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PubMed1997

Rates of synonymous substitution do not indicate selective constraints on the codon use of the plant psbA gene.

The psbA gene of the flowering plant chloroplast genome has a pattern of codon bias that differs from all other angiosperm chloroplast genes. In psbA, unlike all other chloroplast genes, the third-codon-position composition does not reflect the general genome compositional bias of a high A+T content. Instead, in specific synonymous groups, the codon use of psbA more closely corresponds to the tRNA population available for translation. Since it requires a composition unlike the genome composition bias, this pattern of codon use is likely to be the result of selection. Selective constraints on codon use are expected to result in decreased rates of synonymous substitution, and it has been observed that psbA has the lowest rate of synonymous substitution among plant chloroplast genes. In the present study, this is examined further by testing whether or not those synonymous groups that specifically have an atypical codon use in psbA have correspondingly low rates of silent substitution. An analysis of synonymous substitution rate, performed separately for different degeneracy classes of amino acids, shows that, contrary to the expectation, those sites that are presumed, based on their codon use, to be under selective constraint in psbA do not show low rates of substitution and are not responsible for the overall low rate of synonymous substitution in this gene. Instead, they actually show increased rates of substitution relative to other chloroplast genes. Two hypotheses concerning the role of selection in psbA are advanced to explain the results.

Chloroplasts↗

PubMed1998

A codon-based model designed to describe lentiviral evolution.

A codon-based model designed to describe lentiviral evolution is developed. The model incorporates unequal base compositions in the three codon positions and selection against the CpG dinucleotide within codons to account for a deficit of this dinucleotide exhibited by lentiviral genes. The model is, to a large extent, able to account for the pattern of codon usage exhibited by the HIV1 genes gag, pol, and env, in spite of its parameter paucity. The model is extended to a similar model which operates on pentets (codons and their neighboring bases). The results obtained by the pentet model establish the importance of depression of CpGs across codon boundaries as well as within codons. The goodness of fit of the CpG depression model to the observed evolution in pairwise alignments of HIV1 sequences is assessed. The model provides a significantly better description of the observed evolution than the simpler models examined. The parameter estimates indicate that part of the unusually large biases in nucleotide frequencies observed in HIV1 genes is caused by selection against CpGs. We find that the estimates of expected numbers of substitutions, of transitions to transversions, and of synonymous to nonsynonymous substitution rates are robust to CpG depression, whereas the ratio of CpG-generating substitutions to other substitutions is strongly influenced by the choice of model.

Base Composition↗

PubMed1999

Selection at the wobble position of codons read by the same tRNA in Saccharomyces cerevisiae.

The transfer RNA gene complement of Saccharomyces cerevisiae was utilized for a whole-genome analysis of the deviation from a neutral usage of pyrimidine-ending cognate codons, that is, codons read by a single tRNA species having either inosine or guanosine as the first anticodon base. Mutational pressure at the wobble position was estimated from the base composition of the noncoding portion of the yeast genome. The selective pressure for translational efficiency was inferred from the degree of codon adaptation to tRNA gene redundancy and from mRNA abundance data derived from yeast transcriptome analysis. Amino acid conservation in orthologous comparisons with wholly sequenced microbial genomes was used to estimate translational accuracy requirements. A close correspondence was observed between the usage of wobble position pyrimidines and the frequency predicted by mutational bias. However, in the case of four cognate pairs (Gly: ggu/ggc; Asn: aau/aac; Phe: uuu/uuc; Tyr: uau/ uac) all read by guanosine-starting anticodons, we found evidence for a strong selective pressure driven by translational efficiency. Only for the glycine pair, wobble pyrimidine choice also appears to fulfill a translational accuracy requirement. Wobble pyrimidine selection is strictly related to the number of hydrogen bonds formed by alternative cognate codons: whenever a different number of hydrogen bonds can be formed at the wobble position, there is selection against six- or nine-hydrogen-bonded codon-anticodon pairs. Our results indicate that an intrinsic codon preference, critically dependent on the stability of codon-anticodon interaction and mainly reflecting selection for the optimization of translational efficiency, is built into the translational apparatus.

Codon↗

PubMed1985

Codon usage and tRNA content in unicellular and multicellular organisms.

Choices of synonymous codons in unicellular organisms are here reviewed, and differences in synonymous codon usages between Escherichia coli and the yeast Saccharomyces cerevisiae are attributed to differences in the actual populations of isoaccepting tRNAs. There exists a strong positive correlation between codon usage and tRNA content in both organisms, and the extent of this correlation relates to the protein production levels of individual genes. Codon-choice patterns are believed to have been well conserved during the course of evolution. Examination of silent substitutions and tRNA populations in Enterobacteriaceae revealed that the evolutionary constraint imposed by tRNA content on codon usage decelerated rather than accelerated the silent-substitution rate, at least insofar as pairs of taxonomically related organisms were examined. Codon-choice patterns of multicellular organisms are briefly reviewed, and diversity in G+C percentage at the third position of codons in vertebrate genes--as well as a possible causative factor in the production of this diversity--is discussed.

Animals↗

PubMed2002

Various penetrance of familial medullary thyroid carcinoma in patients with RET protooncogene codon 790/791 germline mutations.

OBJECTIVE: To describe a genotype-phenotype correlation in MEN2 families with germline mutations of codons 790/791 and discuss options for the therapeutic management of gene carriers. SUMMARY BACKGROUND DATA: Heredity of MEN2 syndromes is caused by a heterozygous germline mutation in the protooncogene. Rare mutations of codons 790/791 associated with incomplete penetrant MEN2A/FMTC phenotype were reported in five families, contraindicating the prophylactic thyroidectomy for the genetically affected children. METHODS: Forty-five patients with a putative sporadic MTC were screened for germline mutations by direct DNA sequencing. Family members of identified index cases underwent genetic analysis. Gene carriers were examined clinically and biochemically, and all gene carriers underwent prophylactic thyroidectomy. RESULTS: Five index patients were identified, four of whom harbored mutations in codons 790/791 and one in codon 634. In the kindreds, four L790F carriers and one Y791F carrier were detected. The thyroid gland histology of L790F carriers revealed medullary thyroid carcinoma in two patients (aged 29 and 50 years) and C-cell hyperplasia in two additional patients (aged 9 and 16 years). The Y791F carrier had a normal histology. CONCLUSIONS: Codon 790/791 mutations had diverse penetrance. Whereas prophylactic thyroidectomy in children is a justifiable approach for codon 790 mutation carriers, the indication for thyroidectomy should depend on the clinical course of codon 791 carriers.

Adult↗

PubMed2003

Folding type specific secondary structure propensities of synonymous codons.

We have proposed new amino acid secondary structure propensities in proteins with different folding types based on synonymous codons. They have been derived from 200 all alpha, all beta, alpha/beta, and alpha + beta proteins of known structures and their coding genes. The secondary structure propensities of the same codon in gene coding for different folding type proteins are not the same. For instance, amino acid Ile coded by AUU is indifferent to form the alpha unit in the alpha + beta protein class, but it is a former and a breaker for the alpha unit in the all alpha protein class and the alpha/beta class, respectively. On the other hand, the secondary structure propensities of different synonymous codons in the coding genes with the same folding type are also not all the same. As an example, CGU, CGG, and AGA, which are synonymous codons of Arg, are preferential to form the alpha unit in all alpha proteins, while CGA is an alpha unit breaker and the other two synonymous codons, CGC and AGG, are indifferent to form or break the alpha unit. As a result, protein secondary structure information contained both in mRNA sequences and in amino acid sequences has been introduced in these codon-based amino acid secondary structure propensities. These codon-based amino acid secondary structure propensities are helpful to in vitro protein design and protein secondary structure prediction.

Amino Acid Sequence↗

PubMed1986

Natural selection versus primitive gene structure as determinant of codon usage.

Different codons are not utilized equally in known gene sequences. One of the important biases of codon usage is observed in the form of an enrichment of RNY codons, especially within RNN codon families. Such biases could represent the residue of a primitive repeating-RNY gene structure, or the outcome of natural selection, or both. Analyses based on the rates of silent substitutions, the frequencies of base doublets, and synonymous codon ratios for Escherichia coli, yeast, Drosophila and Xenopus proteins have been performed. The results rule out any significant support for a primitive repeating-RNY or repeating-RRY gene structure, and establish the important role of natural selection in determining the choice of codons. With strong intervention by natural selection, the relationship between primitive gene structure and codon usage necessarily becomes minimal.

Animals↗

PubMed2005

Factors influencing the synonymous codon and amino acid usage bias in AT-rich Pseudomonas aeruginosa phage PhiKZ.

To reveal how the AT-rich genome of bacteriophage PhiKZ has been shaped in order to carry out its growth in the GC-rich host Pseudomonas aeruginosa, synonymous codon and amino acid usage bias of PhiKZ was investigated and the data were compared with that of P. aeruginosa. It was found that synonymous codon and amino acid usage of PhiKZ was distinct from that of P. aeruginosa. In contrast to P. aeruginosa, the third codon position of the synonymous codons of PhiKZ carries mostly A or T base; codon usage bias in PhiKZ is dictated mainly by mutational bias and, to a lesser extent, by translational selection. A cluster analysis of the relative synonymous codon usage values of 16 myoviruses including PhiKZ shows that PhiKZ is evolutionary much closer to Escherichia coli phage T4. Further analysis reveals that the three factors of mean molecular weight, aromaticity and cysteine content are mostly responsible for the variation of amino acid usage in PhiKZ proteins, whereas amino acid usage of P. aeruginosa proteins is mainly governed by grand average of hydropathicity, aromaticity and cysteine content. Based on these observations, we suggest that codons of the phage-like PhiKZ have evolved to preferentially incorporate the smaller amino acid residues into their proteins during translation, thereby economizing the cost of its development in GC-rich P. aeruginosa.

Amino Acids↗

PubMed2003

Glutathione S-transferase GSTM1, GSTT1 and p53 codon 72 polymorphisms in human tumor cells.

The genes of the glutathione S-transferase (GST) family encode enzymes that appear to be critical in cellular protection against the cytotoxic effects, whereas p53 is a tumor suppressor gene. Despite a large number of studies on germline polymorphisms of GSTM1, GSTT1 and p53 genes, there have been very few reports on genotyping of these genes in human malignant tumor cells. In this study, we investigated GSTM1, GSTT1 and p53 codon 72 polymorphisms in a variety of human tumor cell lines originating from different organs to clarify tissue-specific polymorphic frequency of these genes in human solid tumors. The GSTM1 and GSTT1 genetic polymorphisms were evaluated using multiplex PCR techniques and PCR-RFLP analysis was conducted to identify p53 codon 72 genotypes. Gene expression of GSTM1 or GSTT1 was detected by RT-PCR in the cells with respective present genotype for each. Polymorphisms of p53 codon 72 detected by PCR-RFLP were also confirmed using SSCP and sequence analyses. GSTM1 and GSTT1 genotypes were various in 104 cell lines examined. Null GSTM1 genotype was dominant in small cell lung, kidney and ovarian carcinoma cells, whereas null GSTT1 genotype was dominant in cervical and endometrial carcinoma cells. GSTM1 and GSTT1 genotypes in ovarian carcinoma cells were quite similar to those in small cell lung carcinoma cells. Polymorphic frequency of p53 codon 72 was also various among the cells, however, the Pro allele was found in only 1 of 6 kidney, 14 cervical and 4 endometrial carcinoma cell lines. There was a significant difference in GSTM1 and p53 genotypes between 34 small cell and 24 non small cell lung carcinoma cells (P < 0.01). Combined study on the distribution of GSTM1, GSTT1 and p53 genotypes revealed that null GSTM1 genotype was associated with the Arg allele of p53 codon 72 in 58 lung carcinoma cells and null GSTT1 genotype was associated with the Pro/Pro homozygote in 104 tumor cell lines examined. This is the first study examining GSTM1, GSTT1 and p53 codon 72 polymorphisms in a variety of human solid tumor cells and suggesting that polymorphic frequency of these genes may be tissue- and organ-specific. The molecular interaction between GST gene defects and p53 codon 72 genotype in the development of human malignant tumors should be further investigated.

Codon↗

PubMed2006

Identification of the functional initiation codons of a phase-variable gene of Haemophilus influenzae, lic2A, with the potential for differential expression.

Simple sequence repeats located within reading frames mediate phase-variable ON/OFF switches in gene expression by generating frameshifts. Multiple translation initiation codons in different reading frames are found upstream of most Haemophilus influenzae tetranucleotide repeat tracts, raising the possibility of multiple active reading frames and more than two levels of gene expression for these loci. Phase variation between three levels of gene expression (strong, weak, and none) was observed when lic2A was fused to a lacZ reporter gene. The lic2A 5' CAAT repeat tract is preceded by four 5' ATG codons (x, y, z1, and z2) in two reading frames. Each of these initiation codons was inactivated by site-directed mutagenesis. Strong expression from frame 1 was associated with x but not y. Weak expression from frame 2 was mainly dependent on the z2 codon, and there was no expression from frame 3. Using monoclonal antibodies specific for a digalactoside epitope of lipopolysaccharide whose synthesis requires Lic2A, two levels (strong and undetectable) of antibody reactivity were detected, suggesting that weak expression of lic2A is not discernible at the phenotypic level. Inactivation of the x initiation codon resulted in loss of strong expression of the digalactoside epitope and elevated killing by human serum. The failure to detect more than two phenotypes for lic2A, despite clear evidence of weak expression from the z1/z2 initiation codons, leaves open the question of whether or not multiple initiation codons are associated with more complex patterns of phenotypic variation rather than classical phase-variable switching between two phenotypes.

Amino Acid Sequence↗

PubMed1989

Bacillus subtilis mutant allele sup-3 causes lysine insertion at ochre codons: use of sup-3 in studies of translational attenuation.

The mutation sup-3 in Bacillus subtilis suppresses ochre (TAA) mutations at each of three codons in the 5' end of the cat-86 coding sequence. The suppressor is shown to insert lysine at ochre codons. The efficiency of suppression by sup-3 is about 15%, as determined by changing a cat-86 Lys codon (codon 12) to an ochre codon and measuring the level of CAT in the suppressor-containing strain. The results obtained are discussed in light of previous observations that ochre mutations at cat leader codons 2 and 3 can be phenotypically suppressed by sup-3, whereas ochre mutations at leader codons 4 and 5 cannot. Translation of the cat leader is essential to inducible expression of cat. Our data support the interpretation that the nature of amino acids 2 through 5 of the leader peptide contributes to determining whether chloramphenicol can stall a ribosome in the leader, which in turn leads to induction of cat expression.

Amino Acid Sequence↗

PubMed1989

Translation rates of individual codons are not correlated with tRNA abundances or with frequencies of utilization in Escherichia coli.

We analyzed 12 individual codons, which differed widely with respect to the frequency of use in Escherichia coli and the abundance of the corresponding tRNAs, for their influence on the coupling between transcription and translation. This was probed by determining the effects of codon substitutions in the leader peptide gene on transcription past the pyrE attenuator, as described previously by Bonekamp et al. (F. Bonekamp, H. D. Andersen, T. Christensen, and K. F. Jensen, Nucleic Acids Res. 13:4113-4123, 1985). In principle, the results revealed that either RNA polymerase or the (leading) ribosomes pass the different codon strings at different rates. However, under the assumption that the rate of transcription elongation is unaffected by the sequence changes, the results may be interpreted as indicating that different codons are translated at different rates and that these rates do not generally reflect the concentrations of the corresponding tRNAs or the frequencies with which the codons are used in E. coli. Moreover, it seems that codon synonyms that are served by the same isoaccepting tRNA species can deviate as much from each other in translational behavior as synonymous codons that are served by isoacceptors present in the cell in widely different amounts can.

Base Sequence↗

PubMed1990

tRNA(Trp) translation of leader peptide codon 12 and other factors that regulate expression of the tryptophanase operon.

Tryptophanase (tna) operon expression in Escherichia coli is induced by tryptophan. This response is mediated by features of a 319-base-pair leader region preceding the major structural genes of the operon. Translation of the coding region (tnaC) for a 24-amino-acid leader peptide is essential for induction. We have used site-directed mutagenesis to investigate the role of the single Trp codon, at position 12 in tnaC, in regulation of the operon. Codon 12 was changed to either a UAG or UGA stop codon or to a CGG arginine codon. Induction by tryptophan was eliminated by any of these changes. Studies with suppressor tRNAs indicated that tRNA(Trp) translation of codon 12 in tnaC is essential for induction of the operon. Reduction of tna expression by a miaA mutation supports a role for translation by tRNA(Trp) in regulation of the operon. Frameshift mutations and suppression that allows translation of tnaC to proceed beyond the normal stop codon result in constitutive tna operon expression. Deletion of a potential site for Rho factor utilization just beyond tnaC also results in partial constitutive expression. These studies suggest possible models for tryptophan induction of tna operon expression involving tRNA(Trp)-mediated frame shifting or readthrough at the tnaC stop codon.

Chromosome Deletion↗

PubMed1999

Translation initiation at the CUU codon is mediated by the internal ribosome entry site of an insect picorna-like virus in vitro.

AUG-unrelated translation initiation was found in an insect picorna-like virus, Plautia stali intestine virus (PSIV). The positive-strand RNA genome of the virus contains two nonoverlapping open reading frames (ORFs). The capsid protein gene is located in the 3'-proximal ORF and lacks an AUG initiation codon. We examined the translation mechanism and the initiation codon of the capsid protein gene by using various dicistronic and monocistronic RNAs in vitro. The capsid protein gene was translated cap independently in the presence of the upstream cistron, indicating that the gene is translated by internal ribosome entry. Deletion analysis showed that the internal ribosome entry site (IRES) consisted of approximately 250 bases and that its 3' boundary extended slightly into the capsid-coding region. The initiation codon for the IRES-mediated translation was identified as the CUU codon, which is located just upstream of the 5' terminus of the capsid-coding region by site-directed mutagenesis. In vitro translation assays of monocistronic RNAs lacking the 5' part of the IRES showed that this CUU codon was not recognized by scanning ribosomes. This suggests that the PSIV IRES can effectively direct translation initiation without stable codon-anticodon pairing between the initiation codon and the initiator methionyl-tRNA.

Amino Acid Sequence↗

PubMed2006

Support vector machine for classification of meiotic recombination hotspots and coldspots in Saccharomyces cerevisiae based on codon composition.

BACKGROUND: Meiotic double-strand breaks occur at relatively high frequencies in some genomic regions (hotspots) and relatively low frequencies in others (coldspots). Hotspots and coldspots are receiving increasing attention in research into the mechanism of meiotic recombination. However, predicting hotspots and coldspots from DNA sequence information is still a challenging task. RESULTS: We present a novel method for classification of hot and cold ORFs located in hotspots and coldspots respectively in Saccharomyces cerevisiae, using support vector machine (SVM), which relies on codon composition differences. This method has achieved a high classification accuracy of 85.0%. Since codon composition is a fusion of codon usage bias and amino acid composition signals, the ability of these two kinds of sequence attributes to discriminate hot ORFs from cold ORFs was also investigated separately. Our results indicate that neither codon usage bias nor amino acid composition taken separately performed as well as codon composition. Moreover, our SVM based method was applied to the full genome: We predicted the hot/cold ORFs from the yeast genome by using cutoffs of recombination rate. We found that the performance of our method for predicting cold ORFs is not as good as that for predicting hot ORFs. Besides, we also observed a considerable correlation between meiotic recombination rate and amino acid composition of certain residues, which probably reflects the structural and functional dissimilarity between the hot and cold groups. CONCLUSION: We have introduced a SVM-based novel method to discriminate hot ORFs from cold ones. Applying codon composition as sequence attributes, we have achieved a high classification accuracy, which suggests that codon composition has strong potential to be used as sequence attributes in the prediction of hot and cold ORFs.

Algorithms↗

PubMed2003

Different mutation patterns of atovaquone resistance to Plasmodium falciparum in vitro and in vivo: rapid detection of codon 268 polymorphisms in the cytochrome b as potential in vivo resistance marker.

BACKGROUND: Resistance of Plasmodium falciparum to atovaquone in vitro and in vivo has been associated to mutations in the parasite cytochrome b gene. METHODS: Cultures were sequentially subjected to increasing doses of atovaquone alone or in combination with cycloguanil and the cytochrome b gene was sequenced. Additionally, we investigated the parasite cytochrome b gene of a patient returning from Mali with Malarone treatment failure in vivo. RESULTS: All strains that survived atovaquone concentrations in vitro of 2 x 10(-8) to 2 x 10(7) M showed the M133I mutation and one strain with the highest atovaquone concentration the additional mutation L171F. Sequencing of the in vivo treatment failure revealed a point mutation at codon 268 resulting in an amino acid change from tyrosine to serine. Based on the repeated emergence of mutations at codon 268, but no detection of alterations at codon 133 in vivo, we developed a detection method for the diagnostic of codon 268 polymorphisms as a potential atovaquone/proguanil resistance marker. A nested PCR with 3 different pairs of primers for the second round was designed. Each product was digested with restriction enzymes, capable to distinguish the wild type from the two reported mutations at codon 268. CONCLUSION: Mutations at codon 268 of the parasite cytochrome bc1 gene are associated with atovaquone/proguanil treatment failure in vivo and can be used as potential resistance marker This method provides a novel and robust tool to investigate the relevance of codon 268 polymorphisms as resistance marker and to monitor the further emergence of atovaquone/proguanil resistance.

Animals↗

PubMed2005

Do universal codon-usage patterns minimize the effects of mutation and translation error?

BACKGROUND: Do species use codons that reduce the impact of errors in translation or replication? The genetic code is arranged in a way that minimizes errors, defined as the sum of the differences in amino-acid properties caused by single-base changes from each codon to each other codon. However, the extent to which organisms optimize the genetic messages written in this code has been far less studied. We tested whether codon and amino-acid usages from 457 bacteria, 264 eukaryotes, and 33 archaea minimize errors compared to random usages, and whether changes in genome G+C content influence these error values. RESULTS: We tested the hypotheses that organisms choose their codon usage to minimize errors, and that the large observed variation in G+C content in coding sequences, but the low variation in G+U or G+A content, is due to differences in the effects of variation along these axes on the error value. Surprisingly, the biological distribution of error values has far lower variance than randomized error values, but error values of actual codon and amino-acid usages are actually greater than would be expected by chance. CONCLUSION: These unexpected findings suggest that selection against translation error has not produced codon or amino-acid usages that minimize the effects of errors, and that even messages with very different nucleotide compositions somehow maintain a relatively constant error value. They raise the question: why do all known organisms use highly error-minimizing genetic codes, but fail to minimize the errors in the mRNA messages they encode?

Animals↗

PubMed2000

Lack of association of nonautoimmune hyperfunctioning thyroid disorders and a germline polymorphism of codon 727 of the human thyrotropin receptor in a European Caucasian population.

Constitutively activating mutations of the human TSH receptor (hTSHR) gene have been implicated as a major cause of hyperfunctioning nonautoimmune thyroid disease. However, significant geographic differences in the prevalence of these mutations have been observed. Recently, a high frequency of a germline polymorphism at codon 727 of the cytoplasmic tail of the hTSHR has been demonstrated in patients with toxic multinodular goiter. In the present study we assessed whether the codon 727 polymorphism is associated with hyperfunctioning thyroid adenomas. PCR followed by restriction enzyme digestion were used to genotype a total of 128 European Caucasian patients with toxic nonautoimmune thyroid disease (83 with toxic adenoma, 31 with toxic multinodular goiter, and 14 with disseminated autonomy) and to compare their codon 727 polymorphism frequencies with those of 99 healthy controls and 108 patients with Graves' disease. All individuals were drawn from an identical ethnic background. Sequencing of PCR products was used to confirm the mutation analysis. We found no significant differences in codon 727 polymorphism frequencies between patients with autonomously functioning thyroid disorders (13.3%) and the healthy control group (16.2%; P = 0.57). Moreover, the subtypes of toxic nonautoimmune thyroid disease (toxic adenoma, 13.2%; multinodular goiter, 9.6%; disseminated autonomy, 21.4%) were not related to significant differences in codon 727 polymorphism frequencies compared with the healthy control group (P = 0.67, P = 0.40, and P = 0.70, respectively). Additionally, there were no significant differences between patients with Graves' disease (21.3%) and healthy controls (P = 0.38). In conclusion, our data do not support an association between the codon 727 polymorphism of the hTSHR and toxic thyroid adenomas or toxic multinodular goiter in our study population. Thus, the codon 727 polymorphism of the hTSHR does not appear to be involved in the evolution of autoimmune or nonautoimmune hyperthyroidism in the European Caucasian population.

Adenoma↗