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PubMed1994

A graphic approach to analyzing codon usage in 1562 Escherichia coli protein coding sequences.

The occurrence frequencies of the four bases (adenine, cytosine, guanine and thymine) at each of the three codon positions for 1562 Escherichia coli protein coding sequences have been calculated. The 1562 x 4 x 3 = 18,744 data thus obtained have been analyzed by a graphic method in which the four base occurrence frequencies at each codon position for each coding sequence are represented by a point in a three-dimensional space. Thus, the 18,744 data, which would otherwise occupy several printed pages, can be intuitively displayed by a graphy. The point distribution pattern for each of the three codon positions has been analyzed. The results of our analysis indicate that the patterns for the first two codon positions reflect the origin for producing native folding structures of proteins. We thus come to the conclusion that the distribution patterns for the first two codon positions should be basically species-independent, as confirmed by studies for a number of other species. However, the distribution pattern for the third codon position is species-dependent. Based on the point distribution of the third codon position, six collective parameters have been defined to describe the overall feature of the pattern concerned. These collective parameters can be generally used to classify different species, and hence would be a useful vehicle for studies in taxonomy. In addition to E. coli, the collective parameters for a number of other species have been calculated and analyzed.

Animals↗

PubMed2001

A modified mutagenic PCR-RFLP method for K-ras codon 12 and 13 mutations detection in NSCLC patients.

Evidence from many investigators has shown that mutations in the first exon of K- ras gene occur at elevated frequencies in lung, pancreatic and colon carcinoma and seem to be of prognostic importance. The aim of this study was to develop an effective method for the detection of K- ras mutations in codons 12 and 13 in non-small-cell lung cancer (NSCLC) patients in order to investigate correlation with clinical outcome. DNA was extracted from tumour and neighbouring non-neoplastic lung tissues from 70 patients and screened for codon 12 and 13 mutations. We applied a mutagenic PCR-restriction fragment length polymorphism for both codon 12 and 13 mutation detection. Codon 12 mutation was identified in 20% of NSCLC patients, whereas no codon 13 mutation was detected. As expected, the respective non-neoplastic tissues exhibited no mutations. We observed an increased codon 12 mutation prevalence in adenocarcinoma comparing to other types of carcinomas. Follow-up for 29 patients with a mean time of 12 months indicates an increased relapse rate in NSCLC patients with the K- ras codon 12 mutation. Furthermore, a trend towards increased percentage of mutant samples was observed in the advanced stage group of patients. We provide evidence that our approach is a fast and reliable method for screening K- ras exon 1 mutations in tumour samples from NSCLC patients.

Carcinoma, Non-Small-Cell Lung↗

PubMed1996

Both codon context and leader length contribute to efficient expression of two overlapping open reading frames of a cucumber necrosis virus bifunctional subgenomic mRNA.

The importance of codon context and leader length in the translational regulation of p20 and p21 from the bifunctional 0.9-kb subgenomic mRNA cucumber necrosis virus was investigated. Nucleotide substitutions introduced into the -3 and +4 positions of the p21 AUG codon (where the A of the AUG is +1) verified that purines in these positions are favored and demonstrated the similar contribution of the -3 and +4 positions to the efficiency of initiation codon selection in plants. The effect of nucleotide substitutions in the +5 position, most clearly demonstrated when pyrimidines occupy the -3 and +4 positions, also provided direct insight into the influence of the +5 position in plants. The codon context of the upstream p21 initiation codon affected expression from the downstream p20 AUG codon. In addition, an increase in the length of the subgenomic mRNA leader decreased expression from the downstream p20 initiation site. These latter observations are in accordance with the "Kozak rules" for accession of internal AUG codons by leaky ribosomal scanning and provide the first example of an effect of leader length on the efficiency of translation initiation in a plant (viral) mRNA.

Base Sequence↗

PubMed1996

The influence of AUG codons in the hepatitis C virus 5' nontranslated region on translation and mapping of the translation initiation window.

The initiation of translation of hepatitis C virus (HCV) is cap-independent and mediated by an internal ribosome entry site (IRES) that is located in the 5' nontranslated region (5' NTR) of the viral genome. This 5' NTR is relatively long and folds into a complex structure involving multiple hairpins and a pseudoknot. Within the sequence encompassing the IRES there are several AUG triplets. Some of these AUG codons are conserved between HCV genotypes and the related pestiviruses. In this study the 5 AUG codons (positions 13, 32, 85, 96, and 215) that are present in the 5' NTR of the HCV H-strain have been mutagenized to determine their influence on HCV cap-independent translation. The effect of these mutations on the expression of a chloramphenicol acetyl transferase (CAT) gene was tested in vaccinia virus. vTF7-3 infected Hep2 cells transfected with plasmids for the expression of a monocistronic HCV 5' NTR-CAT mRNA. Mutating the AUG codons at positions 13, 32, and 215 does not have a significant effect on CAT expression, inactivating the AUG codons at either position 85 or position 96 severely impaired IRES function. To determine whether ribosomes scan the RNA to select the initiation site, AUG codons were inserted up- and downstream of the authentic HCV polyprotein translation initiation codon (position 342). Analysis of these mutants has revealed that the ribosome is unable to use an AUG codon that is placed either 7 nucleotides upstream or 8 nucleotides downstream of the inactivated AUG at position 342. These results indicate that when scanning is involved in the recognition of the translation initiating AUG, it is limited to a narrow region between nucleotides 335 and 350.

Chromosome Mapping↗

PubMed1991

Codon usage is imposed by the gene location in the transcription unit.

A characteristic profile of the fluctuations of codon usage is observed in bacteriophages and mitochondria. By following the DNA in the direction of transcription, one moves slowly from a region where selective pressure favours codons ending with C to a region where the bias is in favour of codons ending with T; then, abruptly, one again enters a region of codons ending in C. The transcription end point takes place in the area of abrupt change in codon usage. By comparing Drosophila yakuba and mouse mitochondrial genomes, it is possible to show that the strategy of codon usage for a given gene depends on its location along the transcription unit and not on the encoded protein. The choice of codons ending in T or C allows large scale variations of DNA stability which could regulate the speed of propagation of the RNA polymerase.

Animals↗

PubMed1995

Comparison of the patterns of codon usage and bias between Brugia, Echinococcus, Onchocerca and Schistosoma species.

Patterns of codon usage and bias were compared among taxa of the genera Brugia, Echinococcus, Onchocerca and Schistosoma by metric multidimensional scaling and three commonly used indices of bias: Nc, GC3S and B. The overall codon usage for each taxon was compared, as was the codon usage for each individual gene within the taxa. Differences in the patterns of codon usage observed between taxa were dependent on the overall base composition of the genes analysed. The codon usage of Echinococcus was distinct from that of the other taxa. Furthermore, the pattern of codon usage detected by the average codon usage summed across all genes for each taxon was not shown by all genes from that taxon.

Animals↗

PubMed1993

Graphic analysis of codon usage strategy in 1490 human proteins.

The frequencies of bases A (adenine), C (cytosine), G (guanine), and T (thymine) occurring in codon position i, denoted by ai, ci, gi, and ti, respectively (i = 1,2,3), have been calculated and diagrammatized for the 1490 human proteins in the codon usage table for primate genes compiled recently. Based on the characteristic graphs thus obtained, an overall picture of codon base distribution has been provided, and the relevant biological implication discussed. For the first codon position, it is shown in most cases that G is the most dominant base, and that the relationship g1 > a1 > c1 > t1 generally holds true. For the second codon position, A is generally the most dominant base and G is the one with the least occurrence frequently, with the relationship of a2 > t2 > c2 > g2. As to the third codon position, the values of g3 + c3 vary from 0.27 to 1, roughly keeping the relationship of c3 > g3 > a3 = t3 for the majority of cases. Interestingly, if the average frequencies for bases A, C, G, and T are defined as a = (a1 + a2 + a3)/3, c = (c1 + c2 + c3)/3, g = (g1 + g2 + g3)/3, and t = (t1 + t2 + t3)/3, respectively, we find that a2 + c2 + g2 + t2 < 1/3 is valid almost without exception. Such a characteristic inequality might reflect some inherent rule of codon usage, although its biological implications is unclear.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine↗

PubMedDate not supplied

Codon equilibrium I: Testing for homogeneous equilibrium.

We present theoretical considerations that suggest that synonymous-codon usage might be expected to be close to an equilibrium distribution given a very homogeneous process of silent substitution. By homogeneous we mean that substitution depends only on the two bases involved, so that 12 base-substitution rates completely describe the silent substitution process. We have developed a method of statistically testing for such homogeneous equilibrium and applied it to reported data on the codon usages of different classes of organisms. Weakly expressed bacterial sequences and both mammalian and nonmammalian eukaryotic sequences deviate significantly from a random pattern of codon usage, in the direction of homogeneous equilibrium. On the other hand, highly expressed bacterial sequences do not exhibit homogeneous equilibrium, which may be correlated with recent experimental results showing that they are optimized to accept the most abundant tRNAs. To examine the effect of amino acid replacements on the homogeneous model of silent substitution, we divided the amino acids with degenerate codes into two classes, those with high mutabilities and those with low, and performed the same analysis on bacterial and eukaryotic data sets. The codon sets of the highly mutable class of amino acids are not further from homogeneous equilibrium than are the codon sets of the class with low mutabilities. We also found for the eukaryotic data that these independent classes of codon sets show very similar equilibrium patterns. The various results suggest a high level of uniformity in the process of silent fixation in the different synonymous-codon sets, especially in eukaryotes.

Amino Acid Sequence↗

PubMed1990

Evolution of the mitochondrial genetic code. III. Reassignment of CUN codons from leucine to threonine during evolution of yeast mitochondria.

Yeast mitochondria use UUR as the sole leucine codons. CUN, universal leucine codons, are read as threonine by aberrant threonine tRNA with anticodon sequence (UAG). The reassignment of CUN codons to threonine during yeast mitochondrial evolution could have proceeded by the disappearance of CUN codons from the reading frames of messenger RNA, through mutation mainly to UUR leucine codons as a result of AT pressure. We suggest that this was accompanied by a loss of leucine-accepting ability of tRNA Leu(UAG). This tRNA could have then acquired threonine-accepting activity through the appearance of an additional threonyl-tRNA synthetase. CUN codons that subsequently appeared from mutations of various other codons would have been translated as threonine. This change in the yeast mitochondrial genetic code is likely to have evolved through a series of nondisruptive nucleotide substitutions that produced no widespread replacement of leucine by threonine in proteins as a consequence.

Adenine↗

PubMed1989

Evolution of the mitochondrial genetic code. II. Reassignment of codon AUA from isoleucine to methionine.

The reassignment of codon AUA from isoleucine to methionine during mitochondrial evolution may be explained by the codon reassignment (capture) hypothesis without assuming direct replacement of isoleucine by methionine in mitochondrial proteins. According to this hypothesis, codon AUA would have disappeared from the reading frames of messenger RNA. AUA codons would have mutated mainly to AUU isoleucine codons because of constraints resulting from elimination of tRNA Ile with anticodon *CAU (in which *C is lysidine). Later, tRNA Met (CAU) would have undergone structural changes enabling it to pair with both AUG and AUA. AUA codons, formed by mutations of other codons, including AUG, would have reappeared and would have been translated as methionine.

Animals↗

PubMed1999

Synonymous codon choices in the extremely GC-poor genome of Plasmodium falciparum: compositional constraints and translational selection.

We have analyzed the patterns of synonymous codon preferences of the nuclear genes of Plasmodium falciparum, a unicellular parasite characterized by an extremely GC-poor genome. When all genes are considered, codon usage is strongly biased toward A and T in third codon positions, as expected, but multivariate statistical analysis detects a major trend among genes. At one end genes display codon choices determined mainly by the extreme genome composition of this parasite, and very probably their expression level is low. At the other end a few genes exhibit an increased relative usage of a particular subset of codons, many of which are C-ending. Since the majority of these few genes is putatively highly expressed, we postulate that the increased C-ending codons are translationally optimal. In conclusion, while codon usage of the majority of P. falciparum genes is determined mainly by compositional constraints, a small number of genes exhibit translational selection.

Animals↗

PubMed2002

Codon usage by transposable elements and their host genes in five species.

We compared the codon usage of sequences of transposable elements (TEs) with that of host genes from the species Drosophila melanogaster, Arabidopsis thaliana, Caenorhabditis elegans, Saccharomyces cerevisiae, and Homo sapiens. Factorial correspondence analysis showed that, regardless of the base composition of the genome, the TEs differed from the genes of their host species by their AT-richness. In all species, the percentage of A + T on the third codon position of the TEs was higher than that on the first codon position and lower than that in the noncoding DNA of the genomes. This indicates that the codon choice is not simply the outcome of mutational bias but is also subject to selection constraints. A tendency toward higher A + T on the third position than on the first position was also found in the host genes of A. thaliana, C. elegans, and S. cerevisiae but not in those of D. melanogaster and H. sapiens. This strongly suggests that the AT choice is a host-independent characteristic common to all TEs. The codon usage of TEs generally appeared to be different from the mean of the host genes. In the AT-rich genomes of Arabidopsis thaliana, Caenorhabditis elegans, and Saccharomyces cerevisiae, the codon usage bias of TEs was similar to that of weakly expressed genes. In the GC-rich genome of D. melanogaster, however, the bias in codon usage of the TEs clearly differed from that of weakly expressed genes. These findings suggest that selection acts on TEs and that TEs may display specific behavior within the host genomes.

Animals↗

PubMed2003

Selection conflicts, gene expression, and codon usage trends in yeast.

Synonymous codon usage in yeast appears to be influenced by natural selection on gene expression, as well as regional variation in compositional bias. Because of the large number of potential targets of selection (i.e., most of the codons in the genome) and presumed small selection coefficients, codon usage is an excellent model for studying factors that limit the effectiveness of selection. We use factor analysis to identify major trends in codon usage for 5836 genes in Saccharomyces cerevisiae. The primary factor is strongly correlated with gene expression, consistent with the model that a subset of codons allows for more efficient translation. The secondary factor is very strongly correlated with third codon position GC content and probably reflects regional variation in compositional bias. We find that preferred codon usage decreases in the face of three potential limitations on the effectiveness of selection: reduced recombination rate, increased gene length, and reduced intergenic spacing. All three patterns are consistent with the Hill-Robertson effect (reduced effectiveness of selection among linked targets). A reduction in gene expression in closely spaced genes may also reflect selection conflicts due to antagonistic pleiotropy.

Codon↗

PubMed2001

Why are translationally sub-optimal synonymous codons used in Escherichia coli?

Natural selection favors certain synonymous codons which aid translation in Escherichia coli, yet codons not favored by translational selection persist. We use the frequency distributions of synonymous polymorphisms to test three hypotheses for the existence of translationally sub-optimal codons: (1) selection is a relatively weak force, so there is a balance between mutation, selection, and drift; (2) at some sites there is no selection on codon usage, so some synonymous sites are unaffected by translational selection; and (3) translationally sub-optimal codons are favored by alternative selection pressures at certain synonymous sites. We find that when all the data is considered, model 1 is supported and both models 2 and 3 are rejected as sole explanations for the existence of translationally sub-optimal codons. However, we find evidence in favor of both models 2 and 3 when the data is partitioned between groups of amino acids and between regions of the genes. Thus, all three mechanisms appear to contribute to the existence of translationally sub-optimal codons in E. coli.

Codon↗

PubMed2003

Codon usage bias amongst plant viruses.

An internet database (DPVweb) was established containing details of all sequences of viruses, viroids and satellites of plants that are complete or that contain at least one complete gene (n>4600). The start and end positions of each feature (genes, non-translated regions etc) were recorded and checked for accuracy. Client software was written to enable easy selection of sequences and features of a chosen virus and to analyse codon usage bias. Codon usage was analysed for each gene of one example of each fully-sequenced plant virus. There were large differences in codon preferences, related to the nucleotide composition of the genome, particularly the GC content of the third codon position. There was no effect of gene size on codon bias. Genes from the same genome usually had similar coding strategies except where constrained by the overlap of reading frames. Although some synonymous codons were consistently used with low frequency by both plants and viruses, viruses were not generally adapted to use (or avoid) those codons most frequently used by their host plants and there was no obvious association with the type of transmission. Mutational bias, rather than translational selection appears to account for the majority of the variation detected. The software is available at http://www.dpvweb.net/analysis/codons.php.

Codon↗

PubMed1987

Identification of a novel in-frame translational stop codon in human intestine apoB mRNA.

Human apolipoprotein (apo) B exists in plasma as two isoproteins designated apoB-100 and apoB-48. ApoB-100 (512 kDa) and apoB-48 (250 kDa) are synthesized by the liver and intestine respectively. Analysis of apoB cDNA clones isolated from a human intestinal cDNA library revealed that the intestinal apoB mRNA contains a new in-frame translational stop codon. This premature stop codon is generated by a single base substitution of a 'C' to 'T' at nucleotide 6538 which converts the codon 'CAA' coding for the amino acid glutamine residue 2153 to an in-frame stop codon 'TAA'. The generation of a stop codon in the intestinal apoB mRNA appears to be tissue specific since it has not been reported in cDNA clones isolated from human liver cDNA libraries which code for the 4536 amino acid apoB-100. A potential polyadenylation signal sequence 'AATAAA' was also identified 390 bases downstream from the new stop codon. The new stop codon in the human intestinal apoB mRNA provides a potential mechanism for the biosynthesis of intestinal apoB-48.

Amino Acid Sequence↗

PubMed1983

Effects of surrounding sequence on the suppression of nonsense codons.

Using a lacI-Z fusion system, we have determined the efficiency of suppression of nonsense codons in the I gene of Escherichia coli by assaying beta-galactosidase activity. We examined the efficiency of four amber suppressors acting on 42 different amber (UAG) codons at known positions in the I gene, and the efficiency of a UAG suppressor at 14 different UGA codons. The largest effects were found with the amber suppressor supE (Su2), which displayed efficiencies that varied over a 35-fold range, and with the UGA suppressor, which displayed a 170-fold variation in efficiency. Certain UGA sites were so poorly suppressed (less than 0.2%) by the UGA suppressor that they were not originally detected as nonsense mutations. Suppression efficiency can be correlated with the sequence on the 3' side of the codon being suppressed, and in many cases with the first base on the 3' side. In general, codons followed by A or G are well suppressed, and codons followed by U or C are poorly suppressed. There are exceptions, however, since codons followed by CUG or CUC are well suppressed. Models explaining the effect of the surrounding sequence on suppression efficiency are considered in the Discussion and in the accompanying paper.

Base Sequence↗

PubMed1985

Sense codons are found in specific contexts.

The sequence environment of codons in structural genes has been investigated statistically, using computer methods. A set of Escherichia coli genes with abundant products was compared with a set having low gene product levels, in order to detect potential differences associated with expression. The results show striking non-randomness in the nucleotides occurring near codons. These effects are, unexpectedly, very much larger and more homogeneous among the genes with rare products. The intensity of effects in weakly expressed genes suggests that such non-random sequence environments decrease expression. In the weakly expressed set of genes, the 5' neighbor of a codon, and all positions of the 3' neighbor codon are biased. In the highly expressed genes, the first nucleotide of the next codon is a uniquely affected site. The distribution of non-randomness in weakly expressed genes suggests that sequence bias is primarily due to a constraint acting directly on the secondary or tertiary structure of the codon/anticodon. In highly expressed genes, the observed bias suggests an interaction between the codon/anticodon and a site outside the codon/anticodon. Much of the tendency to non-random near-neighbor sequences in weakly expressed genes can be ascribed to a correlation between nearby nucleotides and the wobble nucleotide of the codon, despite the fact that selection of such correlations will alter the amino acid sequence. The favored pattern, in genes expressed at low level, is R YYR or Y RRY. R indicates purine, Y indicates pyrimidine; the space is the boundary between codons. It seems likely that this preference for nearby sequences is the physical basis of the genetic context effect. Under this assumption such sequence biases will affect expression. On this basis, we predict new sites for contextual mutations which decrease expression, and suggest strategy for the design of messages having optimal translational activity.

Amino Acids↗