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PubMed2004

Synonymous codon usage analysis of the mycobacteriophage Bxz1 and its plating bacteria M. smegmatis: identification of highly and lowly expressed genes of Bxz1 and the possible function of its tRNA species.

The extent of codon usage in the protein coding genes of the mycobacteriophage, Bxz1, and its plating bacteria, M. smegmatis, were determined, and it was observed that the codons ending with either G and / or C were predominant in both the organisms. Multivariate statistical analysis showed that in both organisms, the genes were separated along the first major explanatory axis according to their expression levels and their genomic GC content at the synonymous third positions of the codons. The second major explanatory axis differentiates the genes according to their genome type. A comparison of the relative synonymous codon usage between 20 highly- and 20 lowly expressed genes from Bxz1 identified 21 codons, which are statistically over represented in the former group of genes. Further analysis found that the Bxz1- specific tRNA species could recognize 13 out of the 21 over represented synonymous codons, which incorporated 13 amino acid residues preferentially into the highly expressed proteins of Bxz1. In contrast, seven amino acid residues were preferentially incorporated into the lowly expressed proteins by 10 other tRNA species of Bxz1. This analysis predicts for the first time that the Bxz1-specific tRNA species modulates the optimal expression of its proteins during development.

Codon↗

PubMed2001

Codon-usage based regulation of colicin K synthesis by the stress alarmone ppGpp.

The molecular mechanism of the upregulation of Escherichia coli colicin K (Cka) synthesis during stress conditions was studied. Nutrient starvation experiments and the use of relA spoT mutant strains, IPTG-regulated overproduction of ppGpp and lacZ fusions revealed that the stringent response alarmone guanosine 3',5'-bispyrophosphate (ppGpp) is the main positive effector of Cka synthesis. Comparison of the amounts of protein produced (Western blotting) and specific mRNA (Northern blotting) before and after nutrient starvation demonstrated increases in Cka protein with unaltered specific mRNA levels, suggesting a post-transcriptional regulatory mechanism. Reporter (beta-galactosidase) assays using truncated cka of variable length fused to lacZ located the key regulatory region close to the 5' end of the cka mRNA. Closer analysis of this region indicated the presence of several rare codons, including the leucine-encoding codon CUA. Synonymous exchange of the rare codons with more frequently used ones abolished the regulatory effect of ppGpp. Supplementation of the strain with the plasmid CodonPlus carrying several rare tRNA genes yielded similar results, indicating that codon usage (in particular, the fifth codon for the amino acid leucine) and tRNA availability (i.e. tRNAleu) are the key elements of the regulatory function of ppGpp. We conclude that ppGpp regulates Cka synthesis via a novel post-transcriptional mechanism that is based on rare codon usage and variable cognate tRNA availability.

Codon↗

PubMed1991

Codon usage and G + C content in Bradyrhizobium japonicum genes are not uniform.

To date, the sequences of 45 Bradyrhizobium japonicum genes are known. This provides sufficient information to determine their codon usage and G + C content. Surprisingly, B. japonicum nodulation and NifA-regulated genes were found to have a less biased codon usage and a lower G + C content than genes not belonging to these two groups. Thus, the coding regions of nodulation genes and NifA-regulated genes could hardly be identified in codon preference plots whereas this was not difficult with other genes. The codon frequency table of the highly biased genes was used in a codon preference plot to analyze the RSRj alpha 9 sequence which is an insertion sequence (IS)-like element. The plot helped identify a new open reading frame (ORF355) that escaped previous detection because of two sequencing errors. These were now corrected. The deduced gene product of ORF355 in RSRj alpha 9 showed extensive similarity to a putative protein encoded by an ORF in the T-DNA of Agrobacterium rhizogenes. The DNA sequences bordering both ORFs showed inverted repeats and potential target site duplications which supported the assumption that they were IS-like elements.

Amino Acid Sequence↗

PubMed2000

Evolutionary change of codon usage for the histone gene family in Drosophila melanogaster and Drosophila hydei.

The nucleotide divergence in the protein-coding region for replication-dependent and replication-independent histone 3 and 4 genes of Drosophila melanogaster and Drosophila hydei occurred mostly at the synonymous site. Therefore, the pattern of codon usage was analyzed in the two species, considering the genomic codon bias, which is proposed for estimating the genomic composition pressure in the protein-coding regions. The results indicated that the codon usage in the histone gene family could be explained mostly by the genomic codon bias. However, biases for Ala and Arg were commonly observed for the histone 3 and histone 4 gene families, and biases for Ser, Leu, and Glu were observed in a gene-specific manner. This suggests that both genomic codon bias and gene- or codon-specific bias are responsible for the nucleotide differentiation in the protein-coding region of the histone genes.

Animals↗

PubMed1998

Increased immune response elicited by DNA vaccination with a synthetic gp120 sequence with optimized codon usage.

DNA vaccination elicits humoral and cellular immune responses and has been shown to confer protection against several viral, bacterial, and parasitic pathogens. Here we report that optimized codon usage of an injected DNA sequence considerably increases both humoral and cellular immune responses. We recently generated a synthetic human immunodeficiency virus type 1 gp120 sequence in which most wild-type codons were replaced with codons from highly expressed human genes (syngp120). In vitro expression of syngp120 is considerably increased in comparison to that of the respective wild-type sequence. In BALB/c mice, DNA immunization with syngp120 resulted in significantly increased antibody titers and cytotoxic T-lymphocyte reactivity, suggesting a direct correlation between expression levels and the immune response. Moreover, syngp120 is characterized by rev-independent expression and a low risk of recombination with viral sequences. Thus, synthetic genes with optimized codon usage represent a novel strategy to increase the efficacy and safety of DNA vaccination.

AIDS Vaccines↗

PubMed2004

Tissue-specific codon usage and the expression of human genes.

A diverse array of mechanisms regulate tissue-specific protein levels. Most research, however, has focused on the role of transcriptional regulation. Here we report systematic differences in synonymous codon usage between genes selectively expressed in six adult human tissues. Furthermore, we show that the codon usage of brain-specific genes has been selectively preserved throughout the evolution of human and mouse from their common ancestor. Our findings suggest that codon-mediated translational control may play an important role in the differentiation and regulation of tissue-specific gene products in humans.

Adult↗

PubMed1998

Optimization of codon usage of plasmid DNA vaccine is required for the effective MHC class I-restricted T cell responses against an intracellular bacterium.

In an attempt to study codon usage effects of DNA vaccines on the induction of MHC class I-restricted T cell responses against an intracellular bacterium, Listeria monocytogenes, we designed two plasmid DNA vaccines encoding an H-2Kd-restricted epitope of listeriolysin O (LLO) of L. monocytogenes, LLO 91-99. One DNA vaccine, p91wt, carries the wild-type DNA sequence encoding LLO 91-99, and the other one, p91mam, possesses the altered DNA sequence in which the codon usage was optimized for murine system. Our read-through analyses with LLO 91-99/luciferase fusion genes confirmed that the optimized 91mam DNA sequence showed extremely higher translation efficiency than the wild-type sequence in murine cells. Consistent with this, i.m. injections of p91mam, but not of p91wt, into BALB/c mice were capable of inducing specific CTL- and IFN-gamma-producing CD8+ T cells able to confer partial protection against listerial challenge. Taken together, these observations suggest that optimization of codon should be taken into consideration in the construction of DNA vaccines against nonviral pathogens.

Animals↗

PubMed1999

Codon usage tabulated from the international DNA sequence databases; its status 1999.

Frequencies for each of the 206 526 complete protein-coding genes (CDS's) have been compiled from taxonomical divisions of the GenBank DNA sequence database. The sum of the codon use of 7434 organisms has also been calculated. These data files can be obtained from anonymous ftp sites of DDBJ, DISC and EBI. The list of the codon usage of genes in an organism as well as the sum of the codon usage of the organism was made searchable by the name of organism through a web site http://www.dna.affrc.go.jp//CUTG.html

Animals↗

PubMed2002

Influence of parasitic life style on the patterns of codon usage and base frequencies of Ancylostoma and Necator species.

Parametric analyses were used to investigate the nucleotide, codon, and amino acid composition of coding sequences corresponding to hook-worms. Ancylostoma caninum and Necator americanus. Although genomic research has become prevalent within the scientific community, few studies have dealt directly with parasitic species. Parasites have existed throughout the history of mankind due to their wide range of distribution in nature and their ability to evade immune detection. An AT nucleotide bias was identified in both A. caninum and N. americanus sequences. A similar AT bias was also identified in both datasets when considering relative synonymous codon usage. However, the codon bias was much more pronounced in N. americanus as compared to A. caninum. Bias was also present at the amino acid level, and appeared to be partially independent of the nucleotide-based biases. Analysis of parasite genomes will facilitate the development of vaccines against larval forms of parasites. Moreover, the examination of the parasite genes in general, will allow for a more in-depth understanding of the evolution of the parasites and parasitism.

Ancylostoma↗

PubMed1992

Diagrammatization of codon usage in 339 human immunodeficiency virus proteins and its biological implication.

The occurrence frequencies of bases A (adenine), C (cytosine, G (guanine), and T (thymine) occurring in the 1st, 2nd, and 3rd codon positions in the codon usage table of viral genes for the 339 human immunodeficiency virus (HIV) proteins compiled recently have been calculated and diagrammatized. For comparison, the corresponding diagrammatic representations for the 2681 human proteins from the codon usage table for primate genes are also presented. The analyzed results based on these characteristic diagrams indicate that considerably similar features have been found between HIV and human proteins for the 1st and 2nd codon positions; i.e., they are all occupied predominantly by purine, especially base A. However, a significant difference in the 3rd codon position between HIV and human proteins has been observed; i.e., human proteins are of high C + G content and low A + G content in the 3rd codon position, whereas the case is just the opposite for HIV proteins. The biological implication of such a duality on the codon bias of HIV against human proteins is discussed. It is suggested that the 1st and 2nd codon positions can be termed as the structure-determining position, and the 3rd codon position termed as the species-determining position. The diagrammatic representation and analysis method described here possess a great potential for the study of molecular evolution from the viewpoint of the genetic code for which data have been accumulated rapidly and will continue to grow at a much faster pace.

Base Composition↗

PubMed1998

Phylogenetic position and codon usage of two centrin genes from the rumen ciliate protozoan, Entodinium caudatum.

A lambda phage cDNA expression library was constructed from washed suspensions of the rumen ciliate protozoan, Entodinium caudatum, which had been maintained in an isolated, monofaunated sheep. The library was screened using an anti-E. caudatum antiserum raised in rabbits against sonically disrupted protozoa, DNA sequences for two centrins or caltractins, a subfamily of the EF-hand Ca(2+)-modulated proteins which are closely related, highly conserved cytoskeletal proteins, were identified and characterised. Their phylogenetic position was established relative to other centrin gene sequences. The two proteins showed homology to Paramecium tetraurelia centrins: 50 and 52% identities and 71 and 75% similarities in the protein sequence, over 99 and 110 amino acids fragments. Codon usage and indices revealed the E. caudatum follows universal codon usage, but with a restricted number of codons, and has a low G&C content.

Animals↗

PubMed1999

Transfer RNA genes and their significance to codon usage in the Pseudomonas aeruginosa lamboid bacteriophage D3.

Using tRNAscan-SE and FAStRNA we have identified four tRNA genes in the delayed early region of the bacteriophage D3 genome (GenBank accession No. AF077308). These are specific for methionine (AUG), glycine (GGA), asparagine (AAC), and threonine (ACA). The D3 Thr- and Gly-tRNAs recognize codons, which are rarely used in Pseudomonas aeruginosa and presumably, influence the rate of translation of phage proteins. BLASTN searches revealed that the D3 tRNA genes have homology to tRNA genes from Gram-positive bacteria. Analysis of codon usage in the 91 ORFs discovered in D3 indicates patterns of codon usage reminiscent of Escherichia coli or P. aeruginosa.

Bacteriophages↗

PubMed1991

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

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.

Amino Acyl-tRNA Synthetases↗

PubMed1988

Specific codon usage pattern and its implications on the secondary structure of silk fibroin mRNA.

We have identified two distinctive regions of the repetitive unit nucleotide sequence of fibroin mRNA of Bombyx mori. The codon usage for the major amino acids, glycine, alanine and serine is distinctly different in these two regions, indicating that it is determined by the fibroin mRNA or gene structure but not by the tRNA population. Comparative computer analyses of nucleotide substitutions in the unit sequence suggest that selection has operated on the codon usage to optimize the secondary structure characteristic of the fibroin mRNA.

Amino Acid Sequence↗

PubMed1999

Papillomavirus capsid protein expression level depends on the match between codon usage and tRNA availability.

Translation of mRNA encoding the L1 and L2 capsid proteins of papillomavirus (PV) is restricted in vivo to differentiated epithelial cells, although transcription of the L1 and L2 late genes occurs more widely. The codon composition of PV late genes is quite different from that of most mammalian genes. To test the possibility that PV late gene codon composition determines the efficiency of PV late gene expression in some cell types, synthetic bovine papillomavirus type 1 (BPV1) late genes were constructed with codon composition modified to resemble the typical mammalian gene. Expression of these genes from a strong promoter in Cos-1 cells was compared with expression of wild-type BPV1 late genes from the same promoter. Both unmodified and modified PV late genes were transcribed in Cos-1 cells, but only the codon-modified genes were translated. In vitro translation of wild-type but not synthetic BPV1 L1 mRNA was markedly enhanced by addition of aminoacyl-tRNAs. Codon composition thus limits BPV1 late gene translation in Cos-1 cells, and this limitation can be overcome by modification of the codon composition of the genes or by provision of excess tRNA. Replacement of codons in the green fluorescent protein (gfp) gene with those frequently used in PV late genes did not alter gfp transcription in Cos-1 cells but almost abolished translation, supporting the hypothesis that the observed differences in efficiency of translation of modified and unmodified PV capsid genes were related to codon usage rather than mRNA structure. As tRNA populations vary within and between tissues in the same eukaryotic organism, we speculate that matching of tRNA availability to codon usage may be one determinant of the restriction of expression of PV late genes to differentiated epithelium.

Amino Acid Sequence↗

PubMed1999

Strand asymmetry and codon usage bias in the chloroplast genome of Euglena gracilis.

It is shown that the two strands of the chloroplast genome from Euglena gracilis are asymmetric with regards to nucleotide composition. This asymmetry switches at both the origin of replication and a location that is halfway around the circular genome from the origin. In both halves of the genome the leading strand is G+T-rich, having a bias toward G over C and T over A, and the lagging strand is A+C-rich. This asymmetry is probably the result of a difference in mutation dynamics between the leading and lagging strands. In addition to composition asymmetry, the two strands differ with regards to coding content. In both halves of the genome the vast majority of genes are coded by the leading strand. These two aspects of strand asymmetry are then applied to a statistical test for selection on codon usage. The results indicate that selection on codon usage is limited to genes on the leading strand; no gene on the A+C-rich lagging strand shows evidence for selection, suggesting that highly expressed genes are coded predominantly on the strand of DNA that is the leading strand during replication. On the basis of these observations it is proposed that the coding strand bias is generated by selection to code highly expressed genes on the leading strand to coordinate the direction of replication and transcription, thereby increasing the potential rate of both reactions.

Animals↗

PubMed1992

An analysis of the codon usage of Pasteurella haemolytica A1.

Analysis of approximately 17 kbp of nucleotide sequences from three different regions of the genome of Pasteurella haemolytica A1 showed that the mol% G+C of P. haemolytica A1 DNA is 38.5%. When only the coding sequences (approx. 10 kbp) were analysed, a similar value of 38.8% was obtained. A comparison of the relative synonymous codon usage values of the cloned genes showed that P. haemolytica A1 has a very different codon usage pattern from that of Escherichia coli.

Base Composition↗

PubMed2003

Patterns of codon usage bias in three dicot and four monocot plant species.

Codon usage in nuclear genes of four monocot and three dicot species was analyzed to find general patterns in codon choice of plant species. Codon bias was correlated with GC content at the third codon position. GC contents were higher in monocot species than in dicot species at all codon positions. The high GC contents of monocot species might be the result of relatively strong mutational bias that occurred in the lineage of the Poaceae species. In both dicot and monocot species, the effective number of codons (ENCs) for most genes was similar to that for the expected ENCs based on the GC content at the third codon positions. G and C ending codons were detected as the "preferred" codons in monocot species, as in Drosophila. Also, many "preferred" codons are the same in dicot species. Pyrimidine (C and T) is used more frequently than purine (G and A) in four-fold degenerate codon groups.

Amino Acid Sequence↗