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PubMed2004

Online synonymous codon usage analyses with the ade4 and seqinR packages.

UNLABELLED: Correspondence analysis of codon usage data is a widely used method in sequence analysis, but the variability in amino acid composition between proteins is a confounding factor when one wants to analyse synonymous codon usage variability. A simple and natural way to cope with this problem is to use within-group correspondence analysis. There is, however, no user-friendly implementation of this method available for genomic studies. Our motivation was to provide to the community a Web facility to easily study synonymous codon usage on a subset of data available in public genomic databases. AVAILABILITY: Availability through the Pole Bioinformatique Lyonnais (PBIL) Web server at http://pbil.univ-lyon1.fr/datasets/charif04/ with a demo allowing us to reproduce the figure in the present application note. All underlying software is distributed under a GPL licence. CONTACT: http://pbil.univ-lyon1.fr/members/lobry.

Algorithms↗
PubMed1992

Search for Ha-ras codon 61 mutations in liver tumours caused by hexachlorobenzene and Aroclor 1254 in C57BL/10ScSn mice with iron overload.

C57BL/10ScSn mice administered iron--dextran and fed the environmental pollutants hexachlorobenzene (HCB) and polychlorinated biphenyls (PCBs) develop hepatic nodules and carcinomas within 18 months. A range of lesions from the livers were analysed for the presence of mutations in the Ha-ras proto-oncogene at codon 61 using the polymerase chain reaction to amplify DNA from formalin-fixed sections, followed by oligonucleotide hybridization. Only two mutations from 23 preneoplastic and neoplastic lesions induced by HCB were detected (a focus of altered cells and a trabecular cell carcinoma). With Aroclor 1254 no mutations were detected in 28 areas at various stages of carcinogenesis analysed. Sequencing of the two mutations generated by HCB showed a C-->T transversion at the first base of codon 61 (carcinoma) and an A-->T transversion at the second base (proliferative focus). Thus, in marked contrast to some other systems of mouse liver tumour induction, hepatocarcinogenesis caused by HCB and PCBs in C57BL/10ScSn mice is an example of carcinogenesis which does not involve a high frequency of Ha-ras gene mutation at codon 61.

Animals↗
PubMed1993

Mutagenesis of H-ras codons 11 and 12 in human fibroblasts by N-ethyl-N-nitrosourea.

Codon 12 of the ras protooncogenes represents a mutational hotspot in human cancer. A distinct pattern of base pair changes has been observed that may allow insight into the class of carcinogens that induced the mutations. In an attempt to identify candidate carcinogens we have studied the mutability of codons 11 (GCC) and 12 (GGC) of the c-H-ras1 gene in human foreskin fibroblasts to N-ethyl-N-nitrosourea (ENU) by restriction fragment length polymorphism/polymerase chain reaction (RFLP/PCR). This genotypic mutation system allows the quantitation of low frequencies of mutated sequences without expansion and phenotypic selection of mutated cells. ENU induced the transition of G to A in the middle position of codon 12 with highest efficiency. This is the same mutation that is found predominantly in human tumors. These mutations are most likely the consequence of miscoding opposite O6-ethylguanine adducts and our data indicate strong bias for the coding strand. No evidence was obtained for spontaneous deamination of the CpG-dinucleotide despite its high content in 5-methylcytosine.

Base Sequence↗
PubMed1993

The role of O6-alkylguanine-DNA alkyltransferase in protecting Rat4 cells against the mutagenic effects of O6-substituted guanine residues incorporated in codon 12 of the H-ras gene.

The role of rat O6-alkylguanine-DNA alkyltransferase (AGT) in modulating mutagenesis by O6-substituted guanines in the rat H-ras gene was examined. Rat4 cells were transfected with vectors carrying O6-methyl-, O6-ethyl- or O6-benzylguanine residues in place of the normal guanines at either the first, second, or both the first and second positions in codon 12 (GGA) of the H-ras coding sequence. The percentage of transformed colonies was determined for cells grown in normal medium or in medium containing O6-benzylguanine to completely deplete AGT. In parallel experiments with O6-methylguanine-containing vectors, the percentage of cellular DNA harboring codon 12 mutations was determined for normal cells and cells lacking AGT. A reasonable correspondence was observed between the percentage of mutated DNA and the percentage of transformed colonies produced in both types of cells. The results indicate that the contribution of AGT to the repair of O6-substituted guanine damage decreases as the O6 substituent is changed from methyl > ethyl > benzyl. Additionally, cellular AGT appears to repair an O6-methylguanine more readily at the first position of codon 12 than the second position. However, other repair mechanisms in these mammalian cells appear to play a major role in correcting low levels of O6-substituted guanine damage including O6-methylguanine damage.

Base Sequence↗
PubMed1995

A polymorphism at codon 160 of human O6-methylguanine-DNA methyltransferase gene in young patients with adult type cancers and functional assay.

O6-methylguanine-DNA methyltransferase (MGMT) plays an important role in repair of alkylating agent-induced DNA damage. Among the alkylation products of DNA, O6-methylguanine is one of the most critical lesions leading to the induction of mutations. The enzyme MGMT transfers the methyl group from O6-methylguanine of DNA to its own cysteine residue. Although mutations of other DNA repair genes involved in nucleotide excision repair and mismatch repair have been proven to be related to human tumorigenesis, the question of whether MGMT gene mutation might play a role in human carcinogenesis has hitherto not been elucidated. If there is a population with decreased enzyme activity due to defective MGMT gene, the affected individuals should be at risk of developing cancer early in life because of an increased susceptibility to alkylating agents. To test this hypothesis, germ line mutations of the MGMT gene were investigated in 12 young patients with adult type cancers (mean, 16.7 years old, 8 hepatocellular carcinomas, 3 gastric cancers, 1 cholangiocellular carcinoma) and 28 elderly patients who died of non-cancer diseases as controls (mean, 66 years old). A point mutation at codon 160 in exon 5, GGA to AGA, converting glycine to arginine was found in three of the young patients (25%), while the same mutation was found in three out of 28 (10.7%) in the control group. The mutated codon was located 15 codons from a functional cysteine residue toward the carboxyl terminal. Investigation of enzyme function, even in cases of bi-allelic mutation, revealed comparable activities for both mutated and wild type MGMT. Thus, we conclude the mutation is a normal polymorphism of the MGMT gene, present in approximately 15% of the population, although this does not rule out a possible influence in other tissues.

Adolescent↗
PubMed1996

O6-ethylguanine and O6-benzylguanine incorporated site-specifically in codon 12 of the rat H-ras gene induce semi-targeted as well as targeted mutations in Rat4 cells.

To examine the miscoding properties of modified guanine residues bearing increasingly bulky O6-substituents, Rat4 cells, grown in the presence of O6-benzylguanine to deplete the DNA repair protein O6-alkylguanine-DNA alkyltransferase, were transfected with plasmids carrying H-ras genes in which O6-methyl, O6-ethyl- and O6-benzylguanine were substituted for the first, second or both the first and second guanine residues of codon 12 (GGA). DNA from isolated transformed colonies was amplified by PCR and directly sequenced by high-temperature manual and automated methods. The results show that O6-ethylguanine and O6-benzylguanine induced semi-targeted as well as targeted mutations, in contrast to O6-methylguanine, which induced only targeted mutations. When incorporated in place of the first guanine of H-ras codon 12, the targeted mutations induced by all these modified guanines were exclusively G-->A transitions. When incorporated at the second position of codon 12, O6-benzylguanine induced G-->A, G-->T and G-->C mutations. O6-Ethylguanine at the second position induced chiefly G-->A transitions, and O6-methylguanine induced G-->A transitions exclusively. Semi-targeted mutations were strictly G-->A at the base 3' to a position 1 adduct or 5' to a position 2 adduct. The mechanism for induction of targeted mutations probably involves decreasing preference to thymidine incorporation opposite an O6-modified guanine as the size of the O6-substituent increases, while the mechanism for non-targeted mutations may be related to abasic site formation or to translesion synthesis which might be made error-prone by obstructive DNA lesions in this context.

Animals↗
PubMed1996

An aflatoxin-associated mutational hotspot at codon 249 in the p53 tumor suppressor gene occurs in hepatocellular carcinomas from Mexico.

The p53 tumor suppressor gene is commonly mutated in human hepatocellular carcinoma (HCC). The most frequent mutation in HCC in populations exposed to a high dietary intake of aflatoxin B1 (AFB1) is an AGGarg-->AGTser missense mutation in codon 249 of the p53 gene. We analyzed HCCs from Monterrey, Mexico, for the codon 249ser hotspot mutation. We also analyzed the serum AFB1-albumin adduct levels of the donors and family members to measure the current AFB1 exposure in this population. Moreover, the presence of hepatitis B and/or C viral infection (HBV or HCV) was analyzed serologically in the patients. Tumor cells were microdissected from tissue sections and exon 7 p53 sequences were amplified by polymerase chain reaction from genomic DNA and sequenced directly. The serological tests for anti-p53 antibodies, HBV or HCV were done by ELISA. Immunohistochemical analysis of p53 protein was done using a polyclonal rabbit antiserum (CM-1). Eight of 21 cases were positive by p53 immunohistochemistry. Of the 16 cases sequenced for exon 7 of p53 three codon 249 AGGarg-->AGTser mutations were found. Serum antibodies recognizing p53 protein were found in one of 18 patients. Positive serology for HBV and/or HCV was found in 12 of 20 cases. The serum AFB1-albumin adduct levels in this population ranged from 0.54 to 4.64 pmol aflatoxin/mg albumin. These results indicate that dietary AFB1 and hepatitis viruses are etiological agents in the molecular pathogenesis of HCC in this geographic region of Mexico.

Adult↗
PubMed1999

Codon 72 polymorphism of p53 as a risk factor for patients with human papillomavirus-associated squamous intraepithelial lesions and invasive cancer of the uterine cervix.

Squamous intraepithelial lesions (SIL) and invasive cancer of the uterine cervix are thought to be a series of lesions derived from normal cervical squamous tissue. Infection by high risk human papillomavirus (HPV) and integration of viral DNA may initially lead normal cervical cells to become pre-malignant cells in SIL and result in cervical malignancies later on. High risk HPVs, including types 16 and 18, produce a viral protein, E6, which is required for viral replication in host cells. The E6 protein is able to bind to host p53 causing inactivation of its function through the mechanism of ubiquitin-dependent degradation. It has recently been reported that the extent of p53 dysfunction caused by HPVs depends on the status of a polymorphism at codon 72 of p53, Pro or Arg. In that study, it was demonstrated that a patient homozygous for the Arg allele had about a seven times higher risk of developing cervical cancer than a patient homozygous for Pro. In an attempt to confirm this result and elucidate whether this allelic deviation of the Arg genotype seen in invasive cervical cancer occurs in the pre-malignant lesion SIL, we analyzed 219 SIL and 101 invasive cancer samples from Japanese patients using a PCR-based assay. Samples from 88 SIL and 76 invasive cancers were identified as HPV-infected samples and used for further analyses. In these, the frequencies of Arg homozygotes were 31.8, 33.0 and 36.8% in controls, SIL and invasive cancer, respectively. The distributions of the different alleles of codon 72 (Pro/Pro, Pro/Arg and Arg/Arg) did not show significant differences between either control and SIL groups or control and invasive cancer groups. Also, no difference in the frequency of Arg/Arg genotype was detected even between the control and HSIL groups or control and invasive cancer infected with high risk HPVs groups. In conclusion, there was no obvious relationship between the Arg genotype at codon 72 of p53 and predisposition to HPV-associated cervical neoplasia.

Amino Acid Sequence↗
PubMed2001

Polymorphic hCHK2/hCds1 codon 84 allele and risk of squamous cell carcinoma of the head and neck--a case-control analysis.

Checkpoint kinase 2 (hCHK2/hCds1) is a tumor suppressor gene involved in cell-cycle control. A hCHK2/hCds1 polymorphism in codon 84 (A-->G at nucleotide 252) was recently identified in Li-Fraumeni syndrome patients. Because cell cycle regulates DNA repair that is associated with cancer risk, we hypothesized that this new polymorphism exists in the general population and is associated with cancer risk. To test this hypothesis, we evaluated the role of this polymorphism in a case-control study of 215 non-Hispanic white patients with newly diagnosed squamous cell carcinoma of the head and neck (SCCHN) and 229 frequency-matched cancer-free controls. We found that the hCHK2/hCds1 codon 84 variant was rare and less frequent in non-Hispanic white cases (0.0186) than in controls (0.0437; P = 0.033). Although no variant homozygotes were detected in these cases and controls, heterozygosity protected against SCCHN, representing a 60% reduction of risk (adjusted odds ratio = 0.40; 95% confidence intervals, 0.17-0.93) compared with wild-type homozygotes. The variant allele was also rare in other ethnic groups (0.0487, 0.0095 and 0.0541 in 115 African Americans, 105 Hispanic Americans and 111 native Chinese, respectively), and only one variant homozygous individual (a Chinese subject) was identified. These results suggest that this hCHK2/hCds1 codon 84 polymorphism is rare and may have a protective role in the aetiology of SCCHN in non-Hispanic whites. Larger studies are warranted to confirm this finding and further mechanistic studies are needed to understand biological relevance of this polymorphism.

Aged↗
PubMed2006

Polymorphism in the ERCC2 codon 751 is associated with arsenic-induced premalignant hyperkeratosis and significant chromosome aberrations.

In West Bengal, India more than 6 million people are exposed to high levels of arsenic through drinking water. Since, only 15-20% of the exposed individuals show arsenic-induced skin lesions, it is assumed that genetic variation might play an important role in arsenic toxicity and carcinogenicity. Arsenic exposure often leads to the development of hyperkeratosis, the precursor of arsenic-induced skin cancer. ERCC2 (excision repair cross-complementing rodent repair deficiency, complementation group 2) is a nucleotide excision repair pathway gene, and its SNPs have been implicated in several types of epithelial cancers. We investigated the possible association of ERCC2 codon 751 A-->C polymorphism (lysine to glutamine) with arsenic-induced hyperkeratosis and correlated ERCC2 genotypes with increased frequencies of chromosomal aberration to ascertain whether any genotype leads to sub-optimal DNA repair. For this association study, 318 unrelated arsenic exposed subjects (165 with hyperkeratosis and 153 without any arsenic-induced skin lesions), drinking water contaminated with arsenic to a similar extent, were recruited. Genotyping was done through PCR-RFLP procedure. Lys/Lys genotype was significantly over-represented in the arsenic-induced hyperkeratosis-exhibiting group [odds ratio (OR) = 4.77, 95% confidence interval (CI) = 2.75-8.23]. A statistically significant increase in both CA/cell and percentage of aberrant cells was observed in the individuals with AA genotype compared to those with AC or CC genotype combined (P < 0.01) in each of the two study groups, as also, in the total study population. This study indicates that ERCC2 codon 751 Lys/Lys genotype is significantly associated with arsenic-induced premalignant hyperkeratosis and is possibly due to sub-optimal DNA repair capacity of the ERCC2 codon 751 Lys/Lys genotype.

Adult↗
PubMed2001

A novel stop codon readthrough mechanism produces functional Headcase protein in Drosophila trachea.

Translational regulation provides an efficient means to control the localization and production of proteins. The headcase (hdc) mRNA in Drosophila generates two overlapping proteins as a result of translational readthrough of an internal UAA stop codon. This readthrough event is necessary for the function of hdc as a branching inhibitor during tracheal development. By ectopic expression of different Hdc proteins in the trachea, we show that the long Hdc form alone, can function as a potent branching inhibitor whose activity is proportional to its amount. The suppression of termination in the hdc mRNA is not stop-codon dependent, suggesting that the readthrough does not involve codon specific suppressors. We have identified an 80 nucleotide sequence immediately downstream of the UAA, which is necessary and sufficient to confer termination readthrough in a heterologous mRNA. We present a novel mechanism of eukaryotic translational termination suppression that may regulate the amount of functional Hdc.

Animals↗
PubMed1999

C to U editing of the anticodon of imported mitochondrial tRNA(Trp) allows decoding of the UGA stop codon in Leishmania tarentolae.

All mitochondrial tRNAs in kinetoplastid protists are encoded in the nucleus and imported into the organelle. The tRNA(Trp)(CCA) can decode the standard UGG tryptophan codon but can not decode the mitochondrial UGA tryptophan codon. We show that the mitochondrial tRNA(Trp) undergoes a specific C to U nucleotide modification in the first position of the anticodon, which allows decoding of mitochondrial UGA codons as tryptophan. Functional evidence for the absence of a UGA suppressor tRNA in the cytosol, using a reporter gene, was also obtained, which is consistent with a mitochondrial localization of this editing event. Leishmania cells have dealt with the problem of a lack of expression within the organelle of this non-universal tRNA by compartmentalizing an editing activity that modifies the anticodon of the imported tRNA.

Animals↗
PubMed1983

Codon substitution in evolution and the "saturation" of synonymous changes.

A mathematical model for codon substitution is presented, taking into account unequal mutation rates among different nucleotides and purifying selection. This model is constructed by using a 61 X 61 transition probability matrix for the 61 nonterminating codons. Under this model, a computer simulation is conducted to study the numbers of silent (synonymous) and amino acid-altering (nonsynonymous) nucleotide substitutions when the underlying mutation rates among the four kinds of nucleotides are not equal. It is assumed that the substitution rates are constant over evolutionary time, the codon frequencies being in equilibrium, and, thus, the numbers of synonymous and nonsynonymous substitutions both increase linearly with evolutionary time. It is shown that, when the mutation rates are not equal, the estimate of synonymous substitutions obtained by F. Perler, A. Efstratiadis, P. Lomedico, W. Gilbert, R. Kolodner and J. Dodgson's "Percent Corrected Divergence" method increases nonlinearly, although the true number of synonymous substitutions increases linearly. It is, therefore, possible that the "saturation" of synonymous substitutions observed by Perler et al. is due to the inefficiency of their method to detect all synonymous substitutions.

Amino Acids↗
PubMed1991

Site-directed mutagenesis of a Saccharomyces cerevisiae mitochondrial translation initiation codon.

We have used a generally applicable strategy for gene replacement in yeast mitochondria to mutate the translation initiation codon of the COX3 gene from AUG to AUA. The mutation, cox3-1, substantially reduced, but did not eliminate, translation of cytochrome c oxidase subunit III (coxIII). Strains bearing the mutation exhibited a leaky (partial) nonrespiratory growth phenotype and a reduced incorporation of radiolabeled amino acids into coxIII in vivo in the presence of cycloheximide. Hybridization experiments demonstrated that the mutation had little or no effect on levels of the COX3 mRNA. Residual translation of the cox3-1 mutant mRNA was dependent upon the three nuclearly coded mRNA-specific activators PET494, PET54 and PET122, known from previous studies to work through a site (or sites) upstream of the initiation codon to promote translation of the wild-type mRNA. Furthermore, respiratory growth of cox3-1 mutant strains was sensitive to decreased dosage of genes PET494 and PET122 in heterozygous mutant diploids, unlike the growth of strains carrying wild-type mtDNA. Some residual translation of the cox3-1 mRNA appeared to initiate at the mutant AUA codon, despite the fact that the 610-base 5'-mRNA leader contains numerous AUA triplets. We conclude that, while AUG is an important component of the COX3 translation initiation site, the site probably is also specified by other sequence or structural features.

Codon↗
PubMed1991

The selection-mutation-drift theory of synonymous codon usage.

It is argued that the bias in synonymous codon usage observed in unicellular organisms is due to a balance between the forces of selection and mutation in a finite population, with greater bias in highly expressed genes reflecting stronger selection for efficiency of translation. A population genetic model is developed taking into account population size and selective differences between synonymous codons. A biochemical model is then developed to predict the magnitude of selective differences between synonymous codons in unicellular organisms in which growth rate (or possibly growth yield) can be equated with fitness. Selection can arise from differences in either the speed or the accuracy of translation. A model for the effect of speed of translation on fitness is considered in detail, a similar model for accuracy more briefly. The model is successful in predicting a difference in the degree of bias at the beginning than in the rest of the gene under some circumstances, as observed in Escherichia coli, but grossly overestimates the amount of bias expected. Possible reasons for this discrepancy are discussed.

Amino Acyl-tRNA Synthetases↗
PubMed1993

Codon usage bias and base composition of nuclear genes in Drosophila.

The nuclear genes of Drosophila evolve at various rates. This variation seems to correlate with codon-usage bias. In order to elucidate the determining factors of the various evolutionary rates and codon-usage bias in the Drosophila nuclear genome, we compared patterns of codon-usage bias with base compositions of exons and introns. Our results clearly show the existence of selective constraints at the translational level for synonymous (silent) sites and, on the other hand, the neutrality or near neutrality of long stretches of nucleotide sequence within noncoding regions. These features were found for comparisons among nuclear genes in a particular species (Drosophila melanogaster, Drosophila pseudoobscura and Drosophila virilis) as well as in a particular gene (alcohol dehydrogenase) among different species in the genus Drosophila. The patterns of evolution of synonymous sites in Drosophila are more similar to those in the prokaryotes than they are to those in mammals. If a difference in the level of expression of each gene is a main reason for the difference in the degree of selective constraint, the evolution of synonymous sites of Drosophila genes would be sensitive to the level of expression among genes and would change as the level of expression becomes altered in different species. Our analysis verifies these predictions and also identifies additional selective constraints at the translational level in Drosophila.

Animals↗
PubMed1994

Reduced dosage of genes encoding ribosomal protein S18 suppresses a mitochondrial initiation codon mutation in Saccharomyces cerevisiae.

A yeast mitochondrial translation initiation codon mutation affecting the gene for cytochrome oxidase subunit III (COX3) was partially suppressed by a spontaneous nuclear mutation. The suppressor mutation also caused cold-sensitive fermentative growth on glucose medium. Suppression and cold sensitivity resulted from inactivation of the gene product of RPS18A, one of two unlinked genes that code the essential cytoplasmic small subunit ribosomal protein termed S18 in yeast. The two S18 genes differ only by 21 silent substitutions in their exons; both are interrupted by a single intron after the 15th codon. Yeast S18 is homologous to the human S11 (70% identical) and the Escherichia coli S17 (35% identical) ribosomal proteins. This highly conserved family of ribosomal proteins has been implicated in maintenance of translational accuracy and is essential for assembly of the small ribosomal subunit. Characterization of the original rps18a-1 missense mutant and rps18a delta and rps18b delta null mutants revealed that levels of suppression, cold sensitivity and paromomycin sensitivity all varied directly with a limitation of small ribosomal subunits. The rps18a-1 mutant was most affected, followed by rps18a delta then rps18b delta. Mitochondrial mutations that decreased COX3 expression without altering the initiation codon were not suppressed. This allele specificity implicates mitochondrial translation in the mechanism of suppression. We could not detect an epitope-tagged variant of S18 in mitochondria. Thus, it appears that suppression of the mitochondrial translation initiation defect is caused indirectly by reduced levels of cytoplasmic small ribosomal subunits, leading to changes in either cytoplasmic translational accuracy or the relative levels of cytoplasmic translation products.

Amino Acid Sequence↗
PubMed1996

Molecular evolution between Drosophila melanogaster and D. simulans: reduced codon bias, faster rates of amino acid substitution, and larger proteins in D. melanogaster.

Both natural selection and mutational biases contribute to variation in codon usage bias within Drosophila species. This study addresses the cause of codon bias differences between the sibling species, Drosophila melanogaster and D. simulans. Under a model of mutation-selection-drift, variation in mutational processes between species predicts greater base composition differences in neutrally evolving regions than in highly biased genes. Variation in selection intensity, however, predicts larger base composition differences in highly biased loci. Greater differences in the G+C content of 34 coding regions than 46 intron sequences between D. melanogaster and D. simulans suggest that D. melanogaster has undergone a reduction in selection intensity for codon bias. Computer simulations suggest at least a fivefold reduction in Nes at silent sites in this lineage. Other classes of molecular change show lineage effects between these species. Rates of amino acid substitution are higher in the D. melanogaster lineage than in D. simulans in 14 genes for which outgroup sequences are available. Surprisingly, protein sizes are larger in D. melanogaster than in D. simulans in the 34 genes compared between the two species. A substantial fraction of silent, replacement, and insertion/deletion mutations in coding regions may be weakly selected in Drosophila.

Amino Acids↗