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PubMed2004

Demonstration of GTG as an endogenous initiation codon for a human mRNA transcript revealed by molecular cloning of the serpin endopin 2B.

This study demonstrates utilization of the novel GTG initiation codon for translation of a human mRNA transcript that encodes the serpin endopin 2B, a protease inhibitor. Molecular cloning revealed the nucleotide sequence of the human endopin 2B cDNA. Its deduced primary sequence shows high homology to bovine endopin 2A that possesses cross-class protease inhibition of elastase and papain. Notably, the human endopin 2B cDNA sequence revealed GTG as the predicted translation initiation codon; the predicted translation product of 46 kDa endopin 2B was produced by in vitro translation of 35S-endopin 2B with mammalian (rabbit) protein translation components. Importantly, bioinformatic studies demonstrated the presence of the entire human endopin 2B cDNA sequence with GTG as initiation codon within the human genome on chromosome 14. Further evidence for GTG as a functional initiation codon was illustrated by GTG-mediated in vitro translation of the heterologous protein EGFP, and by GTG-mediated expression of EGFP in mammalian PC12 cells. Mutagenesis of GTG to GTC resulted in the absence of EGFP expression in PC12 cells, indicating the function of GTG as an initiation codon. In addition, it was apparent that the GTG initiation codon produces lower levels of translated protein compared to ATG as initiation codon. Significantly, GTG-mediated translation of endopin 2B demonstrates a functional human gene product not previously predicted from initial analyses of the human genome. Further analyses based on GTG as an alternative initiation codon may predict new candidate genes of the human genome.

Journal Article↗

PubMed1990

Glycine to aspartic acid mutations at codon 13 of the c-Ki-ras gene in human gastrointestinal cancers.

Point mutations of c-ras genes were analyzed in human gastrointestinal cancers. DNA obtained from the tissues was amplified by polymerase chain reaction and then analyzed by dot blot hybridization assay with oligonucleotide probes to detect mutations at codons 12, 13, and 61 of c-Ki-ras, c-Ha-ras, and c-N-ras. In two of 25 cases of stomach cancer point mutations at codon 13 of c-Ki-ras were found. In colorectal cancer, eight of 30 cases showed mutations: four cases of codon 12 and one case at codon 13 of c-Ki-ras and two cases at codon 61 and one case at codon 13 of c-N-ras. These results may indicate involvement of a wide variety of c-ras gene point mutations, in addition to those at codon 12 of c-Ki-ras, in oncogenesis of human gastrointestinal cancers. In all three mutations of c-Ki-ras at codon 13 which had been seldom found in human cancers, glycine to aspartic acid mutations due to identical G to A transition at the second nucleotide were observed.

Aspartic Acid↗

PubMed2006

An asymmetric underlying rule in the assignment of codons: possible clue to a quick early evolution of the genetic code via successive binary choices.

Aminoacyl-tRNA synthetases (aaRSs) are responsible for creating the pool of correctly charged aminoacyl-tRNAs that are necessary for the translation of genetic information (mRNA) by the ribosome. Each aaRS belongs to either one of only two classes with two different mechanisms of aminoacylation, making use of either the 2'OH (Class I) or the 3'OH (Class II) of the terminal A76 of the tRNA and approaching the tRNA either from the minor groove (2'OH) or the major groove (3'OH). Here, an asymmetric pattern typical of differentiation is uncovered in the partition of the codon repertoire, as defined by the mechanism of aminoacylation of each corresponding tRNA. This pattern can be reproduced in a unique cascade of successive binary decisions that progressively reduces codon ambiguity. The deduced order of differentiation is manifestly driven by the reduction of translation errors. A simple rule can be defined, decoding each codon sequence in its binary class, thereby providing both the code and the key to decode it. Assuming that the partition into two mechanisms of tRNA aminoacylation is a relic that dates back to the invention of the genetic code in the RNA World, a model for the assignment of amino acids in the codon table can be derived. The model implies that the stop codon was always there, as the codon whose tRNA cannot be charged with any amino acid, and makes the prediction of an ultimate differentiation step, which is found to correspond to the codon assignment of the 22nd amino acid pyrrolysine in archaebacteria.

Amino Acyl-tRNA Synthetases↗

PubMed1995

Clinicopathologic significance of the K-ras gene codon 12 point mutation in stomach cancer. An analysis of 140 cases.

BACKGROUND: The frequency and clinicopathologic significance of the K-ras gene point mutation in stomach cancer remain to be defined. METHODS: The authors investigated the frequency of K-ras codon 12 point mutations in stomach cancer using a sensitive polymerase chain reaction (PCR)-based method in 140 samples and correlated the findings with various clinicopathologic characteristics of the patients. RESULTS: The overall frequency of K-ras codon 12 point mutations in stomach cancer was 7.9% (11/140). DNA sequencing of nine cases with K-ras codon 12 point mutations identified seven cases with a single-base substitution of GGT to AGT (glycine to serine) and two with single-base substitution of GGT to AGT (aspartic acid). Tumors located in the upper third of the stomach had a significantly higher frequency of K-ras codon 12 mutations (3/8, 37.5%) compared with tumors located in the middle (4/29, 13.8%) or lower (3/99, 3.0%) thirds of the stomach (P = 0.001). No significant difference was observed in the frequency of K-ras codon 12 mutations in terms of other various clinicopathologic characteristics including tumor DNA ploidy and S-phase fraction. After a median follow-up of 26 months, disease free and overall survival were not significantly different between patients with stomach cancer with or without K-ras codon 12 mutation. Among eight patients with stomach cancer located in the upper part of the stomach, none of the three patients with K-ras gene-mutated tumors died versus four of five with tumors without K-ras gene mutations (P = 0.064). CONCLUSIONS: K-ras codon 12 point mutations are uncommon in stomach cancer (7.9%). There was significant correlation between K-ras mutations and vertical tumor location in the stomach, suggesting that different mechanisms may play a role in the pathogenesis of stomach cancer according to the location of tumors in the stomach.

Adult↗

PubMed2005

Studies on codon usage in Thermoplasma acidophilum and its possible implications on the occurrences of lateral gene transfer.

Codon usage studies have been carried out on the coding sequences of Thermoplasma acidophilum, which is an archaeon and grows at very low pH and high temperature. Overall codon usage data analysis indicates that all the four bases are almost equifrequent at the third position of codons, which is expected (since genomic GC % of this genome is about 46%). However, multivariate statistical analysis indicates that there are two major trends in the codon usage variation among the genes in this organism. In the first major trend it is observed that genes having G and C ending codons are clustered at one end while, A and T ending ones are clustered at the other end. We have also found a significant positive correlation between the expressivities of genes and GC contents at the synonymous third codon positions. In the second major trend, it is seen that the genes are clustered into three distinct parts. A comparative analyses of codon usage data of T. acidophilum and Sulfolobus solfataricus reveals that one of the three clusters of genes of T. acidophilum is very similar to a considerable number of S. solfataricus genes, suggesting possible occurrences of lateral gene transfer between these two microorganisms as reported by earlier workers.

Codon↗

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↗