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At least 19 recordsLinked to original sources
PubMed1990

Suppression of the negative effect of minor arginine codons on gene expression; preferential usage of minor codons within the first 25 codons of the Escherichia coli genes.

AGA and AGG codons for arginine are the least used codons in Escherichia coli, which are encoded by a rare tRNA, the product of the dnaY gene. We examined the positions of arginine residues encoded by AGA/AGG codons in 678 E. coli proteins. It was found that AGA/AGG codons appear much more frequently within the first 25 codons. This tendency becomes more significant in those proteins containing only one AGA or AGG codon. Other minor codons such as CUA, UCA, AGU, ACA, GGA, CCC and AUA are also found to be preferentially used within the first 25 codons. The effects of the AGG codon on gene expression were examined by inserting one to five AGG codons after the 10th codon from the initiation codon of the lacZ gene. The production of beta-galactosidase decreased as more AGG codons were inserted. With five AGG codons, the production of beta-galactosidase (Gal-AGG5) completely ceased after a mid-log phase of cell growth. After 22 hr induction of the lacZ gene, the overall production of Gal-AGG5 was 11% of the control production (no insertion of arginine codons). When five CGU codons, the major arginine codon were inserted instead of AGG, the production of beta-galactosidase (Gal-CGU5) continued even after stationary phase and the overall production was 66% of the control. The negative effect of the AGG codons on the Gal-AGG5 production was found to be dependent upon the distance between the site of the AGG codons and the initiation codon. As the distance was increased by inserting extra sequences between the two codons, the production of Gal-AGG5 increased almost linearly up to 8 fold. From these results, we propose that the position of the minor codons in an mRNA plays an important role in the regulation of gene expression possibly by modulating the stability of the initiation complex for protein synthesis.

Amino Acid Sequence↗
PubMed1990

Codon recognition in polypeptide chain termination: site directed crosslinking of termination codon to Escherichia coli release factor 2.

An RNA synthesized in vitro was positioned on the Escherichia coli ribosome at the P site with tRNAala, and with a termination codon, UAA, as the next codon in the A site. Such a complex bound stoichiometric amounts of release factor 2 (RF-2); a corresponding RNA with UAC in place of UAA was not a template for the factor. An RNA containing 4-thio-UAA in place of the UAA supported binding of RF-2, and this has allowed site-directed crosslinking from the first position of the termination codon to answer two long standing questions about the termination of protein biosynthesis, the position of the termination codon and its proximity to the release factor during codon recognition. An RF-2.mRNA crosslinked product was detected, indicating the release factor and the termination codon are in close physical contact during the codon recognition event of termination. The 4-thio-U crosslinked also to the ribosome but only to the 30S subunit, and the proteins and the rRNA site concerned were identified. RF-2 decreased significantly the crosslinking to the ribosomal components, but no new crosslink sites were found. If the stop codon was deliberately displaced from the decoding site by one codon's length then a different pattern of crosslinking in particular to the rRNA resulted. These observations are consistent with a model of codon recognition by RF-2 at the decoding site, without a major shift in position of the codon.

Base Sequence↗
PubMed1987

Influence of the codon following the AUG initiation codon on the expression of a modified lacZ gene in Escherichia coli.

In a lacZ expression vector (pMC1403Plac), all 64 codons were introduced immediately 3' from the AUG initiation codon. The expression of the second codon variants was measured by immunoprecipitation of the plasmid-coded fusion proteins. A 15-fold difference in expression was found among the codon variants. No distinct correlation could be made with the level of tRNA corresponding to the codons and large differences were observed between synonymous codons that use the same tRNA. Therefore the effect of the second codon is likely to be due to the influence of its composing nucleotides, presumably on the structure of the ribosomal binding site. An analysis of the known sequences of a large number of Escherichia coli genes shows that the use of codons in the second position deviates strongly from the overall codon usage in E. coli. It is proposed that codon selection at the second position is not based on requirements of the gene product (a protein) but is determined by factors governing gene regulation at the initiation step of translation.

Base Sequence↗
PubMed1991

Influence of the codon following the initiation codon on the expression of the lacZ gene in Saccharomyces cerevisiae.

A set of 32 different codons were introduced in a lacZ expression vector (pPTK400) immediately 3' from the AUG initiation codon. Expression of the lacZ gene was determined in Saccharomyces cerevisiae by measuring the amount of beta-galactosidase fusion protein using immuno-gel electrophoresis. A 5.3-fold difference in expression was found among the various constructs. It was found that there was no preference for a certain nucleotide in any position of the second codon and there was no distinct correlation between the level of tRNA corresponding to any particular second codon and expression. No correlation could be found between the local secondary structure and expression. When the overall codon usage in yeast and the codon usage in the second position of the mRNA is compared, there is no obvious significant difference in preference. This indicates that in yeast, in contrast to Escherichia coli, the codon choice at the beginning of the mRNA does not deviate from the one further downstream and is determined by the requirements for optimal translation elongation. Important determinants of the optimal context for an initiation codon in yeast therefore must be located mainly 5' from this codon.

Amino Acid Sequence↗
PubMed1991

The signal for a leaky UAG stop codon in several plant viruses includes the two downstream codons.

Expression of the RNA replicase domain of tobacco mosaic virus (TMV) and certain protein-coding regions in other plant viruses, is mediated by translational readthrough of a leaky UAG stop codon. It has been proposed that normal tobacco tyrosine tRNAs are able to read the UAG codon of TMV by non-conventional base-pairing but recent findings that stop codons can also be bypassed as a result of extended translocational shifts (tRNA hopping) have encouraged a re-examination. In light of the alternatives, we investigated the sequences flanking the leaky UAG codon using an in vivo assay in which bypass of the stop codon is coupled to the transient expression of beta-glucuronidase (GUS) reporter genes in tobacco protoplasts. Analysis of GUS constructions in which codons flanking the stop were altered allowed definition of the minimal sequence required for read through as UAG-CAA-UUA. The effects of all possible single-base mutations in the codons flanking the stop indicated that 3' contexts of the form CAR-YYA confer leakiness and that the 3' context permits read through of UAA and UGA stop codons as well as UAG. Our studies demonstrate a major role for the 3' context in the read through process and do not support a model in which teh UAG is bypassed exclusively as a result of anticodon-codon interactions. No evidence for tRNA hopping was obtained. The 3' context apparently represents a unique sequence element that affects translation termination.

Base Composition↗
PubMed1989

Variation in G + C-content and codon choice: differences among synonymous codon groups in vertebrate genes.

The relationship between G + C-content and codon usage in genes of human, mus, rat, bovine and chicken nuclear genomes was investigated. Correlation and lineal regression analyses were carried out on plots that related the frequency of each codon within each synonymous codon group to the G + C-content of the coding sequence as a whole. Under GC pressure, in most of the quartet codon groups there is a preferential choice of the C-ending codon, except in leucine and valine codon groups where the choice of the G-ending codon is preferred. Among ducts, the choice of codons specifying phenylalanine and glutamate shows the strongest dependence on G + C-content. The relationship found between G + C-content and codon usage in these genomes correlate with taxonomic distance.

Animals↗
PubMed1987

Codon replacement in the PGK1 gene of Saccharomyces cerevisiae: experimental approach to study the role of biased codon usage in gene expression.

The coding sequences of genes in the yeast Saccharomyces cerevisiae show a preference for 25 of the 61 possible coding triplets. The degree of this biased codon usage in each gene is positively correlated to its expression level. Highly expressed genes use these 25 major codons almost exclusively. As an experimental approach to studying biased codon usage and its possible role in modulating gene expression, systematic codon replacements were carried out in the highly expressed PGK1 gene. The expression of phosphoglycerate kinase (PGK) was studied both on a high-copy-number plasmid and as a single copy gene integrated into the chromosome. Replacing an increasing number (up to 39% of all codons) of major codons with synonymous minor ones at the 5' end of the coding sequence caused a dramatic decline of the expression level. The PGK protein levels dropped 10-fold. The steady-state mRNA levels also declined, but to a lesser extent (threefold). Our data indicate that this reduction in mRNA levels was due to destabilization caused by impaired translation elongation at the minor codons. By preventing translation of the PGK mRNAs by the introduction of a stop codon 3' and adjacent to the start codon, the steady-state mRNA levels decreased dramatically. We conclude that efficient mRNA translation is required for maintaining mRNA stability in S. cerevisiae. These findings have important implications for the study of the expression of heterologous genes in yeast cells.

Amino Acid Sequence↗
PubMed1990

Third position base changes in codons 5' and 3' adjacent UGA codons affect UGA suppression in vivo.

The base sequence around nonsense codons affects the efficiency of nonsense codon suppression. Published data, comparing different nonsense sites in a mRNA, implicate the two bases downstream of the nonsense codon as major determinants of suppression efficiency. However, the results we report here indicate that the nature of the contiguous upstream codon can also affect nonsense suppression, as can the third (wobble) base of the contiguous downstream codon. These conclusions are drawn from experiments in which the two Ser codons UCU233 and UCG235 in a nonsense mutant form (UGA234) of the trpA gene in Escherichia coli have been replaced with other Ser codons by site-directed mutagenesis. Suppression of these trpA mutants has been studied in the presence of a UGA nonsense suppressor derived from glyT. We speculate that the non-site-specific effects of the two adjacent downstream bases may be largely at the level of the termination process, whereas more site-specific or codon-specific effects may operate primarily on the activity of the suppressor tRNA.

Base Sequence↗
PubMed1986

Codon usage in regulatory genes in Escherichia coli does not reflect selection for 'rare' codons.

It has often been suggested that differential usage of codons recognized by rare tRNA species, i.e. "rare codons", represents an evolutionary strategy to modulate gene expression. In particular, regulatory genes are reported to have an extraordinarily high frequency of rare codons. From E. coli we have compiled codon usage data for highly expressed genes, moderately/lowly expressed genes, and regulatory genes. We have identified a clear and general trend in codon usage bias, from the very high bias seen in very highly expressed genes and attributed to selection, to a rather low bias in other genes which seems to be more influenced by mutation than by selection. There is no clear tendency for an increased frequency of rare codons in the regulatory genes, compared to a large group of other moderately/lowly expressed genes with low codon bias. From this, as well as a consideration of evolutionary rates of regulatory genes, and of experimental data on translation rates, we conclude that the pattern of synonymous codon usage in regulatory genes reflects primarily the relaxation of natural selection.

Base Sequence↗
PubMed1992

Ocular findings associated with rhodopsin gene codon 267 and codon 190 mutations in dominant retinitis pigmentosa.

Two members of a family with autosomal dominant retinitis pigmentosa were found to have a cytosine-to-thymine mutation in the second nucleotide of codon 267 in the rhodopsin gene that resulted in a proline-to-leucine change. Two members of another family with autosomal dominant retinitis pigmentosa showed a guanine-to-thymine mutation in the first nucleotide of codon 190 in the rhodopsin gene that resulted in an aspartate-to-tyrosine change. Three members from a third family with autosomal dominant retinitis pigmentosa were also found to have a mutation in codon 190; however, this guanine-to-adenine mutation in the first nucleotide of codon 190 resulted in an aspartate-to-asparagine change. The relatively less severe functional retinal impairment in our patients with a transmembrane codon 267 rhodopsin gene mutation is generally comparable with that observed in a previously described codon 58 transmembrane mutation. The two families with different intradiscal codon 190 mutations showed a considerable difference in severity of their disease.

Adult↗
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↗
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↗
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↗
PubMed1992

Creutzfeldt-Jakob disease with codon 129 polymorphism (valine): a comparative study of patients with codon 102 point mutation or without mutations.

We examined 7 patients with Creutzfeldt-Jakob disease (CJD) with a methionine-to-valine change at prion protein (PrP) codon 129 (CJD129 patients). These CJD129 patients did not have either a codon 117 or 198 point mutation. For comparison, we also examined 7 patients with Gerstmann-Sträussler syndrome (GSS) with a proline-to-leucine change at PrP codon 102 (GSS102 patients) and 13 patients without any known mutations at codons 102, 117, 129, 178, or 200 (CJDwild patients). CJD129 patients had a long clinical duration and ataxia at onset, but rarely had any periodic synchronous discharge in their electroencephalogram. Unlike CJDwild patients, all CJD129 patients have typical congophilic PrP plaques in their brain. These clinicopathological findings were similar to those of GSS102. However, the distribution and morphology of PrP deposits revealed by immunohistochemistry were different between CJD129 and GSS102. In GSS102 more numerous and various types of PrP plaques are seen throughout the brain, while in CJD129 patients a unicentric core was the major feature of PrP plaques. The change in codon 129 influences the clinical course and pathological findings in CJD.

Adult↗
PubMed1976

The occurrence in amino acid sequences of extensive informational symmetries based on possible codon-codon complementarity in the encoding polynucleotides.

1. A procedure is described for the detection and assessment of informational complementarity in an amino acid sequence; it is based on possible autocomplementarity in the mRNA, and involves codon-to-codon matching. 2. This procedure was applied to myelin basic protein, a variety of protamines, histone IV, silk fibroin, rat skin collagen alpha1 chain and a sheep keratin. A multiplicity of extensive low-probability informational symmetries, based on codon-to-codon matching, were detected. 3. These low-probability orderings, which are independent of the actual mRNA codons, are rationalized in terms of the evolutionary ordering of the amino acid sequences concerned, in such a way that constraints on the secondary structure of the coding polynucleotides were satisfied. This possible interpretation is supported by a number of significant common properties of the protein sequences analysed.

Amino Acid Sequence↗
PubMed1988

Codon choice and gene expression: synonymous codons differ in their ability to direct aminoacylated-transfer RNA binding to ribosomes in vitro.

Phe-tRNA (anticodon GAA)--polypeptide-chain elongation factor Tu-GTP ternary complexes react faster with ribosomes programmed with UUC codons than with ribosomes programmed with UUU codons. A similar preference is shown by Leu-tRNA2 (anticodon GAG) complexes, which react faster with ribosomes programmed with CUC than with those programmed with CUU. The difference is seen in the rate of ternary-complex binding to the ribosome; no differences are seen in peptide-bond formation. Highly expressed mRNAs in Escherichia coli favor codons terminating in cytosine rather than uracil when both codons are read by a single tRNA with an anticodon beginning with guanine. The results suggest that intrinsic differences between the efficiencies of synonymous codons play an important role in modulating gene expression in E. coli.

Base Sequence↗