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PubMed2001

Codon reassignment and the evolving genetic code: problems and pitfalls in post-genome analysis.

The in silico translation of open reading frames, using the 'universal genetic code', must be approached with caution. The uncovering of a number of codon reassignments in nuclear and organellar genomes highlights the importance of experimentally confirming the assignments of all 64 codons for the species whose genome is under investigation. Such alterations to codon meaning also suggest that the genetic code is not 'frozen' and continues to evolve.

Codon↗
PubMed1999

Gene gun DNA vaccination with Rev-independent synthetic HIV-1 gp160 envelope gene using mammalian codons.

DNA immunization with HIV envelope plasmids induce only moderate levels of specific antibodies which may in part be due to limitations in expression influenced by a species-specific and biased HIV codon usage. We compared antibody levels, Th1/Th2 type and CTL responses induced by synthetic genes encoding membrane bound gp160 versus secreted gp120 using optimized codons and the efficient gene gun immunization method. The in vitro expression of syn.gp160 as gp120 + gp41 was Rev independent and much higher than a classical wt.gp160 plasmid. Mice immunized with syn.gp160 and wt.gp160 generated low and inconsistent ELISA antibody titres whereas the secreted gp120 consistently induced faster seroconversion and higher antibody titres. Due to a higher C + G content the numbers of putative CpG immune (Th1) stimulatory motifs were highest in the synthetic gp160 gene. However, both synthetic genes induced an equally strong and more pronounced Th2 response with higher IgG1/IgG2a and IFNgamma/IL-4 ratios than the wt.gp160 gene. As for induction of CTL, synthetic genes induced a somewhat earlier response but did not offer any advantage over wild type genes at a later time point. Thus, optimizing codon usage has the advantage of rendering the structural HIV genes Rev independent. For induction of antibodies the level of expression, while important, seems less critical than optimal contact with antigen presenting cells at locations reached by the secreted gp120 protein. A proposed Th1 adjuvant effect of the higher numbers of CpG motifs in the synthetic genes was not seen using gene gun immunization which may be due to the low amount of DNA used.

AIDS Vaccines↗
PubMedDate not supplied

Cluster analysis of the codon use frequency of MHC genes from different species.

The relative synonymous codon use frequency of 135 MHC genes from four mammal species (Homo sapiens, Pan troglodyte, Macaca mulanta and Rattus norvegicus) is analyzed using a hierarchical cluster method. The result suggests that gene function is the dominant factor that determines codon usage bias, while species is a minor factor that determines further difference in codon usage bias for genes with similar functions. The conclusion may be useful in gene classification and gene function prediction.

Animals↗
PubMed2001

Absence of association between HPV DNA, TP53 codon 72 polymorphism, and risk of oesophageal cancer in a high-risk area of China.

We analyzed TP53 codon 72 polymorphism, HPV DNA in 32 subjects with oesophageal cancer and 57 healthy subjects with normal oesophageal cytology from an area of China with a high prevalence for this cancer (Linxian County, Henan Province). The frequency of the proline allele (0.63) was significantly higher in the Chinese population than in most European or American populations. No significant association was found between TP53 codon 72 genotype and cancer. We also found a low prevalence of HPV DNA (6.7%) in both cancer cases and healthy subjects. Our findings do not support the association between risk of oesophageal cancer, human papilloma virus infection, and TP53 codon 72 polymorphism in a Chinese population at high risk of oesophageal cancer.

Adult↗
PubMed2001

The p53 codon 249 mutant--derived from human functional adrenal tumors--can modify the cell shape of normal adrenocortical transfected cells.

Our previous study has indicated that p53 gene mutation occurred in 73% of human functional adrenal tumors, and the mutation hot spots were focused on codons 100, 102 (exon 4), and 249 (exon 7). Furthermore, a transcriptional activity study revealed that the mutant p53 protein derived from human functional adrenal tumors lost 90% transcriptional activity and the ability to bind with the p53 sequence. In order to investigate the influence of the mutant protein extracted from adrenocortical tumors on normal adrenal cells, we first cloned p53 cDNA from the human primary aldosteronism and constituted it with isopropyl thiogalactoside (IPTG) inducible expression vector as recombinant plasmid. The recombinant plasmid was then transfected to normal bovine adrenocortical cells through electroporation. The results showed that the p53 protein mutations at codons 100 and 102 could neither affect the cell morphology nor enable cell growth on the soft agar. In addition, no significant difference was found in cortisol level between the p53 transfected and the control cells. On the other hand, cell morphological changes and cell proliferation rate increase were observed when we used IPTG to induce the expression of the p53 protein, which mutated at codon 249, in adrenocortical cells. The cell morphology changes included less flattened and decreased elongation when compared to non-transfected cells. However, the cortisol level in transfected cells was not affected by the p53 mutants. Taken together, we concluded that the mutant p53 protein indeed participates in adrenal carcinogenesis; however, it has no influence on hormone production and secretion.

Adrenal Cortex↗
PubMed2002

p53 codon 72 polymorphism and its association with bladder cancer.

p53 codon 72 Arg homozygosity has been associated with increased risk of developing cervical cancer. This association has been tested in various human cancers with controversial results. In the present study we investigated the impact of this polymorphism in a population-based case-control study of bladder cancer. Using allele-specific polymerase chain reaction to detect the p53 codon 72 polymorphism, we tested peripheral blood samples from 50 patients with bladder cancer and 99 healthy individuals of similar age and from the same geographical region. Tumor specimens from all bladder cancer patients were examined for the presence of human papilloma virus (HPV). The distribution of p53 alleles in bladder cancer patients and in controls was statistically significant (P<0.002; odds ratio, 2.67; 95% confidence interval, 1.38-5.20), and homozygosity for arginine at residue 72 was associated with an increased risk for bladder cancer (P<0.00002; odds ratio, 4.69; 95% confidence interval, 2.13-10.41). The presence of HPV was found in six of the 50 patients (12%). This is the first study correlating p53 codon 72 polymorphism with bladder cancer. Our results provide evidence that this p53 polymorphism is implicated in bladder carcinogenesis and that individuals harboring the Arg/Arg genotype have an increased risk of developing bladder cancer.

Adolescent↗
PubMed2002

P53 codon 72 polymorphism and risk of squamous cell carcinoma of the head and neck: a case-control study.

p53 plays an important role in cell-cycle control, as it facilitates DNA repair activities in response to DNA damage. An aberrant cell cycle impairs DNA repair and increases the probability of mutations that lead to carcinogenesis. The p53 codon 72 Arg/Pro polymorphism has been suggested to be associated with susceptibility to tobacco-related cancers, but this association remains controversial. In this hospital-based case-control study of 304 patients newly diagnosed with squamous cell carcinoma of the head and neck (SCCHN) and 333 cancer-free controls, we evaluated the association between this p53 polymorphism and the risk of SCCHN. All subjects were non-Hispanic whites, and the controls were frequency-matched to the cases by age (+/-5 years), sex and smoking status. Our results suggested that there was no difference in the distributions of p53 codon 72 genotypes between cases and controls (odds ratio (OR)=1.04, 95% confidence interval (CI) 0.75-1.44 for Pro/Pro vs. Arg/Arg and OR=1.01, 95% CI 0.54-1.91 for Arg/Pro vs. Arg/Arg). However, there was evidence that the Pro allele was associated with an early age of onset of SCCHN. The median ages of onset of SCCHN were 59, 56 and 53 years for Arg/Arg, Arg/Pro and Pro/Pro cases, respectively (P=0.151 among three genotypes; P=0.057 for Pro/Pro and Arg/Pro combined vs. Arg/Arg). The median ages at onset of oral cancers were 62, 57 and 51 years for Arg/Arg, Arg/Pro and Pro/Pro, respectively (P=0.091 among three genotypes; P=0.046 for Pro/Pro vs. Arg/Arg; P=0.066 for Pro/Pro and Arg/Pro combined vs. Arg/Arg). While the results suggest that the P53 codon 72 polymorphism may contribute to oral cancer susceptibility, larger studies are needed to confirm these findings.

Adult↗
PubMed2003

Association between p21 codon 31 polymorphism and esophageal cancer risk in a Taiwanese population.

P21, which regulates the cell growth cycle, is crucial for normal growth and differentiation. One polymorphism in the p21 codon 31 produces variant proteins with an amino acid change (serine (ser) or arginine (arg)). Although several epidemiologic studies have examined the effect of this polymorphism on cancer risk, the findings remain inconclusive, which has motivated us to evaluate the relationship between p21 codon 31 polymorphism and esophageal cancer risk. In this study, 128 cases of esophageal squamous cell carcinoma and 178 control cases from two hospitals in southern Taiwan were genotyped. Frequencies of arg/arg, arg/ser and ser/ser were 23 (18.0%), 62 (48.4%) and 43 (33.6%) in carcinoma cases and 51 (28.6%), 84 (47.2%) and 43 (24.2%) in control cases, respectively. After factoring out other potential contributing factors, patients with ser/ser or arg/ser were 2.17 times more at risk (95% CI=1.03-4.56) for developing esophageal cancer than those with arg/arg. Males (n=274) were found to have a slightly stronger association (adjusted OR=2.45; 95% CI=1.03-5.80). Although the sample size is relatively small, these findings suggest that a codon 31 polymorphism in p21 may be associated with the development of esophageal cancer.

Adult↗
PubMed1998

Ki-ras codon 12 point mutational activation in Hong Kong colorectal carcinoma patients.

This study investigated the frequency and importance of Ki-ras codon 12 mutations in 99 Hong Kong Chinese colorectal carcinoma specimens by allele-specific oligonucleotide hybridization. The frequency of mutations detected was 30% and the most common mutation observed resulted in aspartic acid substitutions. Previous studies showed that specific Ki-ras mutations have been significantly associated with prognosis. Ki-ras codon 12 point mutational activation in CRC was significantly associated with the differentiation status of tumors in this study. Ethnic differences in the patterns of Ki-ras codon 12 point mutations were observed.

Adult↗
PubMed2003

Codon 201 polymorphism of DCC gene is a prognostic factor in patients with colorectal cancer.

The polymorphism at codon 201 of the "deleted in colorectal carcinoma" (DCC) gene has been liked to susceptibility to colorectal cancer. However, its clinicopathological significance has not been reported. We examined the codon 201 polymorphism and loss of heterozygosity (LOH) by PCR-restriction fragment length polymorphism (PCR-RFLP) in 59 colorectal cancers, 48 samples from transitional mucosa and 67 samples from normal mucosa. The frequencies of the polymorphism did not significantly differ from normal to transitional mucosa and to tumor, but LOH was increased from transitional mucosa to tumor. Almost all of the LOH cases showed the polymorphism. The polymorphism was increased from well/moderately to poorly differentiated and to mucinous carcinoma (P=0.03). The polymorphism was more frequently seen in advanced stages than in earlier stages (P=0.02), and further predicted worse survival (P=0.04). The data suggest that the codon 201 polymorphism of the DCC gene was a target of LOH, and predicted prognosis in colorectal cancer patients.

Aged↗
PubMed2000

Beta2-adrenergic receptor polymorphisms at codon 16, cardiovascular phenotypes and essential hypertension in whites and African Americans.

Beta2-adrenergic receptors (beta2-AR) contribute to cardiovascular regulation by influencing several functions and previous studies suggest that a decreased function of the beta2-AR may be involved in essential hypertension. Beta2-AR are polymorphic and certain polymorphisms of these receptors are of functional importance. We focus here on the Arg16-->Gly16 beta2-AR polymorphism, which shows enhanced agonist-promoted downregulation of the receptor and which, in two recent studies, yielded opposite results in terms of association with essential hypertension: an increased frequency of the Gly16 variant in African-Caribbean hypertensives and of the Arg16 variant in offspring of Norwegian white hypertensive parents. In the current study, we genotyped 243 subjects, including both African-American and white individuals, for codon 16 polymorphism and assessed blood pressure and cardiovascular function using impedance cardiography and pressor sensitivity to phenylephrine. We found similar patterns of cardiovascular function and expression of hypertension with the two genotypes of codon 16. There was no statistically significant difference in the overall allelic distribution of the two genotypes: among African-Americans, 51% of the hypertensives and 50% of the normotensives carried the Arg16 allele, whereas among the white subjects 40% of the hypertensives and 47% of the normotensives were carriers of the Arg16 allele. Although we observed a statistically significant increase in the Arg16/Gly16 heterozygotes in the African-American population, the Gly16 allele was not significantly increased in the African-Americans compared to whites. These findings indicate that the codon 16 polymorphisms are not associated with hypertension in a mixed American study population nor do they appear to substantially impact on a variety of hemodynamic variables.

Adult↗
PubMed2002

Cloning and hemolysin-mediated secretory expression of a codon-optimized synthetic human interleukin-6 gene in Escherichia coli.

Previously, we constructed human interleukin-6 (hIL-6)-secreting Escherichia coli and Salmonella typhimurium strains by fusion of the hIL-6 cDNA to the HlyA(s) secretional signal, utilizing the hemolysin export apparatus for extracellular delivery of a bioactive hIL-6-hemolysin (hIL-6-HlyA(s)) fusion protein. Molecular analysis of the secretion process revealed that low secretion levels were due to inefficient gene expression. To adapt the codon usage in hIL-6 cDNA to the E. coli codon bias, a synthetic hIL-6Ec gene variant was constructed from 20 overlapping oligonucleotides, yielding a 561-bp fragment, which comprises the complete hIL-6 cDNA sequence. Genetic fusion of the hIL-6Ec gene with the hlyA(s) secretional signal as an integral part of the hemolysin operon resulted in 3-fold higher hIL-6-HlyA(s) secretion levels in E. coli, compared to a strain expressing the original hIL-6-hlyA(s) fusion gene. An increase in the electrophoretic mobility of secreted hIL-6-HlyA(s) in non-reducing SDS-PAGE, similar to that found for recombinant mature hIL-6, and the absence of such a mobility shift in the intracellular hIL-6-HlyA(s) protein fraction indicated that in hIL-6-HlyA(s) most probably correct intramolecular disulfide bond formation occurred during the secretion step. To confirm the disulfide bond formation, hIL-6-HlyA(s) was purified by a single-step immunoaffinity chromatography from culture supernatant in yields of 18 microg/L culture supernatant with purity in the range of 60%. These results demonstrate that codon usage has an impact on the hemolysin-mediated secretion of hIL-6 and, furthermore, provide evidence that the hemolysin system enables secretory delivery of disulfide-bridged proteins.

Amino Acid Sequence↗
PubMed1998

Combination of DMT-mononucleotide and Fmoc-trinucleotide phosphoramidites in oligonucleotide synthesis affords an automatable codon-level mutagenesis method.

BACKGROUND: Synthetic DNA has been used to introduce variability into protein-coding regions. In protocols that produce a few mutations per gene, the sampling of amino-acid sequence space is limited by the bias imposed by the genetic code. It has long been apparent that the incorporation of trinucleotides in the synthetic regime would circumvent this problem and significantly enhance the usefulness of the technique. RESULTS: A new method is described for the creation of codon-level degenerate oligodeoxyribonucleotides that combines conventional dimethoxytrityl (DMT) mononucleoside phosphoramidite chemistry with 9-fluorenylmethoxycarbonyl (Fmoc) trinucleotide phosphoramidites (whose synthesis is reported in the paper). The substoichiometric use of these Fmoc-trinucleotides in an automatable, solid-phase synthesis procedure afforded DNA fragments comprising the wild-type sequence and a controllable distribution of mutants within two- and three-codon stretches of DNA, within the multiple cloning site of the conventional cloning vector pUC19. CONCLUSIONS: DMT and Fmoc are compatible protecting groups in conventional oligonucleotide synthesis methods, resulting in controllable levels of codon-based mutagenesis.

Cloning, Molecular↗
PubMed2002

Neurospora crassa supersuppressor mutants are amber codon-specific.

Neurospora crassa has 10 mapped supersuppressor (ssu) genes. In vivo studies indicate that they suppress amber (UAG) premature termination mutations but the spectrum of their functions remains to be elucidated. We examined seven ssu strains (ssu-1, -2, -3, -4, -5, -9, and -10) using cell-free translation extracts. We tested suppression by requiring it to produce firefly luciferase from a reading frame containing premature UAA, UGA, or UAG terminators. All mutants except ssu-3 suppressed UAG codons. Maximal UAG suppression ranged from 15% to 30% relative to controls containing sense codons at the corresponding position. Production from constructs containing UAA or UGA was 1-2%, similar to levels observed with all nonsense codons in wild-type and ssu-3 extracts. UAG suppression was also seen using [35S]Met to radiolabel polypeptides. Suppression enabled ribosomes to continue translation elongation as determined using the toeprint assay. tRNA from supersuppressors showed suppressor activity when added to wild-type extracts. Thus, these supersuppressors produce amber suppressor tRNA.

Amino Acid Sequence↗
PubMed2003

An RNA-modifying enzyme that governs both the codon and amino acid specificities of isoleucine tRNA.

The AUA codon-specific isoleucine tRNA (tRNA(Ile)) in eubacteria has the posttranscriptionally modified nucleoside lysidine (L) at the wobble position of the anticodon (position 34). This modification is a lysine-containing cytidine derivative that converts both the codon specificity of tRNA(Ile) from AUG to AUA and its amino acid specificity from methionine to isoleucine. We identified an essential gene (tilS; tRNA(Ile)-lysidine synthetase) that is responsible for lysidine formation in both Bacillus subtilis and Escherichia coli. The recombinant enzyme complexed specifically with tRNA(Ile) and synthesized L by utilizing ATP and lysine as substrates. The lysidine synthesis of this enzyme was shown to directly convert the amino acid specificity of tRNA(Ile) from methionine to isoleucine in vitro. Partial inactivation of tilS in vivo resulted in an AUA codon-dependent translational defect, which supports the notion that TilS is an RNA-modifying enzyme that plays a critical role in the accurate decoding of genetic information.

Amino Acid Sequence↗
PubMed1997

Unusual effect of clusters of rare arginine (AGG) codons on the expression of human interferon alpha 1 gene in Escherichia coli.

The human interferon (hIFN alpha 1) gene contains 11 arginine (Arg) codons AGG or AGA, which are extremely rare for bacteria, four of which are organized in tandems. The two AGG tandems (corresponding to Arg12 Arg13 and Arg163 Arg164) are known to inhibit the translation of hIFN alpha 1 mRNA and therefore they are considered to be responsible for the poor expression of hIFN alpha 1 gene in bacterial cells. To study the effect of these two tandems on the expression of hIFN alpha 1 in E. coli, four new gene variants were designed to contain preferential Arg codons (CGT) substituted for the rare AGG codons in either the first, the second or both AGG tandems. We found that, whereas the yield of hIFN alpha 1 protein per cell remained unchanged, the level of hIFN alpha 1 mRNA decreased gradually (by a factor of two) with the consecutive substitution of the first, second and both AGG tandems. These results indicated, first, that the AGG clusters might have a stabilizing effect on the mRNA, and second, that mRNAs devoid of such clusters were translated at a higher rate in vivo. The protein products of the four genes (having the same amino acid sequence) showed different specific antiviral activity. The most active was the product of gene hIFN alpha 1(c) in which the second AGG tandem (corresponding to Arg163, Arg164) was preserved while the least active was the protein of gene hIFN alpha 1(d) (devoid of both AGG clusters). The role of the AGG tandems in folding of the gene product is discussed.

Arginine↗
PubMed2000

Mutation of p53 gene codon 63 in saliva as a molecular marker for oral squamous cell carcinomas.

The inactivation of tumor suppressor gene (TSG) is important during multistage carcinogenesis. The p53 TSG is frequently mutated in oral squamous cell carcinomas. These mutations can serve as very specific markers for the presence of tumor cells in a background of normal cells. In this study, 10 oral squamous cell carcinoma patients and 27 normal dental students were collected from Chung Shan Medical and Dental College Hospital, Taichung, Taiwan. Extractions of DNA from saliva were obtained. Exon 4 and intron 6 within the p53 gene were amplified with polymerase chain reactions (PCRs) followed by DNA sequence analysis. DNA sequence analysis of PCR products revealed that five of eight (62.5%) tumor saliva samples and five of 27 (18. 52%) healthy saliva samples contained p53 exon 4 codon 63 mutations. These results were significantly different by using Chi-square test (P<0.05). The majority of the base substitutions were C deletions. Probable hot spots for the mutation were identified at exon 4 codon 63, which has not been observed before in head and neck cancers. Our study indicated that mutation of p53 codon 63 in saliva might be a molecular marker for oral squamous cell carcinomas. In addition, the amount of DNA recovered from saliva in most cases is sufficiently large and its quality suitable to enable PCR amplification which could be used in the search for mutations. The protocol described is rapid, cheap, and easy to perform, and may be useful for epidemiological studies for oral carcinogenesis.

Adult↗
PubMed2006

Role of p53 codon 72 polymorphism in recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) has been associated with low expression of apoptosis-and angiogenesis-related genes. The p53 tumour suppressor gene has been shown to induce apoptosis and angiogenesis. Recently, a low increased frequency of a p53 codon 72 polymorphism has been reported among women experiencing RPL. This study investigated the prevalence of p53 codon 72 polymorphism among women with a history of RPL, to determine whether this polymorphism may serve as a risk factor for miscarriage. Buccal swabs were obtained from 205 women with a history of two or more consecutive spontaneous abortions and 25 women with at least two live births and not more than one elective abortion. DNA was extracted from the buccal swabs and PCR amplification of p53 arginine(Arg)72 and proline(Pro)72 variants was performed. The frequency of homozygous Arg and Pro or heterozygous Arg/Pro genotypes among RPL patients and controls were not significantly different. No significant differences in allelic frequencies of p53 were observed. In addition, the allelic frequencies between controls and those previously reported were the same. It is concluded that p53 codon 72 polymorphisms do not serve as a susceptibility factor affecting the chances of miscarriage in an unselected population.

Abortion, Habitual↗