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PubMed2003

The genome of Campylobacter jejuni: codon and amino acid usage.

The genes from the genome of the AT-rich bacterium Campylobacter jejuni were analysed and characterised with respect to usage and amino acid usage. Codon usage is generally biased for all amino acids having synonymous codons, so that AT-rich synonyms are most frequently used. Markov chain analysis showed that codon bias and over- or underrepresentation of the corresponding tri-letter words are not related. Predicted secondary structure, lipophilicity, codon position within the gene, strand, and position on the (+)-strand were all shown to be determinants of codon usage, and these effects were in part directly explained by compositional phenomena. Codon context and the GC-content at the wobble position of the fourfold degenerate sites exert indirect effects on codon usage. The factors that affect codon usage seem to affect all amino acids, rather than selected amino acids. The usage of amino acids correlates well with the GC-content of genes, i.e. usage of amino acids encoded by GC-rich codons increases with GC-content and vice versa.

Amino Acids↗

PubMedDate not supplied

Codon 201(Gly) polymorphic type of the DCC gene is related to disseminated neuroblastoma.

The deleted in colorectal carcinoma (DCC) gene is a potential tumor-suppressor gene on chromosome 18q21.3. The relatively high frequency of loss of heterozygosity (LOH) and loss of expression of this gene in neuroblastoma, especially in the advanced stages, imply the possibility of involvement of the DCC gene in progression of neuroblastoma. However, only few typical mutations have been identified in this gene, indicating that other possible mechanisms for the inactivation of this gene may exist. A polymorphic change (Arg to Gly) at DCC codon 201 is related to advanced colorectal carcinoma and increases in the tumors with absent DCC protein expression. In order to understand whether this change is associated with the development or progression of neuroblastoma, we investigated codon 201 polymorphism of the DCC gene in 102 primary neuroblastomas by polymerase chain reaction single-strand conformation polymorphism. We found no missense or nonsense mutations, but a polymorphic change from CGA (Arg) to GGA (Gly) at codon 201 resulting in three types of polymorphism: codon 201(Gly) type, codon 201(Arg/Gly) type, and codon 201(Arg) type. The codon 201(Gly) type occurred more frequently in disseminated (stages IV and IVs) neuroblastomas (72%) than in localized (stages I, II, and III) tumors (48%) (P=.035), and normal controls (38%) (P=.024). In addition, the codon 201(Gly) type was significantly more common in tumors found clinically (65%) than in those found by mass screening (35%) (P=.002). The results suggested that the codon 201(Gly) type of the DCC gene might be associated with a higher risk of disseminating neuroblastoma.

Adolescent↗

PubMed1997

Messenger RNA release from ribosomes during 5'-translational blockage by consecutive low-usage arginine but not leucine codons in Escherichia coli.

In '5'-translational blockage', significantly reduced yields of proteins are synthesized in Escherichia coli when consecutive low-usage codons are inserted near translation starts of messages (with reduced or no effect when these same codons are inserted downstream). We tested the hypothesis that ribosomes encountering these low-usage codons near the translation start prematurely release the mRNA. RNA from polysome gradients was fractionated into pools of polysomes and monosomes and a ribosome-free pool. New hybridization probes, called 'molecular beacons', and standard slot blots were used to detect test messages containing either consecutive low-usage AGG (arginine) or synonymous high-usage CGU insertions near the 5' end. The results show an approximately twofold increase in the ratio of free to bound mRNA when the low-usage codons were present in the message compared with when high-usage codons were present. In contrast, there was no difference in the ratio of free to bound mRNA when consecutive low-usage CUA or high-usage CUG (leucine) codons were inserted or when the arginine codons were inserted near the 3' end. These data indicate that at least some mRNA is released from ribosomes during 5'-translational blockage by arginine but not leucine codons, and they support proposals that premature termination of translation can occur in some conditions in vivo in the absence of a stop codon.

Arginine↗

PubMed2000

The accuracy of codon recognition by polypeptide release factors.

The precision with which individual termination codons in mRNA are recognized by protein release factors (RFs) has been measured and compared with the decoding of sense codons by tRNA. An Escherichia coli system for protein synthesis in vitro with purified components was used to study the accuracy of termination by RF1 and RF2 in the presence or absence of RF3. The efficiency of factor-dependent termination at all sense codons differing from any of the three stop codons by a single mutation was measured and compared with the efficiency of termination at the three stop codons. RF1 and RF2 discriminate against sense codons related to stop codons by between 3 and more than 6 orders of magnitude. This high level of accuracy is obtained without energy-driven error correction (proofreading), in contrast to codon-dependent aminoacyl-tRNA recognition by ribosomes. Two codons, UAU and UGG, stand out as hotspots for RF-dependent premature termination.

Codon, Terminator↗

PubMed1988

Human apolipoprotein B (apoB) mRNA: identification of two distinct apoB mRNAs, an mRNA with the apoB-100 sequence and an apoB mRNA containing a premature in-frame translational stop codon, in both liver and intestine.

Human apolipoprotein B (apoB) is present in plasma as two separate isoproteins, designated apoB-100 (512 kDa) and apoB-48 (250 kDa). ApoB is encoded by a single gene on chromosome 2, and a single nuclear mRNA is edited and processed into two separate apoB mRNAs. A 14.1-kilobase apoB mRNA codes for apoB-100, and the second mRNA, which codes for apoB-48, contains a premature stop codon generated by a single base substitution of cytosine to uracil at nucleotide 6538, which converts the translated CAA codon coding for the amino acid glutamine at residue 2153 in apoB-100 to a premature in-frame stop codon (UAA). Two 30-base synthetic oligonucleotides (nucleotides 6523-6552 of apoB mRNA), designated apoB-Stop and apoB-Gln, were synthesized containing the complementary sequence to the stop codon (UAA) and glutamine codon (CAA), respectively. Analysis of intestinal apoB mRNA by hybridization with apoB-Stop and apoB-Gln probes and sequence analysis of apoB clones in two independent human small intestinal cDNA libraries established that intestinal apoB mRNA contained both the apoB mRNA that codes for apoB-100 and the apoB mRNA containing the premature in-frame stop codon, which codes for apoB-48. Investigation of hepatic apoB mRNA and two hepatic cDNA libraries by hybridization with the apoB-Stop and apoB-Gln synthetic probes as well as by cDNA sequencing revealed that liver apoB mRNA also contains both the apoB-100 mRNA and the apoB-48 mRNA containing the stop codon. The combined results from these studies establish that both human intestine and liver contain the two distinct apoB mRNAs, an mRNA that codes for apoB-100 and an apoB mRNA that contains the premature stop codon, which codes for apoB-48. The premature in-frame stop codon is not tissue specific and is present in both human liver and intestine.

Apolipoprotein B-100↗

PubMed1991

TTA codons in some genes prevent their expression in a class of developmental, antibiotic-negative, Streptomyces mutants.

In Streptomyces coelicolor A3(2) and the related species Streptomyces lividans 66, aerial mycelium formation and antibiotic production are blocked by mutations in bldA, which specifies a tRNA(Leu)-like gene product which would recognize the UUA codon. Here we show that phenotypic expression of three disparate genes (carB, lacZ, and ampC) containing TTA codons depends strongly on bldA. Site-directed mutagenesis of carB, changing its two TTA codons to CTC (leucine) codons, resulted in bldA-independent expression; hence the bldA product is the principal tRNA for the UUA codon. Two other genes (hyg and aad) containing TTA codons show a medium-dependent reduction in phenotypic expression (hygromycin resistance and spectinomycin resistance, respectively) in bldA mutants. For hyg, evidence is presented that the UUA codon is probably being translated by a tRNA with an imperfectly matched anticodon, giving very low levels of gene product but relatively high resistance to hygromycin. It is proposed that TTA codons may be generally absent from genes expressed during vegetative growth and from the structural genes for differentiation and antibiotic production but present in some regulatory and resistance genes associated with the latter processes. The codon may therefore play a role in developmental regulation.

Anti-Bacterial Agents↗

PubMed1997

Evolution of codon usage bias in Drosophila.

We first review what is known about patterns of codon usage bias in Drosophila and make the following points: (i) Drosophila genes are as biased or more biased than those in microorganisms. (ii) The level of bias of genes and even the particular pattern of codon bias can remain phylogenetically invariant for very long periods of evolution. (iii) However, some genes, even very tightly linked genes, can change very greatly in codon bias across species. (iv) Generally G and especially C are favored at synonymous sites in biased genes. (v) With the exception of aspartic acid, all amino acids contribute significantly and about equally to the codon usage bias of a gene. (vi) While most individual amino acids that can use G or C at synonymous sites display a preference for C, there are exceptions: valine and leucine, which prefer G. (vii) Finally, smaller genes tend to be more biased than longer genes. We then examine possible causes of these patterns and discount mutation bias on three bases: there is little evidence of regional mutation bias in Drosophila, mutation bias is likely toward A+T (the opposite of codon usage bias), and not all amino acids display the preference for the same nucleotide in the wobble position. Two lines of evidence support a selection hypothesis based on tRNA pools: highly biased genes tend to be highly and/or rapidly expressed, and the preferred codons in highly biased genes optimally bind the most abundant isoaccepting tRNAs. Finally, we examine the effect of bias on DNA evolution and confirm that genes with high codon usage bias have lower rates of synonymous substitution between species than do genes with low codon usage bias. Surprisingly, we find that genes with higher codon usage bias display higher levels of intraspecific synonymous polymorphism. This may be due to opposing effects of recombination.

Animals↗

PubMed2002

Polyamines enhance synthesis of the RNA polymerase sigma 38 subunit by suppression of an amber termination codon in the open reading frame.

The mechanisms by which polyamines stimulate synthesis of the RNA polymerase sigma(38) subunit in Escherichia coli were studied. Polyamine stimulation was observed only in strains in which the 33rd codon of RpoS mRNA is a UAG termination codon instead of a CAG codon for glutamine in wild-type E. coli. Readthrough of the termination codon by Gln-tRNA(supE) was stimulated by polyamines. This stimulation was found to be caused by an increase in both the level of suppressor tRNA(supE) and the binding affinity of Gln-tRNA(supE) for ribosomes. The stimulatory effect was observed with a UAG termination codon but not with UGA and UAA codons. Readthrough of the UAG termination codon at the 270th amino acid position of RpoS mRNA was also stimulated by polyamines, indicating that polyamines stimulate readthrough of a UAG codon regardless of its location within the RpoS mRNA. When cell viability of an E. coli strain having a termination codon in the 33rd position of RpoS mRNA was compared using cells cultured with or without putrescine, it was higher in cells cultured with putrescine than in cells cultured without putrescine. The level of sigma(38) subunit in the cells cultured with putrescine was higher than that in cells cultured without putrescine on days 2, 4, and 8, but the level of sigma(70) subunit was almost the same in cells cultured with or without putrescine. These results confirm that elevated expression of the rpoS gene is important for cell viability at late stationary phase.

Base Sequence↗

PubMed1992

Diagrammatization of codon usage in 339 human immunodeficiency virus proteins and its biological implication.

The occurrence frequencies of bases A (adenine), C (cytosine, G (guanine), and T (thymine) occurring in the 1st, 2nd, and 3rd codon positions in the codon usage table of viral genes for the 339 human immunodeficiency virus (HIV) proteins compiled recently have been calculated and diagrammatized. For comparison, the corresponding diagrammatic representations for the 2681 human proteins from the codon usage table for primate genes are also presented. The analyzed results based on these characteristic diagrams indicate that considerably similar features have been found between HIV and human proteins for the 1st and 2nd codon positions; i.e., they are all occupied predominantly by purine, especially base A. However, a significant difference in the 3rd codon position between HIV and human proteins has been observed; i.e., human proteins are of high C + G content and low A + G content in the 3rd codon position, whereas the case is just the opposite for HIV proteins. The biological implication of such a duality on the codon bias of HIV against human proteins is discussed. It is suggested that the 1st and 2nd codon positions can be termed as the structure-determining position, and the 3rd codon position termed as the species-determining position. The diagrammatic representation and analysis method described here possess a great potential for the study of molecular evolution from the viewpoint of the genetic code for which data have been accumulated rapidly and will continue to grow at a much faster pace.

Base Composition↗

PubMed2003

Codon pairs in the genome of Escherichia coli.

MOTIVATION: The effect of two neighboring codons (codon pairs) on gene expression is mediated via the interaction of their cognate tRNAs occupying the two functional ribosomal sites during the translation elongation step. For steric reasons it is reasonable to assume that not all combinations of codons and therefore of tRNAs are equally favorable when situated on the ribosome surface. Aiming of identifying preferential and rare codon pairs, we have determined the frequency of occurrence of all possible combinations of codon pairs in the entire genome of Escherichia coli (E.coli). RESULTS: The frequency of occurrence of the 3904 codon pairs comprising both sense:sense and sense:stop codon pairs in the full set of E.coli 4289 ORFs was found to vary from zero to 4913 times. For most of the pairs we have observed a significant difference between the real and statistically predicted frequency of occurrence. The analysis of 334 highly expressed and 303 poorly expressed E.coli genes showed that codon pair usage is different for the two gene categories. Using an especially defined criterion (Delta(REG)), the codon pairs are classified as 'hypothetically attenuating' (HAP) and 'hypothetically non-attenuating' (HNAP) and their possible effect on translation is discussed. AVAILABILITY: The program used in this study is available at http://www.bio21.bas.bg/codonpairs/

Algorithms↗

PubMed1992

Novel in-frame two codon translational hop during synthesis of bovine placental lactogen in a recombinant strain of Escherichia coli.

A recombinant Escherichia coli strain was constructed for the overexpression of bovine placental lactogen (bPL), using a bPL structural gene containing 9 of the rare arginine codons AGA and AGG. When high level bPL synthesis was induced in this strain, cell growth was inhibited and bPL accumulated to less than 10% of total cell protein. In addition, about 2% of the recombinant bPL produced from this strain exhibited an altered trypsin digestion pattern. Amino acid residues 74 through 109 normally produce 2 tryptic peptides, but the altered form of bPL lacked these two peptides and instead had a new peptide which was missing arginine residue 86 and one of the two flanking leucine residues. The codon for arginine residue 86 was AGG and the codons for the flanking leucine residues 85 and 87 were TTG. When 5 of the 9 AGA and AGG codons in the bPL structural gene were changed to more preferred arginine codons, cell growth was not inhibited and bPL accumulated to about 30% of total cell protein. When bPL was purified from this modified strain, which included changing the arginine codon at position 86 from AGG to CGT, none of the altered form of bPL was produced. These observations are consistent with a model in which translational pausing occurs at the arginine residue 86 AGG codon because the corresponding arginyl-tRNA species is reduced by the high level of bPL synthesis, and a translational hop occurs from the leucine residue 85 TTG codon to the leucine residue 87 TTG codon. This observation represents the first report of an error in protein synthesis due to an in-frame translational hop within an open reading frame.

Amino Acid Sequence↗

PubMed1996

Codon-reading specificity of an unmodified form of Escherichia coli tRNA1Ser in cell-free protein synthesis.

Unmodified tRNA molecules are useful for many purposes in cell-free protein biosynthesis, but there is little information about how the lack of tRNA post-transcriptional modifications affects the coding specificity for synonymous codons. In the present study, we prepared an unmodified form of Escherichia coli tRNA1Ser, which originally has the cmo5UGA anticodon (cmo5U = uridine 5-oxyacetic acid) and recognizes the UCU, UCA and UCG codons. The codon specificity of the unmodified tRNA was tested in a cell-free protein synthesis directed by designed mRNAs under competition conditions with the parent tRNA1Ser. It was found that the unmodified tRNA with the UGA anti-codon recognizes the UCA codon nearly as efficiently as the modified tRNA. The unmodified tRNA recognized the UCU codon with low, but detectable efficiency, whereas no recognition of the UCC and UCG codons was detected. Therefore, the absence of modifications makes this tRNA more specific to the UCA codon by remarkably reducing the efficiencies of wobble reading of other synonymous codons, without a significant decrease in the UCA reading efficiency.

Amino Acid Sequence↗

PubMed2001

Misreading of termination codons in eukaryotes by natural nonsense suppressor tRNAs.

Translational stop codon readthrough provides a regulatory mechanism of gene expression that is extensively utilised by positive-sense ssRNA viruses. The misreading of termination codons is achieved by a variety of naturally occurring suppressor tRNAs whose structure and function is the subject of this survey. All of the nonsense suppressors characterised to date (with the exception of selenocysteine tRNA) are normal cellular tRNAs that are primarily needed for reading their cognate sense codons. As a consequence, recognition of stop codons by natural suppressor tRNAs necessitates unconventional base pairings in anticodon-codon interactions. A number of intrinsic features of the suppressor tRNA contributes to the ability to read non-cognate codons. Apart from anticodon-codon affinity, the extent of base modifications within or 3' of the anticodon may up- or down-regulate the efficiency of suppression. In order to out-compete the polypeptide chain release factor an absolute prerequisite for the action of natural suppressor tRNAs is a suitable nucleotide context, preferentially at the 3' side of the suppressed stop codon. Three major types of viral readthrough sites, based on similar sequences neighbouring the leaky stop codon, can be defined. It is discussed that not only RNA viruses, but also the eukaryotic host organism might gain some profit from cellular suppressor tRNAs.

Animals↗

PubMed2002

Synonymous codon usage is subject to selection in thermophilic bacteria.

The patterns of synonymous codon usage, both within and among genomes, have been extensively studied over the past two decades. Despite the accumulating evidence that natural selection can shape codon usage, it has not been possible to link a particular pattern of codon usage to a specific external selective force. Here, we have analyzed the patterns of synonymous codon usage in 40 completely sequenced prokaryotic genomes. By combining the genes from several genomes (more than 80 000 genes in all) into a single dataset for this analysis, we were able to investigate variations in codon usage, both within and between genomes. The results show that synonymous codon usage is affected by two major factors: (i) the overall G+C content of the genome and (ii) growth at high temperature. This study focused on the relationship between synonymous codon usage and the ability to grow at high temperature. We have been able to eliminate both phylogenetic history and lateral gene transfer as possible explanations for the characteristic pattern of codon usage among the thermophiles. Thus, these results demonstrate a clear link between a particular pattern of codon usage and an external selective force.

Bacteria↗

PubMed1994

Evolution of codon usage and base contents in kinetoplastid protozoans.

In this study we analyze and compare the trends in codon usage in five representative species of kinetoplastid protozoans (Crithidia fasciculata, Leishmania donovani, L. major, Trypanosoma cruzi and T. brucei), with the purpose of investigating the processes underlying these trends. A principal component analysis shows that the G+C content at the third codon position represents the main source of codon-usage variation, both within species (among genes) and among species. The non-Trypanosoma species exhibit narrow distributions in codon usage, while both Trypanosoma species present large within-species heterogeneity. The three non-Trypanosoma species have very similar codon-usage preferences. These codon preferences are also shared by the highly expressed genes of T. cruzi and to a lesser degree by those of T. brucei. This leads to the conclusion that the codon preferences shared by these species are the ancestral ones in the kinetoplastids. On the other hand, the study of noncoding sequences shows that Trypanosoma species exhibit mutational biases toward A + T richness, while the non-Trypanosoma species present mutational pressure in the opposite direction. These data taken together allow us to infer the origin of the different codon-usage distributions observed in the five species studied. In C. fasciculata and Leishmania, both mutational biases and (translational) selection pull toward G + C richness, resulting in a narrow distribution. In Trypanosoma species the mutational pressure toward A + T richness produced a shift in their genomes that differentially affected coding and noncoding sequences. The effect of these pressures on the third codon position of genes seems to have been inversely proportional to the level of gene expression.

Animals↗

PubMed2006

The repertoire of transfer RNA genes is tuned to codon usage bias in the genomes of Phytophthora sojae and Phytophthora ramorum.

In all, 238 and 155 transfer (t)RNA genes were predicted from the genomes of Phytophthora sojae and P. ramorum, respectively. After omitting pseudogenes and undetermined types of tRNA genes, there remained 208 P. sojae tRNA genes and 140 P. ramorum tRNA genes. There were 45 types of tRNA genes, with distinct anticodons, in each species. Fourteen common anticodon types of tRNAs are missing altogether from the genome in the two species; however, these appear to be compensated by wobbling of other tRNA anticodons in a manner which is tied to the codon bias in Phytophthora genes. The most abundant tRNA class was arginine in both P. sojae and P. ramorum. A codon usage table was generated for these two organisms from a total of 9,803,525 codons in P. sojae and 7,496,598 codons in P. ramorum. The most abundant codon type detected from the codon usage tables was GAG (encoding glutamic acid), whereas the most numerous tRNA gene had a methionine anticodon (CAT). The correlation between the frequencies of tRNA genes and the codon frequencies in protein-coding genes was very low (0.12 in P. sojae and 0.19 in P. ramorum); however, the correlation between amino acid tRNA gene frequency and the corresponding amino acid codon frequency in P. sojae and P. ramorum was substantially higher (0.53 in P. sojae and 0.77 in P. ramorum). The codon usage frequencies of P. sojae and P ramorum were very strongly correlated (0.99), as were tRNA gene frequencies (0.77). Approximately 60% of orthologous tRNA gene pairs in P sojae and P. ramorum are located in regions that have conserved synteny in the two species.

Anticodon↗

PubMed2004

Codon usage bias from tRNA's point of view: redundancy, specialization, and efficient decoding for translation optimization.

The selection-mutation-drift theory of codon usage plays a major role in the theory of molecular evolution by explaining the co-evolution of codon usage bias and tRNA content in the framework of translation optimization. Because most studies have focused only on codon usage, we analyzed the tRNA gene pool of 102 bacterial species. We show that as minimal generation times get shorter, the genomes contain more tRNA genes, but fewer anticodon species. Surprisingly, despite the wide G+C variation of bacterial genomes these anticodons are the same in most genomes. This suggests an optimization of the translation machinery to use a small subset of optimal codons and anticodons in fast-growing bacteria and in highly expressed genes. As a result, the overrepresented codons in highly expressed genes tend to be the same in very different genomes to match the same most-frequent anticodons. This is particularly important in fast-growing bacteria, which have higher codon usage bias in these genes. Three models were tested to understand the choice of codons recognized by the same anticodons, all providing significant fit, but under different classes of genes and genomes. Thus, co-evolution of tRNA gene composition and codon usage bias in genomes seen from tRNA's point of view agrees with the selection-mutation-drift theory. However, it suggests a much more universal trend in the evolution of anticodon and codon choice than previously thought. It also provides new evidence that a selective force for the optimization of the translation machinery is the maximization of growth.

Anticodon↗

PubMed2006

Variation in synonymous codon use and DNA polymorphism within the Drosophila genome.

A strong negative correlation between the rate of amino-acid substitution and codon usage bias in Drosophila has been attributed to interference between positive selection at nonsynonymous sites and weak selection on codon usage. To further explore this possibility we have investigated polymorphism and divergence at three kinds of sites: synonymous, nonsynonymous and intronic in relation to codon bias in D. melanogaster and D. simulans. We confirmed that protein evolution is one of the main explicative parameters for interlocus codon bias variation (r(2) approximately 40%). However, intron or synonymous diversities, which could have been expected to be good indicators of local interference [here defined as the additional increase of drift due to selection on tightly linked sites, also called 'genetic draft' by Gillespie (2000)] did not covary significantly with codon bias or with protein evolution. Concurrently, levels of polymorphism were reduced in regions of low recombination rates whereas codon bias was not. Finally, while nonsynonymous diversities were very well correlated between species, neither synonymous nor intron diversities observed in D. melanogaster were correlated with those observed in D. simulans. All together, our results suggest that the selective constraint on the protein is a stable component of gene evolution while local interference is not. The pattern of variation in genetic draft along the genome therefore seems to be instable through evolutionary times and should therefore be considered as a minor determinant of codon bias variance. We argue that selective constraints for optimal codon usage are likely to be correlated with selective constraints on the protein, both between codons within a gene, as previously suggested, and also between genes within a genome.

Animals↗