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PubMed1999

Significant differences between the G+C content of synonymous codons in orthologous genes and the genomic G+C content.

The relationship between the overall G+C content of the genome (GC) and the GC content at the third codon positions (GC3) of genes, which we refer to as a GC3-plot, was examined using 15 currently available complete genome sequences. A remarkably linear relationship was found between these two quantities, confirming previous observations of a strong positive correlation in the GC3-plot. In order to conduct a more detailed analysis of the GC3-plot, we examined the GC3 content by separating orthologous codons into three categories: synonymously different codons (namely identical amino acids, IA), different amino acids (DA), and identical codons (IC), for a pairwise comparison of two closely related species. When we took pairwise species comparisons between Mycoplasma genitalium (Mg) and Mycoplasma pneumoniae (Mp) and between Mycobacterium tuberculosis (Mt) and Mycobacterium leprae (Ml) as examples, we found that for Mp and Ml, the GC3 for IA deviated the most from the linear expectation in the GC3-plot, whereas for Mg and Mt the deviation was minimal. These findings suggest that the major changes of GC content took place in Mp and Ml, but not in Mg and Mt. This analysis also enables us to predict the future direction of the evolutionary changes of the genomic GC content.

Base Composition↗
PubMed1999

Non-universal usage of the leucine CUG codon and the molecular phylogeny of the genus Candida.

CUG, a universal leucine codon, was reported to be read as serine in 10 species of the genus Candida. We used an in vitro cell-free translation system to identify the amino acid assignment of codon CUG in 78 species and 7 varieties of galactose-lacking Candida species equipped with Q9 as the major ubiquinone. Of these, only 11 species used codon CUG as a leucine codon. The remaining species decoded CUG as serine. Their small subunit ribosomal DNA sequences were also determined and analyzed using both Neighbor-Joining and Maximum Likelihood methods. The species decoding CUG as serine and leucine formed distinct clusters on both molecular phylogenetic trees. Our result suggests that non-universal decoding is not a rare event, and that it is widely distributed in the genus Candida.

Candida↗
PubMed2006

Association of p53 codon 72 polymorphism with risk of hypopharyngeal squamous cell carcinoma in Taiwan.

BACKGROUND: p53 polymorphism at codon 72 is a known risk marker for various malignancies, but it has not been studied in hypopharyngeal cancer. This study investigated the genotype distribution of p53 codon 72 polymorphism in hypopharyngeal cancer patients and non-cancer controls matched for age, gender, alcohol consumption and smoking habit. METHODS: Genomic DNA was extracted from peripheral blood cells of 53 patients with hypopharyngeal cancer and 53 non-cancer controls. Codon 72 polymorphism of p53 was identified by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Patients with hypopharyngeal cancer had higher frequencies of Pro/Pro (26.4% vs. 13.2%) and Pro/Arg (51.0% vs. 45.3%) but lower frequencies of Arg/Arg (22.6% vs. 45.1%) compared to controls. Compared to Arg/Arg genotypes, Pro/Pro genotypes had a relative risk of hypopharyngeal cancer of 3.667 (95% confidence interval, 1.16-11.56; p = 0.03). As a group, patients with Pro/Pro or Arg/Pro who were carriers of the Pro allele had a higher relative risk of hypopharyngeal cancer compared to Arg homozygous carriers (odds ratio, 2.415; 95% confidence interval, 1.04-5.64; p = 0.04). CONCLUSION: This study demonstrated that p53 codon 72 Pro homozygosity is associated with a higher risk of developing hypopharyngeal cancer.

Adult↗
PubMed2003

Effects of codon usage versus putative 5'-mRNA structure on the expression of Fusarium solani cutinase in the Escherichia coli cytoplasm.

Matching the codon usage of recombinant genes to that of the expression host is a common strategy for increasing the expression of heterologous proteins in bacteria. However, while developing a cytoplasmic expression system for Fusarium solani cutinase in Escherichia coli, we found that altering codons to those preferred by E. coli led to significantly lower expression compared to the wild-type fungal gene, despite the presence of several rare E. coli codons in the fungal sequence. On the other hand, expression in the E. coli periplasm using a bacterial PhoA leader sequence resulted in high levels of expression for both the E. coli optimized and wild-type constructs. Sequence swapping experiments as well as calculations of predicted mRNA secondary structure provided support for the hypothesis that differential cytoplasmic expression of the E. coli optimized versus wild-type cutinase genes is due to differences in 5(') mRNA secondary structures. In particular, our results indicate that increased stability of 5(') mRNA secondary structures in the E. coli optimized transcript prevents efficient translation initiation in the absence of the phoA leader sequence. These results underscore the idea that potential 5(') mRNA secondary structures should be considered along with codon usage when designing a synthetic gene for high level expression in E. coli.

Amino Acid Sequence↗
PubMed2001

Occurrence of HIV-1 reverse transcriptase gene mutation at codon 215 in HIV-infected infants.

BACKGROUND: The nucleoside reverse transcriptase inhibitor Zidovudine (ZDV) decreases mother to child transmission of HIV infection. Nevertheless, significant proportions of mothers who are treated during pregnancy with ZDV still transmit the virus. Along with other factors, failure of ZDV prophylaxis may be due to maternal infection with ZDV-resistant strains and their consequent vertical transmission. OBJECTIVES: The purpose of the study was to investigate the occurrence of mutations at codon 215 in HIV-1 infected infants and its association with clinical status and virological parameters. STUDY DESIGN: The cohort consisted of 49 HIV-1 infected infants. Mononuclear cell DNA was isolated from whole blood and served as the input DNA for both a qualitative DNA PCR and the codon 215 assay (nested PCR). HIV-1 viral load (RNA PCR) was measured in plasma by the Roche Amplicor Monitor assay. RESULTS: Twelve of the 49 (24.5%) demonstrated viral strains with mutation at codon 215. A significant difference was found in infants born between 1992 and 1994 (6.3%) compared to those born in 1998-1999 (33.3%). Furthermore, in those infants born in 1998-1999, there was a trend toward an increase in the frequency of zidovudine resistant mutations at codon 215 corresponding to an increase in maternal zidovudine treatment. The mixture of wild and mutant HIV-1 strains was detected in two of 14 infants (14.3%) with a low viral load (<750000 c/ml) compared to nine of 19 (47.4%) infants with extremely high levels of HIV-1 RNA concentration (>750000 c/ml). Only two of 33 tested infants were HIV symptomatic and in both, a mixture of wild and mutant HIV-1 strains was detected. In both infants, the viral load was >750000 c/ml. CONCLUSIONS: This study showed that the overall frequency of ZDV resistant strains in infants born in 1998-1999 was significantly higher than that found in infant samples from 1992 to 1994. By 1998, the standard of care for mothers known to be infected with HIV was treatment with either monotherapy using ZDV or combined therapy using a variety of antiretroviral agents including ZDV. Although the exact role of ZDV resistance in limiting the effectiveness of therapies aimed at blocking vertical transmission of HIV remains to be defined, it is clear that drug resistant strains of HIV are occurring more frequently in all types of HIV infection, including infants.

Anti-HIV Agents↗
PubMed2006

[The changes of rare codon and mRNA structure accelerate expression of qa-3 in Escherichia coli].

The key and crucial step of metabolic engineering during quinic acid biosynthesize using shikimic acid pathway is high expression of quinate 5-dehydrogenase. The gene qa-3 which code quinate 5-dehydrogenase from Neurospora crassa doesn't express in Escherichia coli. By contrast with codon usage in Escherichia coli, there are 27 rare codons in qa-3, including eight AGG/AGA (Arg) and nine GGG (Gly). Two AGG are joined together (called box R) and some GGG codons are relative concentrate (called box G). Along with the secondary structure of mRNA analysed in computer, the free energy of mRNA changes a lot from -374.3 kJ/mol to least -80.5 kJ/mol when some bases in the end of qa-3 were transformed, and moreover, the change of free energy is quite small when only some bases in the box G and box R transformed. After the change of rare codon and optimization of some bases in the end, qa-3 was expression in E. coli and also the enzyme activity of quinate 5-dehydrogenase can be surveyed accurately. All the work above benefit the further research on producing quinic acid engineering bacterium.

Alcohol Oxidoreductases↗
PubMed1995

Schistosoma mansoni: patterns of codon usage and bias.

Codon usage and bias has been examined in 20 genes of Schistosoma mansoni. Significant heterogeneity was detected in the patterns of codon usage and bias among genes by metric multidimensional scaling and three general indicators of bias (GC3S, Nc and B). In keeping with observations on sporozoan parasites, codon usage bias was observed to be dependent on the overall base composition of the genes analysed, which in turn was reflected in the types of codons that were over or under-represented in the sequences.

Animals↗
PubMed2001

Evidence for translational selection in codon usage in Echinococcus spp.

We analysed the intragenomic variation in codon usage in Echinococcus spp. by correspondence analysis. This approach detected a trend among genes which was correlated with expression levels. Among the (presumed) highly expressed sequences we found an increased usage of a subset of codons, almost all of them G- or C- ending. Since an increase in these bases at the synonymous sites is against the mutational bias (these genomes are slightly A+-T- rich), we conclude that codon usage in Echinococcus is the result of an equilibrium between compositional pressure and selection, the latter acting at the level of translation, mainly on highly expressed genes. This is the first report where translational selection for codon usage is detected among Platyhelminthes.

Animals↗
PubMed2000

Effects of anticodon 2'-O-methylations on tRNA codon recognition in an Escherichia coli cell-free translation.

The methylation of 2'-hydroxyl groups is one of the most common posttranscriptional modifications of naturally occurring stable RNA molecules. Some tRNA species have a 2'-O-methyl nucleoside at the first position of the anticodon, and it was suggested that this modification stabilizes the codon-anticodon duplex. However, no tRNA species have been found to have the modification at the second or third position of the anticodon. In the present study, we measured the effects of anticodon 2'-O-methylation on the codon-reading efficiencies of the anticodon variants of the unmodified forms of Escherichia coli tRNA1(Ser), using a cell-free protein synthesis assay. The modification of C in the first position of the anticodon into 2'-O-methylcytidine increased the efficiency of reading the G-ending codon. On the other hand, the modifications of the second and/or third positions were detrimental to the codon-reading activity. Thus, 2'-hydroxyl groups at the second and third positions of the anticodon may have some role in the translation reaction, and this may be the reason why 2'-O-methyl nucleosides are not found in these positions within natural tRNA species.

Amino Acid Sequence↗
PubMed2001

Altered discrimination of start codons and initiator tRNAs by mutant initiation factor 3.

IF3 is essential for ensuring the fidelity of the initiation step of translation in bacterial cells. Mutations at residues R99 and R131 in the C-terminal domain of the factor have previously been shown to increase initiation from the non-canonical GUA codon. Here we show that these mutant forms of IF3 fail to discriminate against initiation from many different non-AUG codons. They also enhance the activity of mutant tRNAs carrying changes in the three consecutive G-C pairs that are conserved in the anticodon stem of initiator tRNAs. In addition, the IF3 mutants stimulate initiations from leaderless mRNAs and from internal initiation codons, in the absence of any SD-anti-SD interaction. These results indicate that IF3 ensures the accuracy of initiation by inspecting both the codon-anticodon pairing and unique features of the initiator tRNA as well as suppressing initiation from other potential start sites within the mRNA.

Base Sequence↗
PubMed1998

tRNA(2Gln) mutants that translate the CGA arginine codon as glutamine in Escherichia coli.

We present a novel missense suppression system for the selection of tRNA(2GIn) mutants that can efficiently translate the CGA (arginine) codon as glutamine. tRNA(2Gln) mutants were cloned from a partially randomized synthetic gene pool using a plasmid vector that simultaneously expresses the tRNA gene and, to ensure efficient aminoacylation, the glutamine aminoacyl-tRNA synthetase gene (glnS). tRNA mutants that insert glutamine at CGA were selected as missense suppressors of a lacZ mutant (lacZ625(CGA)) that contains CGA substituted for an essential glutamine codon. Preliminary characterizations of four suppressors is presented. All of them contain two anticodon mutations: C-->U at position 34 and U-->C at position 35, which allow for cognate translation of CGA. U35 was previously shown to be an important determinant for glutaminylation of tRNA(2Gln) in vitro; suppression in vivo requires overexpression of the glutaminyl-tRNA synthetase gene (glnS). One tRNA variant contains no further mutations and has the highest missense suppression activity (8%). Three other isolates each contain an additional point mutation that alters suppression efficiency. This system will be useful for further studies of tRNA structure and function. In addition, because relatively efficient translation of the rare CGA codon as glutamine is not toxic for Escherichia coli, it may be possible to translate this sense codon with other alternate meanings, a property which could greatly facilitate protein engineering.

Alleles↗
PubMed1986

Codon-induced association of the isolated anticodon loop of tRNAPhe.

The binding of the codon UUC to the isolated anticodon loop of tRNAPhe (yeast) has been studied as a model of codon recognition by a simple adaptor. Fluorescence titrations demonstrate that UUC binds to the isolated anticodon loop with an equilibrium constant of 1.4 X 10(3) M-1 (at 7.2 degrees C). Equilibrium sedimentation curves reveal that UUC binding induces association of anticodon loops beyond the dimer stage. A set of complete sedimentation curves obtained for various reactant concentrations was analyzed according to a model with an infinite number of subsequent association steps for UUC-anticodon loop complexes and with equal affinity for each step. The coupling of association and sedimentation was considered quantitatively, and the information resulting from conservation of mass was used by integration. According to this procedure, the experimental data can be described by an isodesmic association constant of 8 X 10(3) M-1 with satisfactory accuracy. Temperature-jump relaxation detected by fluorescence measurements provides independent evidence for codon-induced association of the anticodon loop. The data are consistent with the following mechanism: UUC preferentially binds to one of two loop conformations with a rate constant of 4.5 X 10(6) M-1 s-1; the UUC-anticodon loop complex undergoes association with a rate constant of 6.5 X 10(6) M-1 s-1. The reactions observed for the isolated anticodon loop are surprisingly similar to those observed previously for the complete tRNA, suggesting that simple hairpin loops are appropriate adaptors for a translation process at an early stage of evolution; the codon-induced association of the hairpin loop should be very useful to facilitate the transfer of cognate amino acids during translation.

Anticodon↗
PubMed1998

Silent nucleotide substitution in the sterol 27-hydroxylase gene (CYP 27) leads to alternative pre-mRNA splicing by activating a cryptic 5' splice site at the mutant codon in cerebrotendinous xanthomatosis patients.

A functionally silent nucleotide substitution of the sterol 27-hydroxylase gene (CYP 27), identified in two families with cerebrotendinous xanthomatosis (CTX), was confirmed to cause alternative pre-mRNA splicing of the gene. Full-length RT-PCR analysis of the CYP 27 gene in a patient from one of the CTX families revealed one major and an additional faint band. Sequence analysis of the cloned RT-PCR product showed three species of cDNA: 3' terminal 13 bp of exon 2 deleted cDNA, exon 2 skipped cDNA, and full-length cDNA with a functionally silent G to T mutation at codon 112 (GGG 112Gly to GGT 112Gly). Only a single base change was identified by genomic DNA sequence analysis of the CYP 27 gene in the patient: T replaced G at the third position of codon 112, 13 bp upstream from the 3' terminus of exon 2. Transfection of constructed minigenes, with or without the mutation, confirmed that this silent mutation resulted in alternative pre-mRNA splicing by activating a cryptic 5' splice site around the mutant codon. The mutation was also identified in two patients from another CTX family, with a compound heterozygous pattern of A for G substitution at codon 372, a mutation reported previously by our group. The results elucidate a novel molecular basis for the CTX and suggest the significance of a silent nucleotide substitution with regard to pre-RNA splicing.

Alternative Splicing↗
PubMedDate not supplied

Identification and repair of positive binding antibodies containing randomly generated amber codons from synthetic phage display libraries.

Phage display technology allows for the rapid isolation and characterization of monoclonal antibodies that have vast potential for therapeutic and diagnostic applications. However, the panning process, which utilizes a host strain that suppresses termination by the amber codon, has an inherent bias toward clones containing randomly generated amber stop codons, complicating identification of positive binding antibodies when the antibody genes are finally expressed in a nonsupressor host. Here, we perform biopanning against a Histone 2A peptide using streptavidin- or anti-biotin-coated beads. After four rounds, a dominant clone is characterized but contains a spurious amber stop codon. A protocol is given that readily corrects the amber codon, allowing for soluble antibody production once the phagemid is transformed into a nonsuppressor bacterial strain. This work also highlights the ability to isolate antibodies against a protein antigen by using only a small peptide (15 amino acids) representing a portion of the antigen.

Amino Acid Sequence↗
PubMed2000

Mutation and transcription analysis of transthyretin gene in Italian families with hereditary amyloidosis: a putative novel hot spot' in codon 47.

Transthyretin gene mutations are associated with autosomal dominant familial amyloidosis. The commonest phenotype in the patients is peripheral neuropathy, but restrictive cardiomyopathy is also a frequent sign. More than 70 different mutations in the gene have been described. Although these mutations are randomly distributed, some hot spots have also been reported notably at position 6, 30, 33, 58, 109, 119 and 122. A few of these codons contain a CpG dinucleotide. We describe an additional 'hot spot' occurring at codon 47, in which we report one novel and two previously described mutations. This codon, however, does not contain a CpG dinucleotide, suggesting that other mechanisms might be responsible for the allelic heterogeneity. All the reported mutations in codon 47 are located in the exon 2 consensus sequence and are potentially involved in splicing. We performed transcription analysis on two livers obtained from transplanted patients carrying the Ala47 mutation. These livers showed a normally spliced message, indicating that this mutation does not affect splicing.

Adolescent↗
PubMed2001

Non-expression of HLA-B*5111N is caused by an insertion into the cytosine island at exon 4 creating a frameshift stop codon.

The identification of the "blank" allele HLA-B*5111N, which was detected in German and Czech individuals, is described. In the pedigree analysis this new allele segregates with the serological haplotype HLA-A2; B-; DR4 which is frequent in Czech population. The non-expression of B*5111N is caused by the insertion of an additional cytosine molecule at the cytosine island between the nucleotides 621-626 (codons 183-185, first three codons of exon 4) leading to a frame shift that creates a stop codon at codon 196. This insertion may be explained either by conversion with the pseudogene HLA-J or by slipped-strand mispairing. In order not to overlook the presence of alleles with altered expression in case of hematopoietic stem cell transplantation, both serological and DNA-based typing should be performed (Note).

Alleles↗
PubMed2003

The normal population distribution of PRNP codon 129 polymorphism.

OBJECTIVES: The common prion protein gene (PRNP) codon 129 polymorphism modifies the susceptibility to and the phenotype of prion diseases. However, no truly representative normal population-based data, or data stratified according to age or gender are available on the distribution of this polymorphism. MATERIAL AND METHODS: Allelic variation of codon 129 in three Finnish populations representing different age groups, and among Finnish, British and Irish blood donors were examined. RESULTS: The PRNP codon 129 genotype distribution in the total Finnish sample was 49% for methionine-methionine (MM), 42% for methionine-valine (MV) and 9% for valine-valine (VV), for the UK blood donors 42% for MM, 47% for MV and 11% for VV, and for the Irish blood donors 34% for MM, 56% for MV, and 10% for VV. CONCLUSIONS: The genotype frequencies were almost identical in all three Finnish populations of different ages, with no gender differences, and did not differ from corresponding figures for the Finnish blood donors. However, the PRNP codon 129 genotype distribution in Finland differed significantly from that of the British and the Irish blood donors and the previously published blood donor data on other Western Europeans and Americans.

Adolescent↗
PubMed1980

Yeast mitochondrial tRNATrp can recognize the nonsense codon UGA.

DNA sequence analysis of mitochondrial genes that code for some mitochondrial proteins has suggested that the opal terminator, UGA, is used as a sense codon in mitochondria. The complete sequences of both the yeast and human genes coding for cytochrome oxidase subunit II contain UGA codons in the reading frame. When the protein sequences predicted by these DNA sequences are compared with the known protein sequence of bovine mitochondrial cytochrome oxidase subunit II, there are regions of homology, in which UGA codons correspond to tryptophan residues. Therefore it has been suggested that UGA specifies tryptophan in the mitochondrial code. We have isolated a yeast mitochondrial tRNATrp and used it to locate the mitochondrial tRNATrp gene in pBR322-mitochondrial DNA recombinants. DNA sequence analysis of this gene revealed that the mitochondrial tRNATrp anticodon is 5'UCA3'. Because there is a U in the wobble position, this tRNA can recognize and insert tryptophan into a growing polypeptide chain in response to the nonsense codon UGA.

Anticodon↗