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PubMed2006

[Codon usage of Chinese hamster ovary cells.].

BACKGROUND: To investigate the optimal codons of dihydrofolate reductase (dhfr) minus Chinese hamster ovary cells (CHO dhfr-). METHODS: A cDNA library of CHO dhfr- containing high abundence mRNA was constructed and protein-coding sequences were obtained after identification and analysis. Codon frequence of CHO dhf- was compared with that of Chinese hamster in CUTG database. Then codon usage variation among cDNA was investigated using correspondence analysis (COA). RESULTS: Fifty qualified cDNAs from CHO dhfr- were selected, which encodes proteins of high abundence. Comparing with the codon frequence of Chinese hamster, the highest frequence of synonymous codons for amino acids in CHO dhfr- cells were the same as Chinese hamster except that of Arg and Pro. This method of COA identifies the first main factor which can account for the largest fractions (14.7%) of variation among cDNAs. Twenty-two synonymous codons were identified as the optimal codons of CHO cell. CONCLUSION: CHO dhfr- cell has its own optimal codons, it is suggested that codon bias is one of reasons for functional diversity of different mammal cells and it is an effective stratagy to modification of the codon usage of the foreign gene according to the optimal codons of CHO dhfr- to increase the production of foreign gene.

Animals↗

PubMed1994

The use of logistic models for the analysis of codon frequencies of DNA sequences in terms of explanatory variables.

The development of the regressive logistic model applicable to the analysis of codon frequencies of DNA sequences in terms of explanatory variables is presented. A codon is a triplet of nucleotides that code for an amino acid, and may be considered as a trivariate response (B1, B2, B3), where Bi (i = 1, 2, 3) is a categorical random variable with values A, C, G, T. The linear order of bases in the DNA and possible statistical dependence of the bases in a given codon make the regressive logistic model a suitable tool for the analysis of codon frequencies. A problem of structural zeros arises from the fact that the stopping codons (terminators) do not code for amino acids; this is solved by normalizing the likelihood function. Codon frequencies may also depend on the function of the gene and they are known to differ between genes of the same genome. Differences also occur between synonymous codons for the same amino acid. Thus, the use of covariates that differ between synonymous codons as well as covariates that are constant within codons of the same amino acid may be useful in explaining the frequencies. As an illustration, the method is applied to the human mitochondrial genome using the following as explanatory variables: (1) TSCORE, a measure of the number of single base mutations required for a given codon to become a terminator; (2) AARISK, an indicator of a codon's ability of changing by a single base substitution to triplets coding for amino acids with very different characteristics; (3) AVDIST, a measure of the typicality of the amino acid coded for by the triplets. The results indicate that models that incorporate dependency structure and covariates are to be preferred to either the models comprising covariates alone or dependency structure alone.

Amino Acid Sequence↗

PubMed1994

Codon usage and bias among individual genes of the coccidia and piroplasms.

Codon usage has been analysed in individual gene sequences, derived from a variety of parasitic protozoa in the class Sporozoa of the phylum Apicomplexa using metric multidimensional scaling. The two groups of codon usage patterns detected reflect the two main subgroups of organisms studied (the coccidia and the piroplasms), and it is the pattern of usage of synonymous codons that has the largest influence on overall codon usage in the individual genes, rather than being the pattern of amino acid composition of the gene product. The magnitude of the codon usage bias in the sequences was determined using three commonly used indices-NC, GC3S and B. In general, although relatively low levels of codon usage bias were detected in these gene sequences, codon usage bias does explain at least some of the codon usage patterns observed. Codon usage bias was observed to be dependent on the overall base composition of the genes analysed, which in turn was reflected in the types of codons that were either over- or under-represented in the nucleotide sequences. In keeping with observations on prokaryotic organisms, it is speculated that the codon usage patterns detected in these parasitic protozoa are the result of directional mutation pressure on the base composition of the genomic DNA.

Animals↗

PubMed1994

The second to last amino acid in the nascent peptide as a codon context determinant.

Forty-two different sense codons, coding for all 20 amino acids, were placed at the ribosomal E site location, two codons upstream of a UGA or UAG codon. The influence of these variable codons on readthrough of the stop codons was measured in Escherichia coli. A 30-fold difference in readthrough of the UGA codon was observed. Readthrough is not related to any property of the upstream codon, its cognate tRNA or the nature of its codon-anticodon interaction. Instead, it is the amino acid corresponding to the second upstream codon, in particular the acidic/basic property of this amino acid, which seems to be a major determinant. This amino acid effect is influenced by the identity of the A site stop codon and the efficiency of its decoding tRNA, which suggests a correlation with ribosomal pausing. The magnitude of the amino acid effect is in some cases different when UGA is decoded by a wildtype form of tRNA(Trp) as compared with a suppressor form of the same tRNA. This indicates that the structure of the A site decoding tRNA is also a determinant for the amino acid effect.

Amino Acids↗

PubMed2002

Third position codon composition suggests two classes of genes within the Cauliflower mosaic virus genome.

The translation of viral mRNAs by host ribosomes is essential for infection. Hence, codon usage of virus genes may influence efficiency of infection. In addition, composition of nucleotides in the third position within codons of genes can reflect evolutionary relationships. In this study, third position codon composition was examined for the seven genes of eight Cauliflower mosaic virus isolates. Genes IV-VII had similar codon composition values and were termed Class 1 genes. Genes I-III possessed corresponding codon composition values and were termed Class 2 genes. The codon composition values of Class 1 and genes differed significantly. Neither Class 1 nor Class 2 genes had codon composition values identical to that of the host plant, Arabidopsis thaliana. However, Class 1 genes possessed codon composition values closer to those of the host than Class 2 genes. Examination of the genomes of three Rous sarcoma virus isolates indicated that codon composition values were similar for the gag, pol, and env genes but these genes differed significantly from the src genes. Since codon composition values for Rous sarcoma virus distinguished a "foreign" gene from the rest of the viral genome, it is possible that the Cauliflower mosaic virus genome is composed of genes from two different sources. Others have suggested that Cauliflower mosaic virus evolved in this manner and our data provide support for this hypothesis.

Arabidopsis↗

PubMed1993

Chloroplast DNA codon use: evidence for selection at the psb A locus based on tRNA availability.

Codon use in the three sequenced chloroplast genomes (Marchantia, Oryza, and Nicotiana) is examined. The chloroplast has a bias in that codons NNA and NNT are favored over synonymous NNC and NNG codons. This appears to be a consequence of an overall high A + T content of the genome. This pattern of codon use is not followed by the psb A gene of all three genomes and other psb A sequences examined. In this gene, the codon use favors NNC over NNT for twofold degenerate amino acids. In each case the only tRNA coded by the genome is complementary to the NNC codon. This codon use is similar to the codon use by chloroplast genes examined from Chlamydomonas reinhardtii. Since psb A is the major translation product of the chloroplast, this suggests that selection is acting on the codon use of this gene to adapt codons to tRNA availability, as previously suggested for unicellular organisms.

Animals↗

PubMed1989

Evolution of the mitochondrial genetic code. I. Origin of AGR serine and stop codons in metazoan mitochondria.

AGA and AGG (AGR) are arginine codons in the universal genetic code. These codons are read as serine or are used as stop codons in metazoan mitochondria. The arginine residues coded by AGR in yeast or Trypanosoma are coded by arginine CGN throughout metazoan mitochondria. AGR serine sites in metazoan mitochondria are occupied mainly in corresponding sites in yeast or Trypanosoma mitochondria by UCN serine, AGY serine, or codons for amino acids other than serine or arginine. Based on these observations, we propose the following evolutionary events. AGR codons became unassigned because of deletion of tRNA Arg (UCU) and elimination of AGR codons by conversion to CGN arginine codons. Upon acquisition by serine tRNA of pairing ability with AGR codons, some codons for amino acids other than arginine mutated to AGR, and were captured by anticodon GCU in serine tRNA. During vertebrate mitochondrial evolution, AGR stop codons presumably were created from UAG stop by deletion of the first nucleotide U and by use of R as the third nucleotide that had existed next to the ancestral UAG stop.

Animals↗

PubMed2005

Relationships among stop codon usage bias, its context, isochores, and gene expression level in various eukaryotes.

It is well known that stop codons play a critical role in the process of protein synthesis. However, little effort has been made to investigate whether stop codon usage exhibits biases, such as widely seen for synonymous codon usage. Here we systematically investigate stop codon usage bias in various eukaryotes as well as its relationships with its context, GC3 content, gene expression level, and secondary structure. The results show that there is a strong bias for stop codon usage in different eukaryotes, i.e., UAA is overrepresented in the lower eukaryotes, UGA is overrepresented in the higher eukaryotes, and UAG is least used in all eukaryotes. Different conserved patterns for each stop codon in different eukaryotic classes are found based on information content and logo analysis. GC3 contents increase with increasing complexity of organisms. Secondary structure prediction revealed that UAA is generally associated with loop structures, whereas UGA is more uniformly present in loop and stem structures, i.e., UGA is less biased toward having a particular structure. The stop codon usage bias, however, shows no significant relationship with GC3 content and gene expression level in individual eukaryotes. The results indicate that genomic complexity and GC3 content might contribute to stop codon usage bias in different eukaryotes. Our results indicate that stop codons, like synonymous codons, exhibit biases in usage. Additional work will be needed to understand the causes of these biases and their relationship to the mechanism of protein termination.

Base Sequence↗

PubMed1990

Analysis of the stop codon context in plant nuclear genes.

A region of 18 nucleotides surrounding the stop codon (the stop codon context) in 748 plant nuclear genes was analyzed. Non-randomness was found both upstream and downstream from the stop codon, suggesting that these sequences may help in ensuring efficient termination of translation. The UAG amber codon is the least-used stop codon and the bias in the nucleotide distribution 5' and 3' to the stop codon was more pronounced for the amber codon than for the other stop codons. This might indicate that the codon context affects termination more at UAG than at UGA or UAA stop codons.

Base Composition↗

PubMed1989

A study of the purine/pyrimidine codon occurrence with a reduced centered variable and an evaluation compared to the frequency statistic.

With the three-letter alphabet [R,Y,N] (R = purine, Y = pyrimidine, N = R or Y), there are 26 codons (NNN being excluded): RNN,...,NNY (six codons at two unspecified bases N), RRN,...,NYY (12 codons at one unspecified base N), RRR,...,YYY (eight specified codons). A statistical methodology that uses the codon frequency and a reduced centered variable leads to similar results for a codon occurrence study, regardless of gene function and regardless of a particular protein coding gene taxonomic population. Therefore, this variable can be considered a new codon usage index, whose use removes certain nonsignificant results found with the frequency statistic. This methodology identifies the common and rare codons (i.e., the codons having the highest and lowest occurrence) and leads to a model of codon evolution at three successive states: RNN, then RNY, and finally RYY. Some biological relations between this model and the YRY(N)6YRY preferential occurrence are also presented.

Base Sequence↗

PubMed1995

Correlation between codon usage, regional genomic nucleotide composition, and amino acid composition in the cytochrome P-450 gene superfamily.

The codon usage bias of 110 mammalian cytochrome P-450 genes has been determined and analyzed in relation to a variety of genetic, biochemical, and physiological parameters. In those P-450 genes exhibiting biased usage the preferred codons generally do not differ among the four species examined (rat, rabbit, man, and mouse) or from the predominantly used codons identified for all sequenced genes in a recent data base analysis (Wada et al. (1992) Nucleic Acids Res. 20 (Suppl.), 2111-2118). Codon usage bias does not correlate with evolutionary relationships, evolutionary age, or with the extent of evolutionary conservation of orthologous proteins; there is no obvious correlation with the level of expression of a given P-450, with its inducibility, nor with its physiologic role; and neither the preferred codons nor the degree of bias differ for P-450s expressed in different tissues. Codon usage bias does correlate with the C+G content at the codon third position, and thus preferred codons usually end in C or G; for those P-450s for which gene sequences are available this bias also correlates with the C + G content of the intronic and flanking regions of these genes. Moreover, a lesser increase in the C + G content at the codon first and second positions is also evident in genes located in regions of high C + G content; this leads to predictable differences in the amino acid compositions of P-450 enzymes that correlate with genomic nucleotide composition and the degree of bias in codon usage.

Amino Acids↗

PubMed2006

Analysis of codon usage pattern in the radioresistant bacterium Deinococcus radiodurans.

The main factors shaping codon usage bias in the Deinococcus radiodurans genome were reported. Correspondence analysis (COA) was carried out to analyze synonymous codon usage bias. The results showed that the main trend was strongly correlated with gene expression level assessed by the "Codon Adaptation Index" (CAI) values, a result that was confirmed by the distribution of genes along the first axis. The results of correlation analysis, variance analysis and neutrality plot indicated that gene nucleotide composition was clearly contributed to codon bias. CDS length was also key factor in dictating codon usage variation. A general tendency of more biased codon usage of genes with longer CDS length to higher expression level was found. Further, the hydrophobicity of each protein also played a role in shaping codon usage in this organism, which could be confirmed by the significant correlation between the positions of genes placed on the first axis and the hydrophobicity values (r=-0.100, P<0.01). In summary, gene expression level played a crucial role, nucleotide mutational bias, CDS length and the hydrophobicity of each protein just in a minor way in shaping the codon usage pattern of D. radiodurans. Notably, 19 codons firstly defined as "optimal codons" may provide useful clues for molecular genetic engineering and evolutionary studying.

Codon↗

PubMed2006

Clonorchis sinensis: codon usage in nuclear genes.

Codon usage in Clonorchis sinensis was analyzed using 12,515 codons from 38 coding sequences. Total GC content was 49.83%, and GC1, GC2 and GC3 contents were 56.32%, 43.15% and 50.00%, respectively. The effective number of codons converged at 51-53 codons. When plotted against total GC content or GC3, codon usage was distributed in relation to GC3 biases. Relative synonymous codon usage for each codon revealed a single major trend, which was highly correlated with GC content at the third position when codons began with A or U at the first two positions. In codons beginning with G or C base at the first two positions, the G or C base rarely occurred at the third position. These results suggest that codon usage is shaped by a bias towards G or C at the third base, and that this is affected by the first and second bases.

Amino Acids↗

PubMed2004

Enhanced expression of a recombinant malaria candidate vaccine in Escherichia coli by codon optimization.

This study was conducted to compare the expression of three constructs of a multistage candidate vaccine (FALVAC-1) against Plasmodium falciparum in an Escherichia coli system: a synthetic gene with P. falciparum codons, a synthetic gene with optimized E. coli codons, and a synthetic gene with P. falciparum codons co-transformed with a RIG plasmid, which encodes three tRNAs (AG(A/G), ATA, GGA) that recognize rare E. coli codons. The expression of the protein increased at least threefold with codon optimization. The presence of the RIG plasmid in the co-transforming cells did not significantly increase the expression level of the gene with P. falciparum codons. The growth of cells transformed by the construct with P. falciparum codons was significantly slower than that of cells transformed by the construct with optimized E. coli codons after induction of protein expression with IPTG. The cells containing the non-codon optimized gene co-expressed with RIG plasmid had the slowest growth at all time points in culture. Thus, codon optimization significantly increases the yield of P. falciparum candidate vaccines in the E. coli expression system.

Amino Acid Sequence↗

PubMed1997

Codon bias evolution in Drosophila. Population genetics of mutation-selection drift.

Although non-random patterns of synonymous codon usage are a prominent feature in the genomes of many organisms, the relatives roles of mutational biases and natural selection in maintaining codon bias remain a contentious issue. In some species, patterns of codon bias and empirical findings on the biology of translation suggest 'major codon preference', a balance among mutation pressure, genetic drift, and weak selection in favor of translationally superior codons. Population genetics theory makes testable predictions to distinguish such a model from a strictly mutational model of codon bias. Major codon preference predicts two fitness classes of synonymous DNA changes: 'preferred' mutations from non-major to major codons and 'unpreferred' changes in the opposite direction. An extension of current statistical methods is employed to reveal differences in the within and between species dynamics of preferred and unpreferred silent mutations in Drosophila simulans. In this lineage, codon bias appears to be maintained under roughly equal magnitudes of natural selection and genetic drift. In the sibling species, D. melanogaster, however, a reduction in N(e)s, the product of effective population size and selection coefficient, appears to have allowed a genome-wide reduction in codon bias.

Animals↗

PubMed2000

Terminating eukaryote translation: domain 1 of release factor eRF1 functions in stop codon recognition.

Eukaryote ribosomal translation is terminated when release factor eRF1, in a complex with eRF3, binds to one of the three stop codons. The tertiary structure and dimensions of eRF1 are similar to that of a tRNA, supporting the hypothesis that release factors may act as molecular mimics of tRNAs. To identify the yeast eRF1 stop codon recognition domain (analogous to a tRNA anticodon), a genetic screen was performed to select for mutants with disabled recognition of only one of the three stop codons. Nine out of ten mutations isolated map to conserved residues within the eRF1 N-terminal domain 1. A subset of these mutants, although wild-type for ribosome and eRF3 interaction, differ in their respective abilities to recognize each of the three stop codons, indicating codon-specific discrimination defects. Five of six of these stop codon-specific mutants define yeast domain 1 residues (I32, M48, V68, L123, and H129) that locate at three pockets on the eRF1 domain 1 molecular surface into which a stop codon can be modeled. The genetic screen results and the mutant phenotypes are therefore consistent with a role for domain 1 in stop codon recognition; the topology of this eRF1 domain, together with eRF1-stop codon complex modeling further supports the proposal that this domain may represent the site of stop codon binding itself.

Alleles↗

PubMed1985

Translational efficiency of the Escherichia coli adenylate cyclase gene: mutating the UUG initiation codon to GUG or AUG results in increased gene expression.

Roy et al. [Roy, A., Haziza, C. & Danchin, A. (1983) EMBO J. 2, 791-797] established that translation of Escherichia coli adenylate cyclase initiates at a UUG codon, and they suggested this might decrease the efficiency of translation. We investigated the effect of varying the initiation codon on the expression of the adenylate cyclase (cya) gene. Using oligonucleotide-directed mutagenesis, we changed the UUG initiation codon to GUG and the more common initiator AUG and assayed for cya gene expression in a number of ways. First, the GUG initiation codon, in place of UUG, doubled cya expression when cya was expressed from the dual cya P1/P2 promoters. The corresponding AUG codon construct was nonviable. Second, when the cya gene was placed under the transcriptional control of the thermoinducible phage lambda PL promoter, the relative amounts of cya gene product were 1:2:6 for the UUG, GUG, and AUG initiation codons, respectively. Finally, the cya P2 promoter, Shine-Dalgarno sequence, and the DNA corresponding to the first 86 codons of cya were fused to DNA encoding the E. coli galactokinase gene beginning at the second codon. The relative amounts of the fusion polypeptides, which had galactokinase activity, were 1:2:3 for the UUG, GUG, and AUG initiation codons, respectively. These results demonstrate that the cya UUG initiation codon limits cya expression at the level of translation.

Adenylyl Cyclases↗

PubMed2006

Selective constraints on codon usage of nuclear genes from Arabidopsis thaliana.

Highly expressed nuclear genes from Arabidopsis thaliana show an increased frequency of codons that match abundant tRNAs, and it has been suggested that this reflects a selective pressure to increase translation efficiency. Here we explore the possibility that the difference in codon usage between highly expressed genes and other Arabidopsis genes is not the result of selection but, rather, arises from mutation biases. Specifically, we explore the possibility that an influence of transcription level on mutational properties coupled with a context dependency of mutations, both of which have been observed in various organisms, contribute to variation in codon-usage bias across genes. Using noncoding sites immediately flanking both high- and low-expression-coding sequences to infer context-dependent composition biases, we analyze codon-usage bias across genes. The data show that mutation bias cannot explain codon usage of high-expression genes in Arabidopsis and, surprisingly, also indicate that even low-expression genes are under selective constraints. In addition, the data indicate that the general preference for certain codons is context dependent; the composition of the 3' nucleotide, that is, the first position of the next codon, is correlated with what codon is found at an increased frequency in highly expressed genes. This context dependency indicates that selective pressure on codon usage is more complex than previously thought. Overall, the study supports previous suggestions that selection plays a significant role in determining codon usage of nuclear genes in A. thaliana.

Arabidopsis↗