Synonymous but not the same: the causes and consequences of codon bias

Plotkin, Joshua B.; Kudla, Grzegorz

doi:10.1038/nrg2899

Cited by 1,364 publications

(1,436 citation statements)

References 145 publications

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“…We found a negative correlation between CBI and ENC ( R 2 = .985), G + Cc ( R 2 = .857) and G + C3s ( R 2 = .909), whereas a positive correlation was found between ENC and G + Cc ( R 2 = .85) and G + C3s ( R 2 = .896) (Figure 2). Results were consistent with the neutral mutational theories, in which the G + C content of mt genome was reported to be the most significant factor in determining codon bias among organisms (Chen, Lee, Hottes, Shapiro, & McAdams, 2004; Plotkin & Kudla, 2011). …”

Section: Resultssupporting

confidence: 88%

Comparative mitochondrial genomic analyses of three chemosynthetic vesicomyid clams from deep‐sea habitats

Liu

Cai

et al. 2018

Ecology and Evolution

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Vesicomyid clams of the subfamily Pliocardinae are among the dominant chemosymbiotic bivalves found in sulfide‐rich deep‐sea habitats. Plastic morphologies and present molecular data could not resolve taxonomic uncertainties. The complete mitochondrial (mt) genomes will provide more data for comparative studies on molecular phylogeny and systematics of this taxonomically uncertain group, and help to clarify generic classifications. In this study, we analyze the features and evolutionary dynamics of mt genomes from three Archivesica species (Archivesica sp., Ar. gigas and Ar. pacifica) pertaining to subfamily Pliocardinae. Sequence coverage is nearly complete for the three newly sequenced mt genomes, with only the control region and some tRNA genes missing. Gene content, base composition, and codon usage are highly conserved in these pliocardiin species. Comparative analysis revealed the vesicomyid have a relatively lower ratio of Ka/Ks, and all 13 protein‐coding genes (PGCs) are under strong purifying selection with a ratio of Ka/Ks far lower than one. Minimal changes in gene arrangement among vesicomyid species are due to the translocation trnaG in Isorropodon fossajaponicum. Additional tRNA genes were detected between trnaG and nad2 in Abyssogena mariana (trnaL3), Ab. phaseoliformis (trnaS3), and Phreagena okutanii (trnaM2), and display high similarity to other pliocardiin sequences at the same location. Single base insertion in multiple sites of this location could result in new tRNA genes, suggesting a possible tRNA arising from nongeneic sequence. Phylogenetic analysis based on 12 PCGs (excluding atp8) supports the monophyly of Pliocardiinae. These nearly complete mitogenomes provide relevant data for further comparative studies on molecular phylogeny and systematics of this taxonomically uncertain group of chemosymbiotic bivalves.

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Section: Resultssupporting

confidence: 88%

Comparative mitochondrial genomic analyses of three chemosynthetic vesicomyid clams from deep‐sea habitats

Liu

Cai

et al. 2018

Ecology and Evolution

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Section: Acc E P Ted P R E P R I Ntmentioning

confidence: 99%

“…In heterologous protein expression, the gene of interest can be over-expressed and can account for up to 30% of the total protein within the cell (Plotkin & Kudla 2011). This may place strain on the cell and hence, the principles of codon bias for heterologous protein expression may differ substantially from those for endogenous expression.…”

Section: Acc E P Ted P R E P R I Ntmentioning

confidence: 99%

Synthetic gene design—The rationale for codon optimization and implications for molecular pharming in plants

Webster

Teh

K.‐C.

2016

Biotech & Bioengineering

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Degeneracy in the genetic code allows multiple codon sequences to encode the same protein. Codon usage bias in genes is the term given to the preferred use of particular synonymous codons. Synonymous codon substitutions had been regarded as "silent" as the primary structure of the protein was not affected; however, it is now accepted that synonymous substitutions can have a significant effect on heterologous protein expression. Codon optimization, the process of altering codons within the gene sequence to improve recombinant protein expression, has become widely practised.Multiple inter-linked factors affecting protein expression need to be taken into consideration when optimizing a gene sequence. Over the years, various computer programmes have been developed to aid in the gene sequence optimization process. However, as the rulebook for altering codon usage to affect protein expression is still not completely understood, it is difficult to predict which strategy, if any, will design the 'optimal' gene sequence.In this review, codon usage bias and factors affecting codon selection will be discussed and the evidence for codon optimization impact will be reviewed for recombinant protein expression using plants as a case study. These developments will be relevant to all recombinant expression systems, however, molecular pharming in plants is an area which has consistently encountered difficulties with low levels of recombinant protein expression, and should benefit from an evidence based rational approach to synthetic gene design. This article is protected by copyright. All rights reserved

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“…These observations indicate that, although global codon bias may be affected by tRNA availability (6,(42)(43)(44), codon choice at a given position may be defined by at least three parameters: (i) amino acid sequence; (ii) mRNA structure near the start codon and RBS; and (iii) RBS-mediated pausing. In some cases, a subset of these parameters may not be under selection, resulting in an evolved sequence that converges for only a subset of the metrics.…”

Section: Discussionmentioning

confidence: 99%

“…Although it is tempting to approximate synonymous codons as equivalent (2), most prokaryotes and many eukaryotes (3, 4) display a strong preference for certain codons over synonymous alternatives (5,6). Although different species have evolved to prefer different codons, codon bias is largely consistent within each species (5).…”

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confidence: 99%

Emergent rules for codon choice elucidated by editing rare arginine codons in Escherichia coli

Napolitano

Landon

Gregg

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The degeneracy of the genetic code allows nucleic acids to encode amino acid identity as well as noncoding information for gene regulation and genome maintenance. The rare arginine codons AGA and AGG (AGR) present a case study in codon choice, with AGRs encoding important transcriptional and translational properties distinct from the other synonymous alternatives (CGN). We created a strain of Escherichia coli with all 123 instances of AGR codons removed from all essential genes. We readily replaced 110 AGR codons with the synonymous CGU codons, but the remaining 13 "recalcitrant" AGRs required diversification to identify viable alternatives. Successful replacement codons tended to conserve local ribosomal binding site-like motifs and local mRNA secondary structure, sometimes at the expense of amino acid identity. Based on these observations, we empirically defined metrics for a multidimensional "safe replacement zone" (SRZ) within which alternative codons are more likely to be viable. To evaluate synonymous and nonsynonymous alternatives to essential AGRs further, we implemented a CRISPR/Cas9-based method to deplete a diversified population of a wild-type allele, allowing us to evaluate exhaustively the fitness impact of all 64 codon alternatives. Using this method, we confirmed the relevance of the SRZ by tracking codon fitness over time in 14 different genes, finding that codons that fall outside the SRZ are rapidly depleted from a growing population. Our unbiased and systematic strategy for identifying unpredicted design flaws in synthetic genomes and for elucidating rules governing codon choice will be crucial for designing genomes exhibiting radically altered genetic codes.codon choice | genome editing | recoded genomes

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Synonymous but not the same: the causes and consequences of codon bias

Cited by 1,364 publications

References 145 publications

Comparative mitochondrial genomic analyses of three chemosynthetic vesicomyid clams from deep‐sea habitats

Comparative mitochondrial genomic analyses of three chemosynthetic vesicomyid clams from deep‐sea habitats

Synthetic gene design—The rationale for codon optimization and implications for molecular pharming in plants

Emergent rules for codon choice elucidated by editing rare arginine codons in Escherichia coli

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