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At least 73 records · Page 4Linked to original sources
PubMed1984

Mechanism of codon recognition by transfer RNA and codon-induced tRNA association.

The steps of UUC recognition by tRNAPhe were analysed by temperature-jump measurements. At ion concentrations close to physiological conditions we found three relaxation processes, which we assigned to (1) formation of codon-anticodon complexes, (2) a conformational change of the anticodon loop coupled with Mg2+ binding, and (3) codon-induced association of tRNA. The relaxation data were evaluated both by the usual procedure (fitting the exponentials evaluated from the individual experiments of a set to a reaction model) and by "global fitting", i.e. fitting a set of relaxation curves obtained at various concentrations directly to a reaction model, thus leaving out the intermediate exponential fitting step. The data can be represented quantitatively by a three-step model: the codon binds to the anticodon at a rate of 4 X 10(6) to 6 X 10(6) M-1S-1 as is usual for the formation of oligomer helices; the conformation change of the anticodon loop is associated with inner sphere complexation of Mg2+ at a rate of 10(3) S-1; the codon-tRNA complexes form dimers at a rate of 5 X 10(6) to 15 X 10(6) M-1S-1. A similar mechanism is found for the binding of the wobble codon UUU to tRNAPhe at increased concentrations of Mg2+. Measurements at different Mg2+ concentrations demonstrate the distinct role of this ion in the codon recognition and the codon-induced tRNA dimerization. We propose a simple mechanism, based upon the special properties of magnesium ions, for long-distance transfer of reaction signals along nucleic acid chains.

Anticodon↗
PubMed1984

An effect of codon context on the mistranslation of UGU codons in vitro.

Effects of codon context on nonsense codon suppression may act either through release factor recognition of termination codons or aminoacyl-tRNA selection by the ribosome. The latter hypothesis has been studied by comparing misreading by Escherichia coli UGA suppressor tryptophan tRNA of UGU (cysteine) codons in two synthetic polymers, poly(U-G) and poly( U5 , G), which differ in sequence around the UGU codons. In vitro translation of these polymers in a cell-free system from E. coli yielded selection errors of 4 X 10(-3) and 1.75 X 10(-2) for UGU codons in poly(U-G) and poly( U5 , G), respectively. This difference suggests that codon context may significantly affect misincorporation of amino acids into protein.

Codon↗
PubMed1991

Absolute in vivo translation rates of individual codons in Escherichia coli. The two glutamic acid codons GAA and GAG are translated with a threefold difference in rate.

We have determined the absolute translation rates for four individual codons in Escherichia coli. We used our previously described system for direct measurements of in vivo translation rates using small, in-frame inserts in the lacZ gene. The inserts consisted of multiple synthetic 30 base-pair DNA oligomers with high densities of the four individual codons, GAA (Glu), GAG (Glu), CCG (Pro) and CGA (Arg). Our method is independent of expression level, of mRNA half-life and of transcription rate. Codon GAA was found to be translated with a rate of 21.6 codons/second whereas codon GAG was translated 3.4-fold slower (6.4 codons/s). These two codons are read by the same tRNA species. Codon CCG and CGA are both read by abundant tRNA species but nevertheless we found them to be translated slowly with rates of 5.8 and 4.2 codons/second, respectively. The context of these codons were varied, but we found no significant influence of context on their translation rates and we suggest a mechanism for why context may not affect translation rates. One insert with a low translation rate gave results that most readily can be explained by assuming queue formation of ribosomes on the insert. Such a queue was found to reduce the expression level by approximately 35%. Our experiments allowed us to estimate the average distance between ribosomes and thereby the translation initiation frequency on the wild-type lacZ mRNA. This was found to be one per three seconds.

Base Sequence↗
PubMed1991

Selection for a pre-C stop codon mutation in a hepatitis B virus variant with a pre-C initiation codon mutation during interferon treatment.

Hepatitis B virus (HBV) variants with a stop codon, a mutated translation initiation codon or other mutations in the pre-C region which prevent e-antigen expression are highly prevalent in anti-HBe chronic carriers and can be positively selected from a mixed virus infection. Our laboratories recently described pre-C variants with two pre-C mutations which prevent HBeAg expression. Here we have investigated whether there is a selective pressure for acquisition of the second pre-C mutation. By direct sequencing of amplified HBV DNA from sera of a chronic carrier taken during a 6-year follow-up, we found that genomes of a virus population virtually all had a pre-C translation initiation codon mutation and about 50% had an additional stop codon mutation. With the onset of interferon treatment, the genomes with the stop codon mutation increased to more than 95% while the frequency of the translation initiation codon mutation in all genomes remained constant. These data indicate positive selection (possibly immune-mediated and HBeAg-targeted) for a second pre-C mutation. This putative enhancement of negative translational control may be present because a pre-C translation initiation codon mutation cannot totally prevent HBeAg expression and is therefore less frequent.

Adult↗
PubMed1999

Studies of codon usage and tRNA genes of 18 unicellular organisms and quantification of Bacillus subtilis tRNAs: gene expression level and species-specific diversity of codon usage based on multivariate analysis.

We examined codon usage in Bacillus subtilis genes by multivariate analysis, quantified its cellular levels of individual tRNAs, and found a clear constraint of tRNA contents on synonymous codon choice. Individual tRNA levels were proportional to the copy number of the respective tRNA genes. This indicates that the tRNA gene copy number is an important factor to determine in cellular tRNA levels, which is common with Escherichia coli and yeast Saccharomyces cerevisiae. Codon usage in 18 unicellular organisms whose genomes have been sequenced completely was analyzed and compared with the composition of tRNA genes. The 18 organisms are as follows: yeast S. cerevisiae, Aquifex aeolicus, Archaeoglobus fulgidus, B. subtilis, Borrelia burgdorferi, Chlamydia trachomatis, E. coli, Haemophilus influenzae, Helicobacterpylori, Methanococcusjannaschii, Methanobacterium thermoautotrophicum, Mycobacterium tuberculosis, Mycoplasma genitalium, Mycoplasma pneumoniae, Pyrococcus horikoshii, Rickettsia prowazekii, Synechocystis sp., and Treponema pallidum. Codons preferred in highly expressed genes were related to the codons optimal for the translation process, which were predicted by the composition of isoaccepting tRNA genes. Genes with specific codon usage are discussed in connection with their evolutionary origins and functions. The origin and terminus of replication could be predicted on the basis of codon usage when the usage was analyzed relative to the transcription direction of individual genes.

Archaea↗
PubMed1998

Selective mutation of K-ras by N-ethylnitrosourea shifts from codon 12 to codon 61 during fetal mouse lung maturation.

Fetal mouse lung before gestation day 17 shows unique sensitivity to causation of rapidly growing tumors by N-ethylnitrosourea (ENU). Since mouse lung tumors present a mutated K-ras oncogene, we hypothesized that this special susceptibility might reflect an unusual vulnerability of the K-ras gene. Of the lung tumors caused by ENU exposure of BALB/c mice on gestation day 14, 8/25 had a codon 12 mutation in K-ras, vs 4/25 in codon 61. Of 15 tumors after day 16 exposure, three had codon 12 and four codon 61 changes. Tumors from day 18 exposure had only codon 61 mutations (11/16), all A:T to G:C changes (CGA). By contrast, codon 12 (GGT) changes included G:C to T:A, to A:T, and to C:G. These results show significant (P<0.01) shift in the sensitivity of particular K-ras codons to ENU mutation, during fetal mouse lung maturation. In a test of a possible relationship to expression of K-ras, K-ras p21 was measured in lungs of fetal mice, and found to increase markedly on day 18 in comparison to days 14 and 16. Both alkylation of DNA and base damage due to reactive oxygen species are postulated as mechanisms for mutation by ENU, whose efficacies vary with state of fetal lung maturation and K-ras expression.

Adenocarcinoma, Papillary↗
PubMed2006

How can third codon positions outperform first and second codon positions in phylogenetic inference? An empirical example from the seed plants.

Greater phylogenetic signal is often found in parsimony-based analyses of third codon positions of protein-coding genes relative to their corresponding first and second codon positions, even for early-derived ("basal") clades. We used the Soltis et al. (2000; Bot. J. Linn. Soc. 133:381-461) data matrix of atpB and rbcL from 567 seed plants to quantify how each of six factors (observed character-state space, frequencies of observed character states, substitution probabilities among nucleotides, rate heterogeneity among sites, overall rate of evolution, and number of parsimony-informative characters) contributed to this phenomenon. Each of these six factors was estimated from the original data matrix for parsimony-informative third codon positions considered separately from first and second codon positions combined. One of the most parsimonious trees found was used as the constraint topology; branch lengths were estimated using likelihood-based distances, and characters were simulated on this tree. Differential frequencies of observed character states were found to be the most limiting of the factors simulated for all three codon positions. Differential frequencies of observed character states and differential substitution probabilities among states were relatively advantageous for first and second codon positions. In contrast, differential numbers of observed character states, differential rate heterogeneity among sites, the greater number of parsimony-informative characters, and the higher overall rate of evolution were relatively advantageous for third codon positions. The amount of possible synapomorphy was predictive of the overall success of resolution.

Base Sequence↗
PubMed2004

AUG codons at the beginning of protein coding sequences are frequent in eukaryotic mRNAs with a suboptimal start codon context.

MOTIVATION: The translation start site plays an important role in the control of translation efficiency of eukaryotic mRNAs. However, mRNAs with a suboptimal context of start AUG codon are relatively abundant. It is likely that at least some mRNAs with suboptimal start codon context contain the other signals providing additional information for efficient AUG recognition. RESULTS: Frequency of AUG codons at the beginning of the coding part of eukaryotic mRNAs was analyzed in relation to the context of translation start codon. It was found that the observed downstream AUG content in the mRNAs with optimal start codon context was close to the expected value, whereas it was significantly higher in the mRNAs with a suboptimal context. It is likely that downstream AUG codons can often be utilized as additional start sites to increase translation rate of mRNAs with a suboptimal context of the annotated start codon and many eukaryotic proteins can be characterized by some N-end heterogeneity.

Adenine↗
PubMed2001

Selection at the amino acid level can influence synonymous codon usage: implications for the study of codon adaptation in plastid genes.

A previously employed method that uses the composition of noncoding DNA as the basis of a test for selection between synonymous codons in plastid genes is reevaluated. The test requires the assumption that in the absence of selective differences between synonymous codons the composition of silent sites in coding sequences will match the composition of noncoding sites. It is demonstrated here that this assumption is not necessarily true and, more generally, that using compositional properties to draw inferences about selection on silent changes in coding sequences is much more problematic than commonly assumed. This is so because selection on nonsynonymous changes can influence the composition of synonymous sites (i.e., codon usage) in a complex manner, meaning that the composition biases of different silent sites, including neutral noncoding DNA, are not comparable. These findings also draw into question the commonly utilized method of investigating how selection to increase translation accuracy influences codon usage. The work then focuses on implications for studies that assess codon adaptation, which is selection on codon usage to enhance translation rate, in plastid genes. A new test that does not require the use of noncoding DNA is proposed and applied. The results of this test suggest that far fewer plastid genes display codon adaptation than previously thought.

Algorithms↗
PubMed1989

Codon usage and gene expression level in Dictyostelium discoideum: highly expressed genes do 'prefer' optimal codons.

Codon usage patterns in the slime mould Dictyostelium discoideum have been re-examined (a total of 58 genes have been analysed). Considering the extreme A + T-richness of this genome (G + C = 22%), there is a surprising degree of codon usage variation among genes. For example, G + C content at silent sites varies from less than 10% to greater than 30%. It was previously suggested [Warrick, H.M. and Spudich, J.A. (1988) Nucleic Acids Res. 16: 6617-6635] that highly expressed genes contain fewer 'optimal' codons than genes expressed at lower levels. However, it appears that the optimal codons were misidentified. Multivariate statistical analysis shows that the greatest variation among genes is in relative usage of a particular subset of codons (about one per amino acid), many of which are C-ending. We have identified these as optimal codons, since (i) their frequency is positively correlated with gene expression level, and (ii) there is a strong mutation bias in this genome towards A and T nucleotides. Thus, codon usage in D. discoideum can be explained by a balance between the forces of mutational bias and translational selection.

Codon↗
PubMed1994

Codon cassette mutagenesis: a general method to insert or replace individual codons by using universal mutagenic cassettes.

We describe codon cassette mutagenesis, a simple method of mutagenesis that uses universal mutagenic cassettes to deposit single codons at specific sites in double-stranded DNA. A target molecule is first constructed that contains a blunt, double-strand break at the site targeted for mutagenesis. A double-stranded mutagenic codon cassette is then inserted at the target site. Each mutagenic codon cassette contains a three base pair direct terminal repeat and two head-to-head recognition sequences for the restriction endonuclease Sapl, an enzyme that cleaves outside of its recognition sequence. The intermediate molecule containing the mutagenic cassette is then digested with Sapl, thereby removing most of the mutagenic cassette, leaving only a three base cohesive overhang that is ligated to generate the final insertion or substitution mutation. A general method for constructing blunt-end target molecules suitable for this approach is also described. Because the mutagenic cassette is excised during this procedure and alters the target only by introducing the desired mutation, the same cassette can be used to introduce a particular codon at all target sites. Each cassette can deposit two different codons, depending on the orientation in which it is inserted into the target molecule. Therefore, a series of eleven cassettes is sufficient to insert all possible amino acids at any constructed target site. Thus codon cassettes are 'off-the-shelf' reagents, and this methodology should be a particularly useful and inexpensive approach for subjecting multiple different positions in a protein sequence to saturation mutagenesis.

Base Sequence↗
PubMed2003

Revisiting the codon adaptation index from a whole-genome perspective: analyzing the relationship between gene expression and codon occurrence in yeast using a variety of models.

Highly expressed genes in many bacteria and small eukaryotes often have a strong compositional bias, in terms of codon usage. Two widely used numerical indices, the codon adaptation index (CAI) and the codon usage, use this bias to predict the expression level of genes. When these indices were first introduced, they were based on fairly simple assumptions about which genes are most highly expressed: the CAI was originally based on the codon composition of a set of only 24 highly expressed genes, and the codon usage on assumptions about which functional classes of genes are highly expressed in fast-growing bacteria. Given the recent advent of genome-wide expression data, we should be able to improve on these assumptions. Here, we measure, in yeast, the degree to which consideration of the current genome-wide expression data sets improves the performance of both numerical indices. Indeed, we find that by changing the parameterization of each model its correlation with actual expression levels can be somewhat improved, although both indices are fairly insensitive to the exact way they are parameterized. This insensitivity indicates a consistent codon bias amongst highly expressed genes. We also attempt direct linear regression of codon composition against genome-wide expression levels (and protein abundance data). This has some similarity with the CAI formalism and yields an alternative model for the prediction of expression levels based on the coding sequences of genes. More information is available at http://bioinfo.mbb.yale.edu/expression/codons.

Codon↗
PubMed1996

Autosomal dominant cone-rod dystrophy associated with mutations in codon 244 (Asn244His) and codon 184 (Tyr184Ser) of the peripherin/RDS gene.

OBJECTIVE: To characterize clinical findings associated with mutations in codon 244 (Asn244His) and codon 184 (Tyr184Ser) of the peripherin/RDS gene. DESIGN: Case reports with clinical features and results of fluorescein angiography, electroretinography, kinetic visual field testing, and DNA analysis. SETTING: University medical center. PATIENTS: Four affected members of two Japanese families with autosomal dominant cone-rod dystrophy associated with transversion mutations in codon 244 (Asn244His) and codon (Tyr184Ser) of the peripherin/RDS gene. RESULTS: Characteristic features included the initial symptoms of decreased visual acuity, macular degeneration, central or paracentral scotoma, cone-mediated electroretinographic responses that were more impaired than rod-mediated responses, and pigmentary degeneration in the midperipheral retina in the late stage. These phenotypic features corresponded to cone-rod dystrophy type 2a by the classification of Szlyk and associates. CONCLUSIONS: The Asn244His and Tyr184Ser mutations in the peripherin/RDS gene cause con-rod dystrophy type 2a. These findings imply that a mutation in codon 244 or codon 184 of the peripherin/RDS gene affects the functions and/or structural stability of cones and rods.

Adult↗
PubMed1995

Differential codon usage for conserved amino acids: evidence that the serine codons TCN were primordial.

The availability of specialized sequence databanks for Escherichia coli, Saccharomyces cerevisiae and Bacillus subtilis made it possible to build a set of 105 protein-coding genes that are homologous in these three species. An analysis of the triplets at both the nucleotide and amino acid level revealed that the codon bias of some amino acids are significantly higher at conserved rather than at non-conserved positions. Comparisons of homologous genes in E. coli and Salmonella typhimurium, and in S. cerevisiae and Drosophila melanogaster, led to the same conclusion. A special case was made for serine in E. coli, whose major codon is AGC for non-conserved and TCC for conserved residues. We interpret this observation as evidence that the primordial codons for serine were TCN, while codons AGY appeared later. This conclusion is substantiated by an analysis of the codon usage of catalytic serine residues in ancient, ubiquitous and essential proteins (ATP synthases and topoisomerases). It is shown that in these proteins the proportion of the catalytic serine residues coded by TCN is significantly higher than the one expected from the overall codon usage of serine residues.

Amino Acid Sequence↗
PubMed2001

Expanding the genetic code: selection of efficient suppressors of four-base codons and identification of "shifty" four-base codons with a library approach in Escherichia coli.

Naturally occurring tRNA mutants are known that suppress +1 frameshift mutations by means of an extended anticodon loop, and a few have been used in protein mutagenesis. In an effort to expand the number of possible ways to uniquely and efficiently encode unnatural amino acids, we have devised a general strategy to select tRNAs with the ability to suppress four-base codons from a library of tRNAs with randomized 8 or 9 nt anticodon loops. Our selectants included both known and novel suppressible four-base codons and resulted in a set of very efficient, non-cross-reactive tRNA/four-base codon pairs for AGGA, UAGA, CCCU and CUAG. The most efficient four-base codon suppressors had Watson-Crick complementary anticodons, and the sequences of the anticodon loops outside of the anticodons varied with the anticodon. Additionally, four-base codon reporter libraries were used to identify "shifty" sites at which +1 frameshifting is most favorable in the absence of suppressor tRNAs in Escherichia coli. We intend to use these tRNAs to explore the limits of unnatural polypeptide biosynthesis, both in vitro and eventually in vivo. In addition, this selection strategy is being extended to identify novel five- and six-base codon suppressors.

Amino Acid Sequence↗
PubMed2003

tRNA1Ser(G34) with the anticodon GGA can recognize not only UCC and UCU codons but also UCA and UCG codons.

The tRNA1Ser (anticodon VGA, V=uridin-5-oxyacetic acid) is essential for translation of the UCA codon in Escherichia coli. Here, we studied the translational abilities of serine tRNA derivatives, which have different bases from wild type at the first positions of their anticodons, using synthetic mRNAs containing the UCN (N=A, G, C, or U) codon. The tRNA1Ser(G34) having the anticodon GGA was able to read not only UCC and UCU codons but also UCA and UCG codons. This means that the formation of G-A or G-G pair allowed at the wobble position and these base pairs are noncanonical. The translational efficiency of the tRNA1Ser(G34) for UCA or UCG codon depends on the 2'-O-methylation of the C32 (Cm). The 2'-O-methylation of C32 may give rise to the space necessary for G-A or G-G base pair formation between the first position of anticodon and the third position of codon.

Anticodon↗
PubMed1987

The codon Adaptation Index--a measure of directional synonymous codon usage bias, and its potential applications.

A simple, effective measure of synonymous codon usage bias, the Codon Adaptation Index, is detailed. The index uses a reference set of highly expressed genes from a species to assess the relative merits of each codon, and a score for a gene is calculated from the frequency of use of all codons in that gene. The index assesses the extent to which selection has been effective in moulding the pattern of codon usage. In that respect it is useful for predicting the level of expression of a gene, for assessing the adaptation of viral genes to their hosts, and for making comparisons of codon usage in different organisms. The index may also give an approximate indication of the likely success of heterologous gene expression.

Animals↗
PubMed1991

An extreme codon preference strategy: codon reassignment.

We argue that in animal mitochondria codon reassignments, such as those for AGA and AGG from arginine to serine or of AUA from isoleucine to methionine, are the result of an interplay between biased mutational forces and selective ones. In particular, there is a marked tendency for animal mitochondria to have very small genomes and to minimize their investment in components required for gene expression. These tendencies are expressed as a reduction in the diversity of tRNA isoacceptor species. In our view, the pressure to simplify tRNA populations, together with mutational bias against certain codons, will account for the codon reassignments observed in animal mitochondria. A parallel to the major codon bias in microorganisms, which likewise tends to reduce the diversity of the tRNA isoacceptor populations under fast growth conditions, may be drawn. Therefore, we suggest that codon reassignments are usefully viewed as an extreme form of codon bias.

Base Composition↗