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PubMed1994

A codon-based model of nucleotide substitution for protein-coding DNA sequences.

A codon-based model for the evolution of protein-coding DNA sequences is presented for use in phylogenetic estimation. A Markov process is used to describe substitutions between codons. Transition/transversion rate bias and codon usage bias are allowed in the model, and selective restraints at the protein level are accommodated using physicochemical distances between the amino acids coded for by the codons. Analyses of two data sets suggest that the new codon-based model can provide a better fit to data than can nucleotide-based models and can produce more reliable estimates of certain biologically important measures such as the transition/transversion rate ratio and the synonymous/nonsynonymous substitution rate ratio.

Animals↗
PubMed1985

Significance of nucleotide sequence alignments: a method for random sequence permutation that preserves dinucleotide and codon usage.

The similarity of two nucleotide sequences is often expressed in terms of evolutionary distance, a measure of the amount of change needed to transform one sequence into the other. Given two sequences with a small distance between them, can their similarity be explained by their base composition alone? The nucleotide order of these sequences contributes to their similarity if the distance is much smaller than their average permutation distance, which is obtained by calculating the distances for many random permutations of these sequences. To determine whether their similarity can be explained by their dinucleotide and codon usage, random sequences must be chosen from the set of permuted sequences that preserve dinucleotide and codon usage. The problem of choosing random dinucleotide and codon-preserving permutations can be expressed in the language of graph theory as the problem of generating random Eulerian walks on a directed multigraph. An efficient algorithm for generating such walks is described. This algorithm can be used to choose random sequence permutations that preserve (1) dinucleotide usage, (2) dinucleotide and trinucleotide usage, or (3) dinucleotide and codon usage. For example, the similarity of two 60-nucleotide DNA segments from the human beta-1 interferon gene (nucleotides 196-255 and 499-558) is not just the result of their nonrandom dinucleotide and codon usage.

Base Sequence↗
PubMed2003

Translational selection is operative for synonymous codon usage in Clostridium perfringens and Clostridium acetobutylicum.

Here, the codon usage patterns of two Clostridium species (Clostridium perfringens and Clostridium acetobutylicum) are reported. These prokaryotes are characterized by a strong mutational bias towards A+T, a striking excess of coding sequences and purine-rich leading strands of replication, strong GC-skews and a high frequency of genomic rearrangements. As expected, it was found that the mutational bias dominates codon usage but there is some variation of synonymous codon choices among genes in the two species. This variation was investigated using a multivariate statistical approach. In the two species, two major trends were detected. One was related to the location of the sequences in the leading or lagging strand of replication, and the other was associated with the preferential use of putatively translational optimal codons in heavily expressed genes. Analyses of the estimated number of synonymous and non-synonymous substitutions among orthologous genes permit us to postulate that optimal codons might be selected not only for speed but also for accuracy during translation.

Amino Acids↗
PubMed2004

Relationship between codon biased genes, microarray expression values and physiological characteristics of Streptococcus pneumoniae.

A codon-profile strategy was used to predict gene expression levels in Streptococcus pneumoniae. Predicted highly expressed (PHE) genes included those encoding glycolytic and fermentative enzymes, sugar-conversion systems and carbohydrate-transporters. Additionally, some genes required for infection that are involved in oxidative metabolism and hydrogen peroxide production were PHE. Low expression values were predicted for genes encoding specific regulatory proteins like two-component systems and competence genes. Correspondence analysis localized 484 ORFs which shared a distinctive codon profile in the right horn. These genes had a mean G+C content (33.4 %) that was lower than the bulk of the genome coding sequences (39.7 %), suggesting that many of them were acquired by horizontal transfer. Half of these genes (242) were pseudogenes, ORFs shorter than 80 codons or without assigned function. The remaining genes included several virulence factors, such as capsular genes, iga, lytB, nanB, pspA, choline-binding proteins, and functions related to DNA acquisition, such as restriction-modification systems and comDE. In order to compare predicted translation rate with the relative amounts of mRNA for each gene, the codon adaptation index (CAI) values were compared with microarray fluorescence intensity values following hybridization of labelled RNA from laboratory-grown cultures. High mRNA amounts were observed in 32.5 % of PHE genes and in 64 % of the 25 genes with the highest CAI values. However, high relative amounts of RNA were also detected in 10.4 % of non-PHE genes, such as those encoding fatty acid metabolism enzymes and proteases, suggesting that their expression might also be regulated at the level of transcription or mRNA stability under the conditions tested. The effects of codon bias and mRNA amount on different gene groups in S. pneumoniae are discussed.

Bacterial Proteins↗
PubMed2005

Polymorphisms at codons 108 and 189 in murine PrP play distinct roles in the control of scrapie incubation time.

Susceptibility to transmissible spongiform encephalopathies (TSEs) is associated strongly with PrP polymorphisms in humans, sheep and rodents. In mice, scrapie incubation time is controlled by polymorphisms at PrP codons 108 (leucine or phenylalanine) and 189 (threonine or valine), but the precise role of each polymorphism in the control of disease is unknown. The L108F and T189V polymorphisms are present in distinct structural regions of PrP and thus provide an excellent model with which to investigate the role of PrP structure and gene variation in TSEs. Two unique lines of transgenic mice, in which 108F and 189V have been targeted separately into the endogenous murine Prnp(a) gene, have been produced. TSE inoculation of inbred lines of mice expressing all allelic combinations at codons 108 and 189 has revealed a complex relationship between PrP allele and incubation time. It has been established that both codons 108 and 189 control TSE incubation time, and that each polymorphism plays a distinct role in the disease process. Comparison of ME7 incubation times in mouse lines that are heterozygous at both codons has also identified a previously unrecognized intramolecular interaction between PrP codons 108 and 189.

Animals↗
PubMed2005

Mass spectrometry of the M. smegmatis proteome: protein expression levels correlate with function, operons, and codon bias.

The fast-growing bacterium Mycobacterium smegmatis is a model mycobacterial system, a nonpathogenic soil bacterium that nonetheless shares many features with the pathogenic Mycobacterium tuberculosis, the causative agent of tuberculosis. The study of M. smegmatis is expected to shed light on mechanisms of mycobacterial growth and complex lipid metabolism, and provides a tractable system for antimycobacterial drug development. Although the M. smegmatis genome sequence is not yet completed, we used multidimensional chromatography and tandem mass spectrometry, in combination with the partially completed genome sequence, to detect and identify a total of 901 distinct proteins from M. smegmatis over the course of 25 growth conditions, providing experimental annotation for many predicted genes with an approximately 5% false-positive identification rate. We observed numerous proteins involved in energy production (9.8% of expressed proteins), protein translation (8.7%), and lipid biosynthesis (5.4%); 33% of the 901 proteins are of unknown function. Protein expression levels were estimated from the number of observations of each protein, allowing measurement of differential expression of complete operons, and the comparison of the stationary and exponential phase proteomes. Expression levels are correlated with proteins' codon biases and mRNA expression levels, as measured by comparison with codon adaptation indices, principle component analysis of codon frequencies, and DNA microarray data. This observation is consistent with notions that either (1) prokaryotic protein expression levels are largely preset by codon choice, or (2) codon choice is optimized for consistency with average expression levels regardless of the mechanism of regulating expression.

Bacterial Proteins↗
PubMed2001

Sequence architecture downstream of the initiator codon enhances gene expression and protein stability in plants.

Nucleotide positions conserved on the 3' side of the initiator codon ATG and the corresponding N-terminal amino acid residues in a number of highly abundant plant proteins were identified by computational analysis of a dataset of highly expressed plant genes. The reporter genes uidA and gfp were modified to introduce these features. Insertion of GCT TCC TCC after the initiator codon ATG augmented expression for both the reporter genes. The insertion of each successive codon improved the expression of beta-glucuronidase (GUS) in an incremental fashion in transient transformation of tobacco (Nicotiana tabacum) leaves. The insertion of alanine-serine (Ser)-Ser resulted in about a 2-fold increase in the stability of GUS. However, this did not account for the 30- to 40-fold increase in GUS activity between the constructs coding for methionine-alanine-Ser-Ser-GUS and the native enzyme. Substitution of the codon for Ser at the third amino acid residue with synonymous codons reduced GUS expression. The results suggest a role for the conserved nucleotides in the +4 to +11 region in augmenting posttranscriptional events in the expression of genes in plants.

Base Composition↗
PubMed1993

Control of start codon choice on a plant viral RNA encoding overlapping genes.

The signals that control initiation of translation in plants are not well understood. To dissect some of these signals, we used a plant viral mRNA on which protein synthesis initiates at two out-of-frame start codons. On the large subgenomic RNA (sgRNA1) of barley yellow dwarf virus-PAV serotype, the coat protein (CP) and overlapping 17K open reading frames (ORFs) are translated beginning at the first and second AUG codons, respectively. The roles of bases at positions -3 and +4 relative to the AUG codons in efficiency of translation initiation were investigated by translation of sgRNA1 mutants in a cell-free extract and by expression of a reporter gene from mutant sgRNA1 leaders in protoplasts. The effects of mutations that disrupted and restored secondary structure encompassing the CP AUG independently of, and in combination with, changes to bases -3 and +4 were also examined. Partial digestion of the 5' end of the sgRNA1 leader with structure-sensitive nucleases gave products that were consistent with the predicted secondary structure. Secondary structure had an overall inhibitory effect on translation of both ORFs. In general, the "Kozak rules" of start codon preference predominate in determining start codon choice. Unexpectedly, for a given CP AUG sequence context, changes that decreased initiation at the downstream 17K AUG also reduced initiation at the CP AUG. To explain this observation, we propose a new model in which pausing of the ribosome at the second AUG allows increased initiation at the first AUG. This detailed analysis of the roles of primary and secondary structure in controlling translation initiation should be of value for understanding expression of any plant gene and in the design of artificial constructs.

Animals↗
PubMed1996

Detection of K-ras point mutations at codon 12 in pancreatic juice for the diagnosis of pancreatic cancer by hybridization protection assay: a simple method for the determination of the types of point mutation.

The present study was undertaken to detect K-ras oncogene point mutations at codon 12 in pure pancreatic juice (PPJ) by the hybridization protection assay (HPA) method for the diagnosis of pancreatic cancer (PC). This assay can be carried out within 30 min and can determine not only the presence of a mutation, but also the mutational type of K-ras at codon 12. The minimal ratio of mutant DNA detectable by the HPA was 5-10% of the total DNA. PPJ was collected through a cannula under duodenal fiberscope control from 20 patients with PC and 20 patients with chronic pancreatitis (CP). Analysis of PPJ by the HPA revealed that the incidence of K-ras point mutations at codon 12 was 55% (11/20) in patients with PC and 0% (0/20) in those with CP. Mutational types of K-ras at codon 12 in PC were aspartic acid (Asp) in nine cases, both Asp and cysteine in one case, and arginine in one case. Analysis of K-ras point mutations at codon 12 in PPJ using the HPA method seems promising as a new genetic test for the diagnosis of PC, because the HPA method is simple, and can easily determine the mutational type.

Base Sequence↗
PubMed2005

PTCH codon 1315 polymorphism and risk for nonmelanoma skin cancer.

BACKGROUND: The PTCH tumour suppressor gene is involved in the development of nearly all basal cell carcinomas (BCCs) of the skin and a fraction of squamous cell carcinomas (SCCs). A nonconservative Pro/Leu nucleotide polymorphism within PTCH exon 23 at codon 1315 was recently reported to be potentially important for the development of breast epithelial cell cancers. Objectives Accordingly, the status of PTCH codon 1315 was analysed for a possible association with the development of nonmelanoma skin cancers (NMSCs) in a pilot study. Because skin cancer risk is affected by specific population-dependent phenotypes such as skin and hair colour, codon 1315 was also analysed for normal allele frequency variation in human populations having differing extents of eumelanin vs. phaeomelanin. METHODS: The single nucleotide polymorphism in codon 1315 of the human PTCH gene was analysed in genomic DNA from six different populations comprising 472 blood samples and from 170 patients in four different categories with NMSC. Polymerase chain reaction and pyrosequencing were used to determine the allele frequencies. Allelic loss was furthermore determined in tumours following microdissection. RESULTS: The Pro/Pro genotype frequency ranged from 30% to 65% between populations, with a significant trend for a reduced frequency of the Pro/Pro genotype in populations having lighter pigmentation (P = 0.020). Pro/Pro frequency showed an increasing trend with increasing tumour case severity (P = 0.027). In 260 samples from 180 Swedish patients with NMSC and a control group of 96 healthy ethnically matched volunteers, no statistically significant pairwise differences between groups were detected in the PTCH codon 1315 allelic distribution, neither was a difference seen for multiple or early onset cases of BCC in the Swedish population. In Swedish patients with single tumours, allelic loss (loss of heterozygosity) was observed in 20 of 30 (67%) patients with BCC and four of 22 (18%) patients with SCC, with no preference in the allele lost. In contrast, the Pro/Pro genotype was frequent in seven U.S. patients having multiple independent BCCs. One of these patients was heterozygous, enabling allelic loss studies. Of 20 independent tumours, 11 had lost an allele; 10 of the 11 had lost Leu, suggesting nonrandom loss that favoured retention of Pro (P = 0.0059). CONCLUSIONS: Our results indicate an association between the eumelanin-to-phaeomelanin shift and a shift from the Pro/Pro genotype to Leu-containing genotypes. Failure to lose Pro during the shift to phaeomelanin may be associated with an increased population risk for BCC and increased individual risk for multiple BCC. During development of a tumour, the effect of Pro may be magnified by loss of the Leu allele.

Basal Cell Carcinoma↗
PubMed1995

No mutation at codon 918 of the RET gene in a family with multiple endocrine neoplasia type 2B.

Multiple endocrine neoplasia type 2B (MEN 2B) is a rare cancer syndrome which is inherited in an autosomal dominant manner. The molecular basis of this condition has recently been defined as a mutation of codon 918 of exon 16 of the RET proto-oncogene. The mutation in codon 918 has been described in 69 out of 72 families with MEN 2B. We have studied a brother and sister who undoubtedly have the features of MEN 2B as evidenced by medullary thyroid carcinoma, phaeochromocytoma, mucosal neuromas and skeletal abnormalities. Neither of these patients has the classic gene mutation at codon 918 of exon 16 of the RET proto-oncogene, and although exons 2-20 have also been sequenced, no abnormality has been found. DNA analysis is a sensitive method of screening families for the MEN 2 syndromes. The absence of the mutation at codon 918 in a phenotypically normal individual would refute the diagnosis of MEN 2B, but in an individual with some of the features of MEN 2B would make the clinician reconsider the diagnosis. This family demonstrates that, although it is rare, the absence of the mutation in codon 918 of exon 16 of the RET proto-oncogene does not always exclude the diagnosis of MEN 2B. In such families routine biochemical screening for medullary thyroid carcinoma and phaeochromocytoma must be maintained for all individuals at genetic risk.

Adolescent↗
PubMed2004

A codon 31ser-arg polymorphism of the WAF-1/CIP-1/p21/tumour suppressor gene in Chinese primary open-angle glaucoma.

PURPOSE: Glaucomatous neuropathy is a type of cell death by apoptosis. Apoptosis is a genetically controlled form of cell death, and one of its primary regulatory steps is the activation of the tumour suppressor protein p53, of which p21 is an effector protein. The association between p21 codon 31 polymorphism and primary open-angle glaucoma (POAG) patients was evaluated in this study. METHODS: The study included 58 POAG patients and a control group of 59 healthy volunteers. Polymerase chain reaction-based analysis was used to resolve the p21 codon 31 polymorphism. RESULTS: The genotype frequencies of p21 codon 31 polymorphism were statistically different (p < 0.05) between the two groups. The Arg allele of the p21 codon 31 polymorphism was more frequently found in POAG patients than in healthy individuals (odds ratio: 2.389, 95% confidence interval: 1.14-5.01). CONCLUSION: This study suggests that an association exists between the Arg allele of the p21 codon 31 polymorphism and POAG in the Chinese population.

Adult↗
PubMed1998

KRAS codon 12 mutations in Australian non-small cell lung cancer.

BACKGROUND: In certain non-small cell lung cancer (NSCLC) populations, codon 12 mutations of the KRAS oncogene comprising mostly G-T transversions have diagnostic and prognostic value. However, it is not known if these findings are applicable to all populations of lung cancer patients. AIMS: To examine for KRAS codon 12 mutations in Australian NSCLC patients. METHODS: Tumour samples and corresponding normal lung tissue from 108 Australian patients with NSCLC undergoing curative resection were studied for mutations of KRAS codon 12 using a sensitive PCR assay. Mutations were confirmed by DNA sequencing and correlated with histological subtype, tumour stage, the presence of nodal metastases and survival. RESULTS: Eleven KRAS codon 12 mutations were detected in 108 NSCLCs, with most (8/11) occurring in the adenocarcinoma subtype (17% prevalence), but were not associated with adverse outcome or clinico-pathological features. G-T transversions were surprisingly infrequent (37% of adenocarcinoma mutations). CONCLUSIONS: These data add to the evidence suggesting geographical differences in the spectrum and significance of KRAS codon 12 mutational genotypes in NSCLC. While these may be due to genetic variation and/or differences in carcinogen exposure, there is a need for larger population based studies before this potentially important biomarker can be recommended universally for optimising lung cancer management.

Adenocarcinoma↗
PubMed2006

A genetic and bioinformatic analysis of Streptomyces coelicolor genes containing TTA codons, possible targets for regulation by a developmentally significant tRNA.

The rarest codon in the high G+C genome of Streptomyces coelicolor is TTA, corresponding in mRNA to the UUA codon that is recognized by a developmentally important tRNA encoded by the bldA gene. There are 145 TTA-containing genes in the chromosome of S. coelicolor. Only 42 of these are represented in the genome of Streptomyces avermitilis, among which only 12 have a TTA codon in both species. The TTA codon is less represented in housekeeping genes and orthologous genes, and is more represented in functional-unknown, extrachromosomal or weakly expressed genes. Twenty one TTA-containing chromosomal genes in S. coelicolor were disrupted, including 12 of the 42 genes that are common to both S. avermitillis and S. coelicolor. None of the mutant strains showed any obvious phenotypic differences from the wild-type strain under tested conditions. Possible reasons for this, and the role and evolution of the observed distribution of TTA codons among Streptomyces genes were discussed.

Codon↗
PubMed1999

Recognition of the codon-anticodon helix by ribosomal RNA.

Translational fidelity is established by ribosomal recognition of the codon-anticodon interaction within the aminoacyl-transfer RNA (tRNA) site (A site) of the ribosome. Experiments are presented that reveal possible contacts between 16S ribosomal RNA and the codon-anticodon complex. N1 methylation of adenine at position 1492 (A1492) and A1493 interfered with A-site tRNA binding. Mutation of A1492 and A1493 to guanine or cytosine also impaired A-site tRNA binding. The deleterious effects of A1492G or A1493G (or both) mutations were compensated by 2'fluorine substitutions in the mRNA codon. The results suggest that the ribosome recognizes the codon-anticodon complex by adenine contacts to the messenger RNA backbone and provide a mechanism for molecular discrimination of correct versus incorrect codon-anticodon pairs.

Adenine↗
PubMed1987

Apolipoprotein B-48 is the product of a messenger RNA with an organ-specific in-frame stop codon.

The primary structure of human apolipoprotein (apo) B-48 has been deduced and shown by a combination of DNA excess hybridization, sequencing of tryptic peptides, cloned complementary DNAs, and intestinal messenger RNAs (mRNAs) to be the product of an intestinal mRNA with an in-frame UAA stop codon resulting from a C to U change in the codon CAA encoding Gln2153 in apoB-100 mRNA. The carboxyl-terminal Ile2152 of apoB-48 purified from chylous ascites fluid has apparently been cleaved from the initial translation product, leaving Met2151 as the new carboxyl-terminus. These data indicate that approximately 85% of the intestinal mRNAs terminate within approximately 0.1 to 1.0 kilobase downstream from the stop codon. The other approximately 15% have lengths similar to hepatic apoB-100 mRNA even though they have the same in-frame stop codon. The organ-specific introduction of a stop codon to a mRNA appears unprecedented and might have implications for cryptic polyadenylation signal recognition and RNA processing.

Amino Acid Sequence↗
PubMed2000

Enhanced production of recombinant Mycobacterium tuberculosis antigens in Escherichia coli by replacement of low-usage codons.

A major obstacle to development of subunit vaccines and diagnostic reagents for tuberculosis is the inability to produce large quantities of these proteins. To test the hypothesis that poor expression of some mycobacterial genes in Escherichia coli is due, in part, to the presence of low-usage E. coli codons, we used site-directed mutagenesis to convert low-usage codons to high-usage codons for the same amino acid in the Mycobacterium tuberculosis genes for antigens 85A and 85B and superoxide dismutase. Replacement of five codons in the wild-type gene for antigen 85B increased recombinant protein production in E. coli 54-fold. The recombinant antigen elicited proliferation and gamma interferon production by lymphocytes from healthy tuberculin reactors and was recognized by monoclonal antibodies to native antigen 85, indicating that the recombinant antigen contained T-cell and B-cell epitopes. Northern blotting demonstrated only a 1.7- to 2.5-fold increase in antigen 85B mRNA, suggesting that the enhanced protein production was due primarily to enhanced efficiency of translation. Codon replacement in the genes encoding antigen 85A and superoxide dismutase yielded four- to sixfold increases in recombinant protein production, suggesting that this strategy may be generally applicable to overexpression of mycobacterial genes in E. coli.

Animals↗
PubMed1987

Organization and codon usage of the streptomycin operon in Micrococcus luteus, a bacterium with a high genomic G + C content.

The DNA sequence of the Micrococcus luteus str operon, which includes genes for ribosomal proteins S12 (str or rpsL) and S7 (rpsG) and elongation factors (EF) G (fus) and Tu (tuf), has been determined and compared with the corresponding sequence of Escherichia coli to estimate the effect of high genomic G + C content (74%) of M. luteus on the codon usage pattern. The gene organization in this operon and the deduced amino acid sequence of each corresponding protein are well conserved between the two species. The mean G + C content of the M. luteus str operon is 67%, which is much higher than that of E. coli (51%). The codon usage pattern of M. luteus is very different from that of E. coli and extremely biased to the use of G and C in silent positions. About 95% (1,309 of 1,382) of codons have G or C at the third position. Codon GUG is used for initiation of S12, EF-G, and EF-Tu, and AUG is used only in S7, whereas GUG initiates only one of the EF-Tu's in E. coli. UGA is the predominant termination codon in M. luteus, in contrast to UAA in E. coli.

Amino Acid Sequence↗