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PubMed1990

Initiation of translation at CUG, GUG, and ACG codons in mammalian cells.

Site-directed mutants of the ACG start codon of the C' protein encoded in the polycistronic Sendai virus P/C mRNA revealed that CUG, GUG, and ACG codons initiated translation rather efficiently (10-30% of the AUG initiation) in COS-1 host cells. In addition, AUA and AUU codons initiated translation at about 5% efficiency, while UUG did not initiate translation. The sequence context of these start codons (purine residues at -3 and +4) was crucial in their recognition by the ribosome. The location of the non-AUG codons in the P/C mRNA did not play a role in its recognition by ribosomes. By using CUG, the most efficient non-AUG start codon, instead of the original ACG codon and inserting an additional upstream CUG codon in the P/C mRNA, the amount of the C' protein was increased and a novel protein was synthesized. Syntheses of an increased level of C' and the novel protein did not affect downstream initiations of the P and C proteins, suggesting that more ribosomes bind the mRNA than are actually utilized for initiation of translation.

Animals↗

PubMed1992

Synonymous codon preferences in bacteriophage T4: a distinctive use of transfer RNAs from T4 and from its host Escherichia coli.

Codon usage data of bacteriophage T4 genes were compiled and synonymous codon preferences were investigated in comparison with tRNA availabilities in an infected cell. Since the genome of T4 is highly AT rich and its codon usage pattern is significantly different from that of its host Escherichia coli, certain codons of T4 genes need to be translated by appropriate host transfer RNAs present in minor amounts. To avoid this predicament, T4 phage seems to direct the synthesis of its own tRNA molecules and these phage tRNAs are suggested to supplement the host tRNA population with isoacceptors that are normally present in minor amounts. A positive correlation was found in that the frequency of E. coli optimal codons in T4 genes increases as the number of protein monomers per phage particle increases. A negative correlation was also found between the number of protein monomers per phage and the frequency of "T4 optimal codons", which are defined as those codons that are efficiently recognized by T4 tRNAs. From these observations it was proposed that tRNAs from the host are predominantly used for translation of highly expressed T4 genes while tRNAs from T4 tend to be used for translation of weakly expressed T4 genes. This distinctive tRNA-usage in T4 may be an optimization of translational efficiency, and an adjustment of T4-encoded tRNAs to the synonymous codon preferences, which are largely influenced by the high genomic AT-content, would have occurred during evolution.

Bacteriophage T4↗

PubMedDate not supplied

Coevolution of codon usage and transfer RNA abundance.

The use of synonymous codons is strongly biased in the bacterium Escherichia coli and yeast, comprising both bias between codons recognized by the same transfer RNA and bias between groups of codons recognized by different synonymous tRNAs. A major determinant of the second sort of bias is tRNA content, codons recognized by abundant tRNAs being used more often than those recognised by rare tRNAs, particularly in highly expressed genes, probably owing to selection at the level of translation against codons recognized by rare tRNAs. Conversely, codon usage is likely to exert selection pressure on tRNA abundance. Here I develop a model for the coevolution of codon usage and tRNA abundance which explains why there are unequal abundances of synonymous tRNAs leading to biased usage between groups of codons recognized by them in unicellular organisms.

Biological Evolution↗

PubMed1998

The p53 codon 249 mutational hotspot in hepatocellular carcinoma is not related to selective formation or persistence of aflatoxin B1 adducts.

Sequence-dependent formation and lack of repair of polycyclic aromatic hydrocarbon-induced DNA adducts correlates well with the positions of p53 mutational hotspots in smoking-related lung cancers (Denissenko et al, 1996, 1998). The mycotoxin aflatoxin B1 (AFB1) is considered to be a major causative agent in hepatocellular carcinoma (HCC) in regions with presumed high food contamination by AFB1. A unique mutational hotspot, a G to T transversion at the third base of codon 249 of the p53 gene is observed in these tumors. To test whether a selectivity of AFB1 adduct formation is related to this peculiar mutational spectrum, we have mapped AFB1-DNA adducts at nucleotide resolution using ligation-mediated PCR and terminal transferase-dependent PCR. Human HepG2 cells were exposed to AFB1 metabolically activated in the presence of rat liver microsomes. Significant adduct formation was seen at the third base of codon 249. However, this was not the major site of AFB1 adducts and strong adduction was also observed at codons 226, 243, 244, 245 and 248 in exon 7 of the p53 gene and at several codons in exon 8. The damage at codon 249 does not consist of a unique abasic site or ring-opened aflatoxin B1 adduct but rather is consistent with the principal N7-guanine adduct of AFB1. Time course experiments indicate that, under the conditions used, AFB1 adducts are not removed in a strand-selective manner and adduct removal from the third base of codon 249 proceeds at a relatively fast rate (50% in 7 h). The incomplete correspondence between sites of persistent AFB1 damage and the specific codon 249 mutation suggests that AFB1 may not be involved in mutation of this site or that additional mechanisms such as parallel infection with hepatitis B virus may be required for selection of codon 249 mutants in HCC.

Aflatoxin B1↗

PubMed1996

The role of the AUU initiation codon in the negative feedback regulation of the gene for translation initiation factor IF3 in Escherichia coli.

The expression of the infC gene encoding translation initiation factor IF3 is negatively autoregulated at the level of translation, i.e. the expression of the gene is derepressed in a mutant infC background where the IF3 activity is lower than that of the wild type. The special initiation codon of infC, AUU, has previously been shown to be essential for derepression in vivo. In the present work, we provide evidence that the AUU initiation codon causes derepression by itself, because if the initiation codon of the thrS gene, encoding threonyl-tRNA synthetase, is changed from AUG to AUU, its expression is also derepressed in an infC mutant background. The same result was obtained with the rpsO gene encoding ribosomal protein S15. We also show that derepression of infC, thrS, and rpsO is obtained with other 'abnormal' initiation codons such as AUA, AUC, and CUG which initiate with the same low efficiency as AUU, and also with ACG which initiates with an even lower efficiency. Under conditions of IF3 excess, the expression of infC is repressed in the presence of the AUU or other 'abnormal' initiation codons. Under the same conditions and with the same set of 'abnormal' initiation codons, the repression of thrS and rpsO expression is weaker. This result suggests that the infC message has specific features that render its expression particularly sensitive to excess of IF3. We also studied another peculiarity of the infC message, namely the role of a GC-rich sequence located immediately downstream of the initiation codon and conserved through evolution. This sequence was proposed to interact with a conserved region in 16S RNA and enhance translation initiation. Unexpectedly, mutating this GC-rich sequence increases infC expression, indicating that this sequence has no enhancing role. Chemical and enzymatic probing of infC RNA synthesized in vitro indicates that this GC-rich sequence might pair with another region of the mRNA. On the basis of our in vivo results we propose, as suspected from earlier in vitro results, that IF3 regulates the expression of its own gene by using its ability to differentiate between 'normal' and 'abnormal' initiation codons.

Bacterial Proteins↗

PubMed1988

Possible evolution of splice-junction signals in eukaryotic genes from stop codons.

Splice-junction sequence signals are strongly conserved structural components of eukaryotic genes. These sequences border exon/intron junctions and aid in the process of removing introns by the RNA splicing machinery. Although substantial research has been undertaken to understand the mechanism of splicing, little is known about the origin and evolution of these splice signal sequences. Based on the previously published theory that the primitive genes evolved in pieces from primordial genetic sequences to avoid the interfering stop codons, a "stop-codon walk" mechanism is proposed in this paper to have assisted in the evolution of coding genes. This mechanism predicts the presence of stop codons in splice-junction signals inside the introns. Evidence of the consistent presence of stop codons in the splice-junction signals, in a position where they are expected, is shown by the analysis of codon statistics in these signal sequences in the GenBank databank. The results suggest that the splice-junction signals may have evolved from stop codons as a consequence of a selective pressure to avoid stop codons during the original evolution of coding genes. They also suggest that other splice signals within the introns, such as the branch-point sequence, may have evolved from stop codons for similar reasons.

Biological Evolution↗

PubMed1997

The atypical codon usage of the plant psbA gene may be the remnant of an ancestral bias.

The psbA gene of the chloroplast genome has a codon usage that is unusual for plant chloroplast genes. In the present study the evolutionary status of this codon usage is tested by reconstructing putative ancestral psbA sequences to determine the pattern of change in codon bias during angiosperm divergence. It is shown that the codon biases of the ancestral genes are much stronger than all extant flowering plant psbA genes. This is related to previous work that demonstrated a significant increase in synonymous substitution in psbA relative to other chloroplast genes. It is suggested, based on the two lines of evidence, that the codon bias of this gene currently is not being maintained by selection. Rather, the atypical codon bias simply may be a remnant of an ancestral codon bias that now is being degraded by the mutation bias of the chloroplast genome, in other words, that the psbA gene is not at equilibrium. A model for the evolution of selective pressure on the codon usage of plant chloroplast genes is discussed.

Base Sequence↗

PubMed2000

Animal products and K-ras codon 12 and 13 mutations in colon carcinomas.

K-ras gene mutations (codons 12 and 13) were determined by PCR-based mutant allele-specific amplification (MASA) in tumour tissue of 185 colon cancer patients: 36% harboured mutations, of which 82% were located in codon 12. High intakes of animal protein, calcium and poultry were differently associated with codon 12 and 13 mutations: odds ratios (OR) and 95% confidence intervals (95% CI) for codon 12 versus codon 13 were 9.0 (2.0-42), 4.1 (1.4-12) and 15 (1.4-160), respectively. In case-control comparisons, high intakes of animal protein and calcium were positively associated with colon tumours harbouring codon 12 mutations [for animal protein per 17 g, OR (95% CI) = 1.5 (1.0-2.1); for calcium per 459 mg, 1.2 (0.9-1.6)], while inverse associations were observed for tumours with K-ras mutations in codon 13 [for animal protein 0.4 (0.2-1.0); for calcium 0.6 (0. 3-1.2)]. Transition and transversion mutations were not differently associated with these dietary factors. These data suggest a different dietary aetiology of colon tumours harbouring K-ras codon 12 and 13 mutations.

Adult↗

PubMed1994

Synonymous codon usage in Drosophila melanogaster: natural selection and translational accuracy.

I present evidence that natural selection biases synonymous codon usage to enhance the accuracy of protein synthesis in Drosophila melanogaster. Since the fitness cost of a translational misincorporation will depend on how the amino acid substitution affects protein function, selection for translational accuracy predicts an association between codon usage in DNA and functional constraint at the protein level. The frequency of preferred codons is significantly higher at codons conserved for amino acids than at nonconserved codons in 38 genes compared between D. melanogaster and Drosophila virilis or Drosophila pseudoobscura (Z = 5.93, P < 10(-6)). Preferred codon usage is also significantly higher in putative zinc-finger and homeodomain regions than in the rest of 28 D. melanogaster transcription factor encoding genes (Z = 8.38, P < 10(-6)). Mutational alternatives (within-gene differences in mutation rates, amino acid changes altering codon preference states, and doublet mutations at adjacent bases) do not appear to explain this association between synonymous codon usage and amino acid constraint.

Animals↗

PubMed1985

Codon-defined ribosomal pausing in Escherichia coli detected by using the pyrE attenuator to probe the coupling between transcription and translation.

This communication describes an assay for the relative translation efficiency of individual codons which makes use of the pyrE attenuator to probe the coupling between transcription and translation at the end of an artificial leader peptide. By cloning of short synthetic DNA fragments the codons to be tested were placed in the middle of the leader peptide and the downstream transcription of a pyrE"lacZ gene was monitored by measuring beta-galactosidase activity. The substitution, one by one, of three AGG codons for arginine with three CGT codons for the same amino acid residue was found to cause a two fold increase per codon of transcription over the pyrE attenuator, such that an eight fold higher frequency of pyrE expression was seen when all three AGG codons were replaced by CGT codons. No such effect of codon composition was observed, when the cells were grown with a low UTP pool which causes a reduction of the mRNA chain growth rate.

Base Sequence↗

PubMed1988

The AGG codon is translated slowly in E. coli even at very low expression levels.

Data are presented which indicate that AGG codons for arginine are translated significantly more slowly than the CGU codons for the same amino acid even when their expression level from the probe is very low. The two types of codons were inserted (three in tandem) on a multicopy plasmid in an artificial leader peptide gene in front of the pyrE attenuator where the frequency of transcription termination is regulated by the degree of coupling between transcription and translation. Transcription of the operon is initiated from the lac-promoter dependent on the concentration of the lac-operon inducer IPTG. At all induction levels it was found that the frequency of transcription past the pyrE attenuator was approximately nine times lower when the AGG codons were present in the leader than with CGT codons present. This shows that AGG codons decouple translation from transcription in the pyrE attenuator region even when the concentration of this codon is not increased significantly relative to that in the unperturbed wild type strain. Thus the results indicate that AGG codons are always slowly translated in Escherichia coli.

Adenine↗

PubMed1999

An extra tRNAGly(U*CU) found in ascidian mitochondria responsible for decoding non-universal codons AGA/AGG as glycine.

Amino acid assignments of metazoan mitochondrial codons AGA/AGG are known to vary among animal species; arginine in Cnidaria, serine in invertebrates and stop in vertebrates. We recently found that in the mitochondria of the ascidian Halocynthia roretzi these codons are exceptionally used for glycine, and postulated that they are probably decoded by a tRNA(UCU). In order to verify this notion unambig-uously, we determined the complete RNA sequence of the mitochondrial tRNA(UCU) presumed to decode codons AGA/AGG in the ascidian mitochondria, and found it to have an unidentified U derivative at the anticodon first position. We then identified the amino acids attached to the tRNA(U*CU), as well as to the conventional tRNAGly(UCC) with an unmodified U34, in vivo. The results clearly demonstrated that glycine was attached to both tRNAs. Since no other tRNA capable of decoding codons AGA/AGG has been found in the mitochondrial genome, it is most probable that this tRNA(U*CU) does actually translate codons AGA/AGG as glycine in vivo. Sequencing of tRNASer(GCU), which is thought to recognize only codons AGU/AGC, revealed that it has an unmodified guanosine at position 34, as is the case with vertebrate mitochondrial tRNASer(GCU) for codons AGA/AGG. It was thus concluded that in the ascidian, codons AGU/AGC are read as serine by tRNASer(GCU), whereas AGA/AGG are read as glycine by an extra tRNAGly(U*CU). The possible origin of this unorthodox genetic code is discussed.

Animals↗

PubMed2000

Optimizing heterologous expression in dictyostelium: importance of 5' codon adaptation.

Expression of heterologous proteins in Dictyostelium discoideum presents unique research opportunities, such as the functional analysis of complex human glycoproteins after random mutagenesis. In one study, human chorionic gonadotropin (hCG) and human follicle stimulating hormone were expressed in Dictyostelium. During the course of these experiments, we also investigated the role of codon usage and of the DNA sequence upstream of the ATG start codon. The Dictyostelium genome has a higher AT content than the human, resulting in a different codon preference. The hCG-beta gene contains three clusters with infrequently used codons that were changed to codons that are preferred by Dictyostelium. The results reported here show that optimizing the first 5-17 codons of the hCG gene contributes to 4- to 5-fold increased expression levels, but that further optimization has no significant effect. These observations suggest that optimal codon usage contributes to ribosome stabilization, but does not play an important role during the elongation phase of translation. Furthermore, adapting the 5'-sequence of the hCG gene to the Dictyostelium 'Kozak'-like sequence increased expression levels approximately 1.5-fold. Thus, using both codon optimization and 'Kozak' adaptation, a 6- to 8-fold increase in expression levels could be obtained for hCG.

Amino Acid Sequence↗

PubMed2000

Intercodon dinucleotides affect codon choice in plant genes.

In this work, 710 CDSs corresponding to over 290 000 codons equally distributed between Brassica napus, Arabidopsis thaliana, Lycopersicon esculentum, Nicotiana tabacum, Pisum sativum, Glycine max, Oryza sativa, Triticum aestivum, Hordeum vulgare and Zea mays were considered. For each amino acid, synonymous codon choice was determined in the presence of A, G, C or T as the initial nucleotide of the subsequent triplet; data were statistically analysed under the hypothesis of an independent assortment of codons. In 33.4% of cases, a frequency significantly (P: = 0.01) different from that expected was recorded. This was mainly due to a pervasive intercodon TpA and CpG deficiency. As a general rule, intercodon TpAs and CpGs were preferably replaced by CpAs and TpGs, respectively. In several instances, codon frequencies were also modified to avoid homotetramer and homotrimer formation, to reduce intercodon ApCs downstream (1,2) GG or AG dinucleotides, as well as to increase GpA or ApG intercodons under certain contexts. Since TpA, CpG and homotetra(tri)mer deficiency directly or indirectly accounted for 77% of significant variation in the codon frequency, it can be concluded that codon usage mirrors precise needs at the DNA structure level. Plant species exhibited a phylogenetically-related adaptation to structural constraints. Codon usage flexibility was reflected in strikingly different arrays of optimum codons for probe design.

Base Composition↗

PubMed1996

Introns and reading frames: correlation between splicing sites and their codon positions.

Computer analyses of the entire GenBank database were conducted to examine correlation between splicing sites and codon positions in reading frames. Intron insertion patterns (i.e., splicing site locations with respect to codon positions) have been analyzed for all of the 74 codons of all the eukaryote taxonomic groups: primates, rodents mammals, vertebrates, invertebrates, and plants. We found that reading frames are interrupted by an intron at a codon boundary (as opposed to the middle of a codon) significantly more often than expected. This observation is consistent with the exon shuffling hypothesis, because exons that end at codon boundaries can be concatenated without causing a frame shift and thus are evolutionarily advantageous. On the other hand, when introns interrupt at the middles of codons, they exist in between the first and second bases much more frequently than between the second and third bases, despite the fact that boundaries between the first and second bases of codons are generally far more important than those between the second and third bases. The reason for this is not clear and yet to be explained. We also show that the length of an exon is a multiple of 3 more frequently than expected. Furthermore, the total length of two consecutive exons is also more frequently a multiple of 3. All the observations above are consistent with results recently published by Long, Rosenberg, and Gilbert (1995).

Algorithms↗

PubMed1996

Codon usage in the Mycobacterium tuberculosis complex.

The usage of alternative synonymous codons in Mycobacterium tuberculosis (and M. bovis) genes has been investigated. This species is a member of the high-G+C Gram-positive bacteria, with a genomic G+C content around 65 mol%. This G+C-richness is reflected in a strong bias towards C- and G-ending codons for every amino acid: overall, the G+C content at the third positions of codons is 83%. However, there is significant variation in codon usage patterns among genes, which appears to be associated with gene expression level. From the variation among genes, putative optimal codons were identified for 15 amino acids. The degree of bias towards optimal codons in an M. tuberculosis gene is correlated with that in homologues from Escherichia coli and Bacillus subtilis. The set of selectively favoured codons seems to be quite highly conserved between M. tuberculosis and another high-G+C Gram-positive bacterium, Corynebacterium glutamicum, even though the genome and overall codon usage of the latter are much less G+C-rich.

Bacillus subtilis↗

PubMed1993

Codon usage patterns in chromosomal and retrotransposon genes of the mosquito Anopheles gambiae.

Codon usage was compiled for fourteen chromosomal genes and four retrotransposons from the mosquito Anopheles gambiae. Variation exists among chromosomal genes in the degree of bias. The genes showing the highest bias are probably most highly expressed. In these genes, the base composition at the third codon position is much richer in G + C than is the overall coding sequence. Thus, codon usage is biased toward G- or C-ending codons. Codon usage in each retrotransposon is quite different, not only from chromosomal genes but also from the other retrotransposons. Codon usage comparisons among homologous genes from An. gambiae and two other Dipterans, the yellow fever mosquito Aedes aegypti and the fruitfly Drosophila melanogaster, show that while there are similarities, particularly between An. gambiae and D. melanogaster in the preference for G- and C-ending codons, each species has evolved a distinct pattern of codon usage.

Animals↗

PubMed1997

Evidence of rare codon clusters within Escherichia coli coding regions.

It is known that there is a high occurrence of rare codons at the start of coding region. Here it is shown that although the remainder of the gene is likely to contain a relatively low number of rare codons, rare and non-rare codons do not form a random sequence. It is apparent that throughout the coding region there is a higher than expected number of rare codon clusters. For example once a rare codon has occurred there is a greater chance than expected of the next six codons containing another rare codon. This non-random distribution implies that rare codons may have an as yet unidentified biological role.

Base Sequence↗