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At least 217 records · Page 12Linked to original sources
PubMed1991

Correlations between the compositional properties of human genes, codon usage, and amino acid composition of proteins.

We have analyzed the correlation that exists between the GC levels of third and first or second codon position for about 1400 human coding sequences. The linear relationship that was found indicates that the large differences in GC level of third codon positions of human genes are paralleled by smaller differences in GC levels of first and second codon positions. Whereas third codon position differences correspond to very large differences in codon usage within the human genome, the first and second codon position differences correspond to smaller, yet very remarkable, differences in the amino acid composition of encoded proteins. Because GC levels of codon positions are linearly correlated with the GC levels of the isochores harboring the corresponding genes, both codon usage and amino acid composition are different for proteins encoded by genes located in isochores of different GC levels. Furthermore, we have also shown that a linear relationship with a unit slope and a correlation coefficient of 0.77 exists between GC levels of introns and exons from the 238 human genes currently available for this analysis. Introns are, however, about 5% lower in GC, on average, than exons from the same genes.

Amino Acid Sequence↗
PubMed1998

Selection on the codon bias of chloroplast and cyanelle genes in different plant and algal lineages.

In the plant chloroplast genome the codon usage of the highly expressed psbA gene is unique and is adapted to the tRNA population, probably due to selection for translation efficiency. In this study the role of selection on codon usage in each of the fully sequenced chloroplast genomes, in addition to Chlamydomonas reinhardtii, is investigated by measuring adaptation to this pattern of codon usage. A method is developed which tests selection on each gene individually by constructing sequences with the same amino acid composition as the gene and randomly assigning codons based on the nucleotide composition of noncoding regions of that genome. The codon bias of the actual gene is then compared to a distribution of random sequences. The data indicate that within the algae selection is strong in Cyanophora paradoxa, affecting a majority of genes, of intermediate intensity in Odontella sinensis, and weaker in Porphyra purpurea and Euglena gracilis. In the plants, selection is found to be quite weak in Pinus thunbergii and the angiosperms but there is evidence that an intermediate level of selection exists in the liverwort Marchantia polymorpha. The role of selection is then further investigated in two comparative studies. It is shown that average relative codon bias is correlated with expression level and that, despite saturation levels of substitution, there is a strong correlation among the algae genomes in the degree of codon bias of homologous genes. All of these data indicate that selection for translation efficiency plays a significant role in determining the codon bias of chloroplast genes but that it acts with different intensities in different lineages. In general it is stronger in the algae than the higher plants, but within the algae Euglena is found to have several unusual features which are noted. The factors that might be responsible for this variation in intensity among the various genomes are discussed.

Chloroplasts↗
PubMed1998

An evaluation of measures of synonymous codon usage bias.

Synonymous codons are not generally used at equal frequencies, and this trend is observed for most genes and organisms. Several methods have been proposed and used to estimate the degree of the nonrandom use of the different synonymous codons. The estimates obtained by these methods, however, show different levels of both precision and dispersion when coding regions of a finite number of codons are under analysis. Here, we present a study, based on computer simulation, of how the different methods proposed to evaluate the nonrandom use of synonymous codons are affected by the length of the coding region analyzed. The results show that some of these methods are heavily influenced by the number of codons and that the comparison of codon usage bias between coding regions of different lengths shows a methodological bias under different conditions of nonrandom use of synonymous codons. The study of the dispersion of the estimates obtained by the different methods gives, on the other hand, an indication of the methods to be applied to compare values of codon usage bias among coding regions of equivalent length.

Animals↗
PubMed1992

Codon context effect in virus translational readthrough. A study in vitro of the determinants of TMV and Mo-MuLV amber suppression.

To assess the role of codon context on the efficiency of eukaryotic suppression of termination codons, we have compared, in a rabbit cell-free translation system, the readthrough efficiency related to two synthetic transcripts differing by the codon context around an amber codon. The codon contexts are derived from tobacco mosaic virus (TMV) and Moloney murine leukemia virus (Mo-MuLV) RNAs. The Mo-MuLV-like codon context does not promote suppression. Substituting TMV-derived triplets in the Mo-MuLV-like codon context shows that the two codons downstream from the TMV UAG signal are important determinants of suppression, as recently demonstrated in vivo.

Amino Acid Sequence↗
PubMed1989

Novel third-letter bias in Escherichia coli codons revealed by rigorous treatment of coding constraints.

A novel bias in codon third-letter usage was found in Escherichia coli genes with low fractions of "optimal codons", by comparing intact sequences with control random sequences. Third-letter usage has been found to be biased according to preference in codon usage and to doublet preference from the following first letter. The present study examines third-letter usage in the context of the nucleotide sequence when these preferences are considered. In order to exclude any influence by these factors, the random sequences were generated such that the amino acid sequence, codon usage, and the doublet frequency in each gene were all preserved. Comparison of intact sequences with these randomly generated sequences reveals that third letters of codons show a strong preference for the purine/pyrimidine pattern of the next codons: purine (R) is preferred to pyrimidine (Y) at the third site when followed by an R-Y-R codon, and pyrimidine is preferred when followed by an R-R-Y, an R-Y-Y or a Y-R-Y codon. This bias is probably related to interactions of tRNA molecules in the ribosome.

Amino Acids↗
PubMed1989

Codon usage determines translation rate in Escherichia coli.

We wish to determine whether differences in translation rate are correlated with differences in codon usage or with differences in mRNA secondary structure. We therefore inserted a small DNA fragment in the lacZ gene either directly or flanked by a few frame-shifting bases, leaving the reading frame of the lacZ gene unchanged. The fragment was chosen to have "infrequent" codons in one reading frame and "common" codons in the other. The insert in these constructs does not seem to give mRNAs that are able to form extensive secondary structures. The translation time for these modified lacZ mRNAs was measured with a reproducibility better than plus or minus one second. We found that the mRNA with infrequent codons inserted has an approximately three-seconds longer translation time than the one with common codons. In another set of experiments we constructed two almost identical lacZ genes in which the lacZ mRNAs have the potential to generate stem structures with stabilities of about -75 kcal/mol. In this way we could investigate the influence of mRNA structure on translation rate. This type of modified gene was generated in two reading frames with either common or infrequent codons similar to our first experiments. We find that the yield of protein from these mRNAs is reduced, probably due to the action in vivo of an RNase. Nevertheless, the data do not indicate that there is any effect of mRNA secondary structure on translation rate. In contrast, our data persuade us that there is a difference in translation rate between infrequent codons and common codons that is of the order of sixfold.

Bacterial Proteins↗
PubMed1994

Codon context and protein synthesis: enhancements of the genetic code.

The sequence around stop codons strongly affects termination efficiency and the probability of alternative events to termination such as frameshifting and stop codon readthrough. Where tRNA suppressors of nonsense codons are present, both the efficiency of suppression and of the termination process appear to be affected by stop codon context. Since context can affect suppressor tRNA function directly, an influence on sense codon translation or suppression might be expected, but has not yet been clearly demonstrated. Statistical analyses of coding sequences indicate non-random contexts for both stop and sense codons, and non-random occurrence of codon pairs. Highly expressed genes show clear preferences among stop codons and their contexts, whereas inefficient stop signals are exploited in a variety of recoding processes.

Codon↗
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↗
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↗
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↗