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At least 19 recordsLinked to original sources
PubMed1990

Suppression of the negative effect of minor arginine codons on gene expression; preferential usage of minor codons within the first 25 codons of the Escherichia coli genes.

AGA and AGG codons for arginine are the least used codons in Escherichia coli, which are encoded by a rare tRNA, the product of the dnaY gene. We examined the positions of arginine residues encoded by AGA/AGG codons in 678 E. coli proteins. It was found that AGA/AGG codons appear much more frequently within the first 25 codons. This tendency becomes more significant in those proteins containing only one AGA or AGG codon. Other minor codons such as CUA, UCA, AGU, ACA, GGA, CCC and AUA are also found to be preferentially used within the first 25 codons. The effects of the AGG codon on gene expression were examined by inserting one to five AGG codons after the 10th codon from the initiation codon of the lacZ gene. The production of beta-galactosidase decreased as more AGG codons were inserted. With five AGG codons, the production of beta-galactosidase (Gal-AGG5) completely ceased after a mid-log phase of cell growth. After 22 hr induction of the lacZ gene, the overall production of Gal-AGG5 was 11% of the control production (no insertion of arginine codons). When five CGU codons, the major arginine codon were inserted instead of AGG, the production of beta-galactosidase (Gal-CGU5) continued even after stationary phase and the overall production was 66% of the control. The negative effect of the AGG codons on the Gal-AGG5 production was found to be dependent upon the distance between the site of the AGG codons and the initiation codon. As the distance was increased by inserting extra sequences between the two codons, the production of Gal-AGG5 increased almost linearly up to 8 fold. From these results, we propose that the position of the minor codons in an mRNA plays an important role in the regulation of gene expression possibly by modulating the stability of the initiation complex for protein synthesis.

Amino Acid Sequence↗
PubMed1982

Preferential codon usage in prokaryotic genes: the optimal codon-anticodon interaction energy and the selective codon usage in efficiently expressed genes.

By considering the nucleotide sequence of several highly expressed coding regions in bacteriophage MS2 and mRNAs from Escherichia coli, it is possible to deduce some rules which govern the selection of the most appropriate synonymous codons NNU or NNC read by tRNAs having GNN, QNN or INN as anticodon. The rules fit with the general hypothesis that an efficient in-phase translation is facilitated by proper choice of degenerate codewords promoting a codon-anticodon interaction with intermediate strength (optimal energy) over those with very strong or very weak interaction energy. Moreover, codons corresponding to minor tRNAs are clearly avoided in these efficiently expressed genes. These correlations are clearcut in the normal reading frame but not in the corresponding frameshift sequences +1 and +2. We hypothesize that both the optimization of codon-anticodon interaction energy and the adaptation of the population to codon frequency or vice versa in highly expressed mRNAs of E. coli are part of a strategy that optimizes the efficiency of translation. Conversely, codon usage in weakly expressed genes such as repressor genes follows exactly the opposite rules. It may be concluded that, in addition to the need for coding an amino acid sequence, the energetic consideration for codon-anticodon pairing, as well as the adaptation of codons to the tRNA population, may have been important evolutionary constraints on the selection of the optimal nucleotide sequence.

Anticodon↗
PubMed2004

A codon window in mRNA downstream of the initiation codon where NGG codons give strongly reduced gene expression in Escherichia coli.

The influences on gene expression by codons at positions +2, +3, +5 and +7 downstream of the initiation codon have been compared. Most of the +2 codons that are known to give low gene expression are associated with a higher expression if placed at the later positions. The NGG codons AGG, CGG, UGG and GGG, but not GGN or GNG (where N is non-G), are unique since they are associated with a very low gene expression also if located at positions +2, +3 and +5. All codons, including NGG, give a normal gene expression if placed at positions +7. The negative effect by the NGG codons is true for both the lacZ and 3A' model genes. The low expression is suggested to originate at the translational level, although it is not the result of mRNA secondary structure or a lowered intracellular mRNA pool.

Codon↗
PubMed1997

Codon 4 ACT-->ACA, codon 5 CCT-->TCT, and codon 6 GAG-->TAG mutations in cis position: a form of thalassemia trait.

A female of Uttar Pradesh, of Indian origin, who had a transfusion-dependent child, carried codon 4 ACT-->ACA, codon 5 CCT-->TCT, and codon 6 GAG-->TAG mutations at the cis position. The mutation was detected through sequencing of the amplified beta-globin gene. Heterozygosity is expressed as a thalassemia trait with moderate anemia, low MCV (57 fl), raised HbA2 (6.7%), and normal fetal hemoglobin (1.4%).

Child, Preschool↗
PubMed2005

A small-molecule-based approach to sense codon-templated natural-unnatural hybrid peptides. Selective silencing and reassignment of the sense codon by orthogonal reacylation stalling at the single-codon level.

In the presence of the stable sulfamoyl analogue of phenylalanyl adenylate (Phe-SA), the UUU/UUC sense codon for phenylalanine (Phe) can be silenced and reassigned to a naphthylalanine (Nap) conjugated to tRNAPhe. We have demonstrated the efficiency and selectivity or orthogonality of the Phe-to-Nap reassignment induced by an "orthogonal reacylation stalling" strategy at the single-codon level in the translation of mRNAs of dihydrofolate reductase and a 24-mer oligopeptide. We used a prokaryotic translation system with an essential preincubation, during which the endogenous precharged phenylalanyl-tRNAPhe undergoes deacylation and the reacylation of the resulting tRNAPhe is stalled by the action of Phe-SA to inhibit the phenylalanyl-tRNA synthetase activity. We discuss the significance of the present small-molecule-based approach to sense-codon templated natural-unnatural peptides.

Acylation↗
PubMed1999

The nonrandom location of synonymous codons suggests that reading frame-independent forces have patterned codon preferences.

Biased codon usage is common in eukaryotic and prokaryotic genes. Evidence from Escherichia, Saccharomyces, and Drosophila indicates that it favors translational efficiency and accuracy. However, to date no functional advantages have been identified in the codon-anticodon interactions involving the most frequently used (preferred) codons. Here we present evidence that forces not related to the individual codon-anticodon interaction may be involved in determining which synonymous codons are preferred or avoided. We show that the "off-frame" trinucleotide motif preferences inferrable from Drosophila coding regions are often in the same direction as Drosophila's "in-frame" codon preferences, i.e., its codon usage. The off-frame preferences were inferred from the nonrandomness of the location of confamilial synonymous codons along coding regions-a pattern often described as a context dependence of nucleotide choice at synonymous positions or as codon-pair bias. We relied on randomizations of the location of confamilial codons that do not alter, and cannot be influenced by, the encoded amino acid sequences, codon usage, or base composition of the genes examined. The statistically significant congruency of in-frame and off-frame trinucleotide preferences suggests that the same kind of reading-frame-independent force(s) may also influence synonymous codon choice. These forces may have produced biases in codon usage that then led to the evolution of the translational advantages of these motifs as preferred codons. Under this scenario, tRNA pool size differences between preferred and nonpreferred codons initially were evolved to track the default overrepresentation of codons with preferred motifs. The motif preference hypothesis can explain the structuring of codon preferences and the similarities in the codon usages of distantly related organisms.

Amino Acid Sequence↗
PubMed1994

Role of the AGA/AGG codons, the rarest codons in global gene expression in Escherichia coli.

AGA and AGG codons for arginine are the least used codons in Escherichia coli. Previous findings have shown that these codons are used preferentially within the first 25 codons in E. coli genes. More than 100 genes having a single AGA/AGG codon within the first 25 codons were identified to be associated with various essential cellular functions. The lacZ gene, containing 5 AGG codons after the tenth codon from the initiation codon, was constructed as a model system. The production of beta-galactosidase was inhibited almost completely during the stationary phase, whereas the production of the control beta-galactosidase without AGG codons was not. The inhibitory effect by the 5 AGG codons was substantially suppressed either by coexpressing the argU gene for tRNA(ArgUCU/CCU) or by moving the 5 AGG codons by > 50 codons away from the initiation codon. In addition, the production of a number of proteins resolved by two-dimensional gel electrophoresis was enhanced significantly during the stationary phase in the cells harboring a plasmid containing argU. At least one of them was identified as the hns product encoded by an ORF having an AGA codon at the nineteenth position. On the basis of these results, it is proposed that the expression of a group of essential genes for various cellular functions that have a single AGA/AGG codon very close to the initiation codon are globally regulated by the availability of the least abundant tRNA(ArgUCU/CCU). A model for this regulation is proposed.

Arginine↗
PubMed2004

Transporter associated with antigen processing gene 1 codon 333 and codon 637 polymorphisms are associated with primary open-angle glaucoma.

INTRODUCTION: Genetic factors in the immune system are widely suspected to have a role in the etiology of glaucoma. In this study, we evaluated the association between primary open-angle glaucoma (POAG) and the transporter associated with antigen processing (TAP) gene polymorphisms. The TAP gene polymorphisms we evaluated were TAP1-1 codon 333 A/G (Ile-Val), TAP1-2 codon 637 (Asp-Gly), TAP2-1 codon 379 (Val-Ile), TAP2-2 codon 665 (Thr-Ala) and codon 687 (Stop-Gln), and TAP2-3 codon 565 (Ala-Tht). Due to the lack of predictive markers for glaucoma, many glaucoma patients are only diagnosed when their visual acuity and visual field has irreversibly deteriorated. Our aim was to confirm whether or not the TAP1 and TAP2 genes can be used to identify suspectability to glaucoma. METHODS: Sixty-six patients with POAG and 105 healthy volunteers were enrolled in this case-control study. We resolved the TAP1 and TAP2 gene polymorphisms by PCR-based analysis. RESULTS: There was a significant difference in the distribution of TAP1-1 codon 333 and TAP1-2 codon 637 gene polymorphisms (p = 0.0375 and 0.01, respectively) between POAG patients and healthy controls. However, there was no significant difference between the two groups in TAP2-1 codon 370, TAP2-2 codon 665, and TAP2-3 codon 565 (p = 0.273, 0.19, and 0.131, respectively). In TAP1-1 codon 333, there was a significant difference between the "GG" homozygote and "GA" heterozygote (OR 4.32; 95% CI 1.336, 13.969). In TAP1-2 codon 637, there was a significant difference between the "GG" homozygote and "GA" heterozygote (OR 15; 95% CI 1.733, 129.860). There was also a significant difference between "GG" homozygote and "AA" homozygote (OR 10.8; 95% CI 1.286, 91.880). Therefore, TAP1-1 codon 333 and TAP1-2 codon 637 gene polymorphisms were useful genetic markers of POAG. The prevalence of the TAP1-2 "GG" homozygote differs significantly between POAG patients and healthy controls, although in the alleles of the both TAP genes, there were no significant differences between the two groups. CONCLUSION: The immune system acts as an arbiter to help determine whether under stress a neuronal cell will survive or sacrifice itself to injuries. TAP1-1 and TAP1-2 play an important role in the immune system. TAP1-1 and TAP1-2 gene polymorphisms may, by way of post-transcriptional changes and altered regulation of gene expression, be involve the immune system in the development of POAG.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

UGA codon context which spans three codons. Reversal by ms2i6A37 in tRNA, mutation in rpsD(S4) or streptomycin.

Mutant UGA codon contexts which previously have been identified at different positions in the lacI part of a fused lacIlacZ gene were characterized with respect to translational readthrough in another genetic surrounding at a constant location. Although readthrough levels are systematically higher in this new location the "tight/leaky" characteristics of these codon contexts are essentially fully determined by the two codons flanking the nonsense codon itself. Analysis of some UGA hybrid contexts shows that the contribution to the codon context character by the codon either at the 5'-side (CCA or AGC) or at the 3'-side (NGU) is independent of the nature of the codon at the other side of UGA if this codon is decoded by trpT(Su9) suppressor tRNA. In a trpT(Su9), miaA double mutant strain, which lacks the ms2i6A37 modification in this tRNA, suppression is decreased at all UGA contexts investigated. However, in one case the contribution to the codon context character by the determinant flanking at one side is negatively affected by the nature of the codon at the other side of UGA. Thus, the character of a nonsense codon context in this case results from both flanking codons acting in a co-operative manner with the tRNA reading the middle UGA codon. This negative context effect is counteracted by a rpsD12 (ribosomal protein S4) mutation or by a sublethal concentration of streptomycin in the growth medium. It is suggested that the ms2i6A37 base in trpT(Su9) suppressor tRNA increases the efficiency of this tRNA by protecting it from ribosomal proofreading which is induced by codon context.

Bacterial Proteins↗
PubMed1993

Effects of consecutive AGG codons on translation in Escherichia coli, demonstrated with a versatile codon test system.

A system for testing the effects of specific codons on gene expression is described. Tandem test and control genes are contained in a transcription unit for bacteriophage T7 RNA polymerase in a multicopy plasmid, and nearly identical test and control mRNAs are generated from the primary transcript by RNase III cleavages. Their coding sequences, derived from T7 gene 9, are translated efficiently and have few low-usage codons of Escherichia coli. The upstream test gene contains a site for insertion of test codons, and the downstream control gene has a 45-codon deletion that allows test and control mRNAs and proteins to be separated by gel electrophoresis. Codons can be inserted among identical flanking codons after codon 13, 223, or 307 in codon test vectors pCT1, pCT2, and pCT3, respectively, the third site being six codons from the termination codon. The insertion of two to five consecutive AGG (low-usage) arginine codons selectively reduced the production of full-length test protein to extents that depended on the number of AGG codons, the site of insertion, and the amount of test mRNA. Production of aberrant proteins was also stimulated at high levels of mRNA. The effects occurred primarily at the translational level and were not produced by CGU (high-usage) arginine codons. Our results are consistent with the idea that sufficiently high levels of the AGG mRNA can cause essentially all of the tRNA(AGG) in the cell to become sequestered in translating peptidyl-tRNA(AGG) -mRNA-ribosome complexes stalled at the first of two consecutive AGG codons and that the approach of an upstream translating ribosome stimulates a stalled ribosome of frameshift, hop, or terminate translation.

Arginine↗
PubMed2000

DNA G+C content of the third codon position and codon usage biases of human genes.

The human genome, as in other eukaryotes, has a wide heterogeneity in the DNA base composition. The evolutionary basis for this heterogeneity has been unknown. A previous study of the human genome (846 genes analyzed) has shown that, in the major range of the G+C content in the third codon position (0.25-0.75), biases from the Parity Rule 2 (PR2) among the synonymous codons of the four-codon amino acids are similar except in the highest G+C range (Sueoka, N., 1999. Translation-coupled violation of Parity Rule 2 in human genes is not the cause of heterogeneity of the DNA G+C content of third codon position. Gene 238, 53-58.). PR2 is an intra-strand rule where A=T and G=C are expected when there are no biases between the two complementary strands of DNA in mutation and selection rates (substitution rates). In this study, 14,026 human genes were analyzed. In addition, the third codon positions of two-codon amino acids were analyzed. New results show the following: (a) The G+C contents of the third codon position of human genes are scattered in the G+C range of 0.22-0.96 in the third codon position. (b) The PR2 biases are similar in the range of 0.25-0.75, whereas, in the high G+C range (0.75-0.96; 13% of the genes), the PR2-bias fingerprints are different from those of the major range. (c) Unlike the PR2 biases, the G+C contents of the third codon position for both four-codon and two-codon amino acids are all correlated almost perfectly with the G+C content of the third codon position over the total G+C ranges. These results support the notion that the directional mutation pressure, rather than the directional selection pressure, is mainly responsible for the heterogeneity of the G+C content of the third codon position.

Amino Acids↗
PubMedDate not supplied

Codon usage and tRNA genes in eukaryotes: correlation of codon usage diversity with translation efficiency and with CG-dinucleotide usage as assessed by multivariate analysis.

The species-specific diversity of codon usage in five eukaryotes (Schizosaccharomyces pombe, Caenorhabditis elegans, Drosophila melanogaster, Xenopus laevis, and Homo sapiens) was investigated with principal component analysis. Optimal codons for translation were predicted on the basis of tRNA-gene copy numbers. Highly expressed genes, such as those encoding ribosomal proteins and histones in S. pombe, C. elegans, and D. melanogaster, have biased patterns of codon usage which have been observed in a wide range of unicellular organisms. In S. pombe and C. elegans, codons contributing positively to the principal component with the largest variance (Z1-parameter) corresponded to the optimal codons which were predicted on the basis of tRNA gene numbers. In D. melanogaster, this correlation was less evident, and the codons contributing positively to the Z1-parameter corresponded primarily to codons with a C or G in the codon third position. In X. laevis and H. sapiens, codon usage in the genes encoding ribosomal proteins and histones was not significantly biased, suggesting that the primary factor influencing codon-usage diversity in these species is not translation efficiency. Codon-usage diversity in these species is known to reflect primarily isochore structures. In the present study, the second additional factor was explained by the level of use of codons containing CG-dinucleotides, and this is discussed with respect to transcription regulation via methylation of CG-dinucleotides, which is observed in mammalian genomes.

Animals↗
PubMed2003

The effective number of codons for individual amino acids: some codons are more optimal than others.

The aim of this study was to evaluate the codon bias using the effective number of codons for individual amino acids (N(c)(AA)) and to assess the codon bias in relation to the definition of optimal codons, using Escherichia coli as a model organism. We show that a general correlation exists between the effective number of codons (Ncirc(c)) or codon adaptation index (CAI) and N(c)(AA), but that this correlation is not equally strong for all amino acids within a degeneracy group. For example, leucine codons contribute more to Ncirc(c) and the codon adaptation index than serine codons. A possible explanation is that some optimal codons are more optimal than others, in terms of the selectional advantage they offer. This hypothesis is confirmed by further analysis on the correlations that exist between values for relative synonymous codon usage (RSCU), N(c)(AA), and the codon adaptation index.

Amino Acids↗
PubMed1993

Synonymous codon usage in Zea mays L. nuclear genes is varied by levels of C and G-ending codons.

A multivariate statistical method called correspondence analysis was used to examine the codon usage of one-hundred-and-one nuclear genes of maize (Zea mays L.). Forty percent of the variation in codon usage was due to bias toward G or C-ending versus A or U-ending codons. Differences in levels of G-ending codons showed the weakest correlation with the major codon usage bias. The bias toward C or U versus A or G in the silent third nucleotide position of synonymous codons accounted for approximately 10% of the variation in codon usage. The G+C content of the silent third nucleotide position of coding regions was not strongly correlated with G+C content of introns. Codon usage was strongly biased toward codons ending in G or C for a number of highly expressed genes including most light-regulated chloroplast proteins, ABA-induced proteins, histones, and anthocyanin biosynthetic enzymes. Codon usage of genes encoding storage proteins and regulatory proteins, such as transposases, kinases, phosphatases and transcription factors, was more random than that of genes encoding cytosolic enzymes with similar bias toward G or C-ending codons. Codon usage in maize may reflect both regional bias on nucleotide composition and selection on the silent third nucleotide position.

Base Composition↗
PubMed2001

Codon bias at the 3'-side of the initiation codon is correlated with translation initiation efficiency in Escherichia coli.

The codon that follows the AUG initiation triplet (+2 codon) affects gene expression in Escherichia coli. We have extended this analysis using two model genes lacking any apparent Shine-Dalgarno sequence. Depending on the identity of the +2 codon a difference in gene expression up to 20-fold could be obtained. The effects did not correlate with the levels of intracellular pools of cognate tRNA for the +2 codon, with putative secondary mRNA structures, or with mRNA stability. However, most +2 iso-codons that were decoded by the same species of tRNA gave pairwise similar effects, suggesting that the effect on gene expression was associated with the decoding tRNA. High adenine content of the +2 codon was associated with high gene expression. Of the fourteen +2 codons that mediated the highest efficiency, all except two had an adenine as the first base of the codon. Analysis of the 3540 E. coli genes from the TransTerm database revealed that codons associated with high gene expression in the two expression systems are over-represented at the +2 position in natural genes. Codons that are associated with low gene expression are under-represented. The data suggest that evolution has favored codons at the +2 position that give high translation initiation.

Codon↗
PubMed2006

Selection intensity on preferred codons correlates with overall codon usage bias in Caenorhabditis remanei.

Adaptive codon usage provides evidence of natural selection in one of its most subtle forms: a fitness benefit of one synonymous codon relative to another. Codon usage bias is evident in the coding sequences of a broad array of taxa, reflecting selection for translational efficiency and/or accuracy as well as mutational biases. Here, we quantify the magnitude of selection acting on alternative codons in genes of the nematode Caenorhabditis remanei, an outcrossing relative of the model organism C. elegans, by fitting the expected mutation-selection-drift equilibrium frequency distribution of preferred and unpreferred codon variants to the empirical distribution. This method estimates the intensity of selection on synonymous codons in genes with high codon bias as N(e)s = 0.17, a value significantly greater than zero. In addition, we demonstrate for the first time that estimates of ongoing selection on codon usage among genes, inferred from nucleotide polymorphism data, correlate strongly with long-term patterns of codon usage bias, as measured by the frequency of optimal codons in a gene. From the pattern of polymorphisms in introns, we also infer that these findings do not result from the operation of biased gene conversion toward G or C nucleotides. We therefore conclude that coincident patterns of current and ancient selection are responsible for shaping biased codon usage in the C. remanei genome.

Animals↗
PubMed2006

Phylogenetic estimation under codon models can be biased by codon usage heterogeneity.

In theory, codon models that account for the dependence of nucleotide substitutions between codon positions as well as differences between synonymous and non-synonymous changes best describe the sequence evolution in protein coding genes. However, in practice we know little about the degree to which violations of the assumptions of codon model-based estimates occur, and how significant these artifacts may be. In nucleotide-based phylogenies from first and second codon positions in a concatenated plastid gene data set, two distantly related taxa--dinoflagellate and haptophyte plastids--were robustly grouped together. This artifactual grouping is attributed to the parallel heterogeneity in leucine (Leu) and serine (Ser) codon usages in the data set. Here, by using this data set, we demonstrated that codon-based phylogenetic estimations are seriously biased, robustly uniting the dinoflagellate and haptophyte plastids into a monophyletic clade, when the model assumption of homogeneity of codon composition was violated. Our results suggest that similar phylogenetic artifacts may occur via codon usage heterogeneity in any amino acids in codon model-based estimations. We advise that homogeneity in codon usage across taxa in a data set be confirmed before codon model-based phylogenetic estimation is attempted.

Codon↗
PubMed1990

Codon recognition in polypeptide chain termination: site directed crosslinking of termination codon to Escherichia coli release factor 2.

An RNA synthesized in vitro was positioned on the Escherichia coli ribosome at the P site with tRNAala, and with a termination codon, UAA, as the next codon in the A site. Such a complex bound stoichiometric amounts of release factor 2 (RF-2); a corresponding RNA with UAC in place of UAA was not a template for the factor. An RNA containing 4-thio-UAA in place of the UAA supported binding of RF-2, and this has allowed site-directed crosslinking from the first position of the termination codon to answer two long standing questions about the termination of protein biosynthesis, the position of the termination codon and its proximity to the release factor during codon recognition. An RF-2.mRNA crosslinked product was detected, indicating the release factor and the termination codon are in close physical contact during the codon recognition event of termination. The 4-thio-U crosslinked also to the ribosome but only to the 30S subunit, and the proteins and the rRNA site concerned were identified. RF-2 decreased significantly the crosslinking to the ribosomal components, but no new crosslink sites were found. If the stop codon was deliberately displaced from the decoding site by one codon's length then a different pattern of crosslinking in particular to the rRNA resulted. These observations are consistent with a model of codon recognition by RF-2 at the decoding site, without a major shift in position of the codon.

Base Sequence↗