translation remains to be elucidated in clinical context. Here, we explore the functional impact of sSNVs in the Sonic Hedgehog (SHH) gene, identified in patients affected by holoprosencephaly, a congenital brain defect resulting from incomplete forebrain cleavage. We identified eight sSNVs in SHH, selectively enriched in holoprosencephaly patients as compared to healthy individuals, and systematically assessed their effect at both transcriptional and translational levels using a series of in silico and in vitro approaches. Although no evidence of impact of these sSNVs on splicing, mRNA structure or miRNA regulation was found, five sSNVs introduced significant changes in codon usage and were predicted to impact protein translation. Cell assays demonstrated that these five sSNVs are associated with a significantly reduced amount of the resulting protein, ranging from 5% to 23%. Inhibition of the proteasome rescued the protein levels for four out of five sSNVs, confirming their impact on protein stability and folding. Remarkably, we found a significant correlation between experimental values of protein reduction and computational measures of codon usage, indicating the relevance of in silico models in predicting the impact of sSNVs on translation. Considering the critical role of SHH in brain development, our findings highlight the clinical relevance of sSNVs in holoprosencephaly and underline the importance of investigating their impact on translation in human pathologies.

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The Synonymous V107V Mutation In Factor IX Is Not So Silent and May Cause Hemophilia B In Patients

Blood ◽

10.1182/blood.v116.21.2197.2197 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2197-2197 ◽

Cited By ~ 1

Author(s):

Chava Kimchi-Sarfaty ◽

Vijaya L Simhadri ◽

David Kopelman ◽

Adam Friedman ◽

Nathan Edwards ◽

...

Keyword(s):

Codon Usage ◽

In Silico ◽

Synonymous Codon ◽

Protein Translation ◽

Factor Ix ◽

Hemophilia B ◽

Structure Stability ◽

Synonymous Mutation ◽

Codon Substitution ◽

In Silico Analyses

Abstract Abstract 2197 Hemophilia B is characterized by structural and functional defects in coagulation factor IX (FIX) caused by mutations in the F9 gene. Various mutations (nonsense, missense, etc.) are known to be associated with the disease, including a synonymous V107V mutation reported recently by Knobe and colleagues (Knobe et al., Hemophilia, 2008). However the mechanism by which this synonymous mutation contributes to the disease has not yet been elucidated. Earlier we have shown that synonymous codon substitutions in the mRNA of the multidrug resistance protein (MDR1) may change the conformation of the protein and result in altered functionality (Kimchi-Sarfaty et al., Science, 2008). Here we have performed in silico analyses of the synonymous codon substitution (GTGàGTA) leading to the V107V polymorphism and found that it may change the mRNA structure, stability, codon usage, and 3D structure of the encoded protein. We hypothesize that changes in codon usage might affect the rhythm of protein translation and thus result in slightly altered FIX conformation. In vitro analyses of FIX mRNA and protein expression supported our in silico analyses. The GTGàGTA (V107V) synonymous mutation results in reduced expression levels as well as an encoded protein with a slightly different conformation compared to wild-type FIX. These results show that the V107V polymorphism is not silent and might cause mild hemophilia B. This work sheds further light on ways in which synonymous mutations impact disease. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination policy Disclosures: No relevant conflicts of interest to declare.

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

Bioinformatics and Biology Insights ◽

10.4137/bbi.s12093 ◽

2013 ◽

Vol 7 ◽

pp. BBI.S12093 ◽

Cited By ~ 3

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.

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

Genetics ◽

10.1093/genetics/129.3.897 ◽

1991 ◽

Vol 129 (3) ◽

pp. 897-907 ◽

Cited By ~ 51

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.

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

Genetics ◽

10.1093/genetics/138.1.191 ◽

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.

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Construction of anti-codon table of the plant kingdom and evolution of tRNA selenocysteine (tRNASec)

BMC Genomics ◽

10.1186/s12864-020-07216-3 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Tapan Kumar Mohanta ◽

Awdhesh Kumar Mishra ◽

Abeer Hashem ◽

Elsayed Fathi Abd_Allah ◽

Abdul Latif Khan ◽

...

Keyword(s):

Amino Acids ◽

Zea Mays ◽

Amino Acid ◽

Codon Usage ◽

Synonymous Codon ◽

Protein Translation ◽

Synonymous Codon Usage ◽

Papaver Somniferum ◽

Plant Kingdom ◽

Ostreococcus Tauri

Abstract Background The tRNAs act as a bridge between the coding mRNA and incoming amino acids during protein translation. The anti-codon of tRNA recognizes the codon of the mRNA and deliver the amino acid into the protein translation chain. However, we did not know about the exact abundance of anti-codons in the genome and whether the frequency of abundance remains same across the plant lineage or not. Results Therefore, we analysed the tRNAnome of 128 plant species and reported an anti-codon table of the plant kingdom. We found that CAU anti-codon of tRNAMet has highest (5.039%) whereas GCG anti-codon of tRNAArg has lowest (0.004%) abundance. However, when we compared the anti-codon frequencies according to the tRNA isotypes, we found tRNALeu (7.808%) has highest abundance followed by tRNASer (7.668%) and tRNAGly (7.523%). Similarly, suppressor tRNA (0.036%) has lowest abundance followed by tRNASec (0.066%) and tRNAHis (2.109). The genome of Ipomoea nil, Papaver somniferum, and Zea mays encoded the highest number of anti-codons (isoacceptor) at 59 each whereas the genome of Ostreococcus tauri was found to encode only 18 isoacceptors. The tRNASec genes undergone losses more frequently than duplication and we found that tRNASec showed anti-codon switch during the course of evolution. Conclusion The anti-codon table of the plant tRNA will enable us to understand the synonymous codon usage of the plant kingdom and can be very helpful to understand which codon is preferred over other during the translation.

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CUBAP: an interactive web portal for analyzing codon usage biases across populations

Nucleic Acids Research ◽

10.1093/nar/gkaa863 ◽

2020 ◽

Vol 48 (19) ◽

pp. 11030-11039

Author(s):

Matthew W Hodgman ◽

Justin B Miller ◽

Taylor E Meurs ◽

John S K Kauwe

Keyword(s):

Codon Usage ◽

Synonymous Codon ◽

Association Studies ◽

East Asian ◽

Nucleotide Composition ◽

Synonymous Codon Usage ◽

Genome Wide Association Studies ◽

Genome Wide ◽

African Populations ◽

Place Of Origin

Abstract Synonymous codon usage significantly impacts translational and transcriptional efficiency, gene expression, the secondary structure of both mRNA and proteins, and has been implicated in various diseases. However, population-specific differences in codon usage biases remain largely unexplored. Here, we present a web server, https://cubap.byu.edu, to facilitate analyses of codon usage biases across populations (CUBAP). Using the 1000 Genomes Project, we calculated and visually depict population-specific differences in codon frequencies, codon aversion, identical codon pairing, co-tRNA codon pairing, ramp sequences, and nucleotide composition in 17,634 genes. We found that codon pairing significantly differs between populations in 35.8% of genes, allowing us to successfully predict the place of origin for African and East Asian individuals with 98.8% and 100% accuracy, respectively. We also used CUBAP to identify a significant bias toward decreased CTG pairing in the immunity related GTPase M (IRGM) gene in East Asian and African populations, which may contribute to the decreased association of rs10065172 with Crohn's disease in those populations. CUBAP facilitates in-depth gene-specific and codon-specific visualization that will aid in analyzing candidate genes identified in genome-wide association studies, identifying functional implications of synonymous variants, predicting population-specific impacts of synonymous variants and categorizing genetic biases unique to certain populations.

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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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