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PubMed2003

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

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

Amino Acids↗
PubMed2004

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↗
PubMed1993

Synonymous codon usage in Kluyveromyces lactis.

The nature and variation of synonymous codon usage in 47 open reading frames from Kluyveromyces lactis have been investigated. Using multivariate statistical analysis, a single major trend among K. lactis genes was identified that differentiates among genes by expression level: highly expressed genes have high codon usage bias, while genes of low expression level have low bias. A relatively minor secondary trend differentiates among genes according to G+C content at silent sites. In these respects, K. lactis is similar to both Saccharomyces cerevisiae and Candida albicans, and the same 'optimal' codons appear to be selected in highly expressed genes in all three species. In addition, silent sites in K. lactis and S. cerevisiae have similar G+C contents, but in C. albicans genes they are more A+T-rich. Thus, in all essential features, codon usage in K. lactis is very similar to that in S. cerevisiae, even though silent sites in genes compared between these two species have undergone sufficient mutation to be saturated with changes. We conclude that the factors influencing overall codon usage, namely mutational biases and the abundances of particular tRNAs, have not diverged between the two species. Nevertheless, in a few cases, codon usage differs between homologous genes from K. lactis and S. cerevisiae. The strength of codon usage bias in cytochrome c genes differs considerably, presumably because of different expression patterns in the two species. Two other, linked, genes have very different G+C content at silent sites in the two species, which may be a reflection of their chromosomal locations. Correspondence analysis was used to identify two open reading frames with highly atypical codon usage that are probably not genes.

Base Sequence↗
PubMed2004

Quantitative relationship between synonymous codon usage bias and GC composition across unicellular genomes.

BACKGROUND: Codon usage bias has been widely reported to correlate with GC composition. However, the quantitative relationship between codon usage bias and GC composition across species has not been reported. RESULTS: Based on an informatics method (SCUO) we developed previously using Shannon informational theory and maximum entropy theory, we investigated the quantitative relationship between codon usage bias and GC composition. The regression based on 70 bacterial and 16 archaeal genomes showed that in bacteria, SCUO = -2.06 * GC3 + 2.05*(GC3)2 + 0.65, r = 0.91, and that in archaea, SCUO = -1.79 * GC3 + 1.85*(GC3)2 + 0.56, r = 0.89. We developed an analytical model to quantify synonymous codon usage bias by GC compositions based on SCUO. The parameters within this model were inferred by inspecting the relationship between codon usage bias and GC composition across 70 bacterial and 16 archaeal genomes. We further simplified this relationship using only GC3. This simple model was supported by computational simulation. CONCLUSIONS: The synonymous codon usage bias could be simply expressed as 1+ (p/2)log2(p/2) + ((1-p)/2)log2((l-p)/2), where p = GC3. The software we developed for measuring SCUO (codonO) is available at http://digbio.missouri.edu/~wanx/cu/codonO.

Base Composition↗
PubMed1995

Kinetics of synonymous codon change for an amino acid of arbitrary degeneracy.

The kinetics of synonymous codon change and species divergence is described in a matrix formalism that is equally applicable to all levels of codon degeneracy and all levels of codon or nucleotide bias. Based on the formalism it is possible to calculate the sum of all synonymous substitution rate constants from the observed sequence differences between two species. This sum, the relaxation rate, is equivalent to the Log Det transformation that has recently been proposed as a new measure of evolutionary distance (Lockhardt et al. Mol. Biol. Evol. 11(4):605-612, 1994). The relationship between this measure and the average number of base changes per site (Ks) is discussed. The formalism is tested on some sets of simulated sequence divergence data.

Amino Acids↗
PubMed2002

Shannon information theoretic computation of synonymous codon usage biases in coding regions of human and mouse genomes.

Exonic GC of human mRNA reference sequences (RefSeqs), as well as A, C, G, and T in codon position 3 are linearly correlated with genomic GC. These observations utilize information from the completed human genome sequence and a large, high-quality set of human and mouse coding sequences, and are in accord with similar determinations published by others. A Shannon Information Theoretic measure of bias in synonymous codon usage was developed. When applied to either human or mouse RefSeqs, this measure is nonlinearly correlated with genomic, exonic, and third codon position A, C, G, and T. Information values between orthologous mouse and human RefSeqs are linearly correlated: mouse = 0.092 + 0.55 human. Mouse genes were consistently placed in genomic regions whose GC content was closer to 50% than was the GC content of the human ortholog. Since the (nonlinear) information versus percent GC curve has a minimum at 50% GC and monotonically increases with increasing distance from 50% GC, this phenomenon directly results in the low slope of 0.55. This appears to be a manifestation of an evolutionary strategy for placement of genes in regions of the genome with a GC content that relates synonymous codon bias and protein folding.

Animals↗
PubMed1990

The effect of context on synonymous codon usage in genes with low codon usage bias.

The effect of neighbouring bases on the usage of synonymous codons in genes with low codon usage bias in yeast and E. coli is examined. The codon adaptation index is employed to identify a group of genes in each organism with low codon usage bias, which are likely to be weakly expressed. A similar pattern is found in complementary sequences with respect to synonymous usage of A vs G or of U vs C. It is suggested that this may reflect an effect of context on mutation rates in weakly expressed genes.

Base Sequence↗
PubMed2001

Synonymous codon usage in Cryptosporidium parvum: identification of two distinct trends among genes.

The usage of alternative synonymous codons in the apicomplexan Cryptosporidium parvum has been investigated. A data set of 54 genes was analysed. Overall, A- and U-ending codons predominate, as expected in an A+T-rich genome. Two trends of codon usage variation among genes were identified using correspondence analysis. The primary trend is in the extent of usage of a subset of presumably translationally optimal codons, that are used at significantly higher frequencies in genes expected to be expressed at high levels. Fifteen of the 18 codons identified as optimal are more G+C-rich than the otherwise common codons, so that codon selection associated with translation opposes the general mutation bias. Among 40 genes with lower frequencies of these optimal codons, a secondary trend in G+C content was identified. In these genes, G+C content at synonymously variable third positions of codons is correlated with that in 5' and 3' flanking sequences, indicative of regional variation in G+C content, perhaps reflecting regional variation in mutational biases.

Animals↗
PubMed1999

Significant differences between the G+C content of synonymous codons in orthologous genes and the genomic G+C content.

The relationship between the overall G+C content of the genome (GC) and the GC content at the third codon positions (GC3) of genes, which we refer to as a GC3-plot, was examined using 15 currently available complete genome sequences. A remarkably linear relationship was found between these two quantities, confirming previous observations of a strong positive correlation in the GC3-plot. In order to conduct a more detailed analysis of the GC3-plot, we examined the GC3 content by separating orthologous codons into three categories: synonymously different codons (namely identical amino acids, IA), different amino acids (DA), and identical codons (IC), for a pairwise comparison of two closely related species. When we took pairwise species comparisons between Mycoplasma genitalium (Mg) and Mycoplasma pneumoniae (Mp) and between Mycobacterium tuberculosis (Mt) and Mycobacterium leprae (Ml) as examples, we found that for Mp and Ml, the GC3 for IA deviated the most from the linear expectation in the GC3-plot, whereas for Mg and Mt the deviation was minimal. These findings suggest that the major changes of GC content took place in Mp and Ml, but not in Mg and Mt. This analysis also enables us to predict the future direction of the evolutionary changes of the genomic GC content.

Base Composition↗
PubMed2006

Regions of extreme synonymous codon selection in mammalian genes.

Recently there has been increasing evidence that purifying selection occurs among synonymous codons in mammalian genes. This selection appears to be a consequence of either cis-regulatory motifs, such as exonic splicing enhancers (ESEs), or mRNA secondary structures, being superimposed on the coding sequence of the gene. We have developed a program to identify regions likely to be enriched for such motifs by searching for extended regions of extreme codon conservation between homologous genes of related species. Here we present the results of applying this approach to five mammalian species (human, chimpanzee, mouse, rat and dog). Even with very conservative selection criteria, we find over 200 regions of extreme codon conservation, ranging in length from 60 to 178 codons. The regions are often found within genes involved in DNA-binding, RNA-binding or zinc-ion-binding. They are highly depleted for synonymous single nucleotide polymorphisms (SNPs) but not for non-synonymous SNPs, further indicating that the observed codon conservation is being driven by negative selection. Forty-three percent of the regions overlap conserved alternative transcript isoforms and are enriched for known ESEs. Other regions are enriched for TpA dinucleotides and may contain conserved motifs/structures relating to mRNA stability and/or degradation. We anticipate that this tool will be useful for detecting regions enriched in other classes of coding-sequence motifs and structures as well.

Alternative Splicing↗
PubMed1993

[Stability of messenger RNA of Escherichia coli ompA is affected by the use of synonymous codon].

The ompA gene of E. coli was silently mutated by the substitution of nine codons located towards the end of the gene, by synonymous codons expected to be translated more slowly. At 37 degrees C in vivo the life-time of the ompA messenger RNA (mRNA) is reduced from 4.5 min (w.t.) to 3.8 min (silent mutant). The amount of mRNA of the silent mutant is only 30% of that observed for the w.t. gene. These variations are thought to be due to the uncoupling of transcription from translation, and a lesser protection of the mRNA towards RNase digestion by ribosomes, resulting from a lesser density of the ribosome traffic on the mutated polysome.

Blotting, Northern↗
PubMed1987

Synonymous codon usage in Bacillus subtilis reflects both translational selection and mutational biases.

Codon usage data for 56 Bacillus subtilis genes show that synonymous codon usage in B. subtilis is less biased than in Escherichia coli, or in Saccharomyces cerevisiae. Nevertheless, certain genes with a high codon bias can be identified by correspondence analysis, and also by various indices of codon bias. These genes are very highly expressed, and a general trend (a decrease) in codon bias across genes seems to correspond to decreasing expression level. This, then, may be a general phenomenon in unicellular organisms. The unusually small effect of translational selection on the pattern of codon usage in lowly expressed genes in B. subtilis yields similar dinucleotide frequencies among different codon positions, and on complementary strands. These patterns could arise through selection on DNA structure, but more probably are largely determined by mutation. This prevalence of mutational bias could lead to difficulties in assessing whether open reading frames encode proteins.

Bacillus subtilis↗
PubMed2003

Effect of strong directional selection on weakly selected mutations at linked sites: implication for synonymous codon usage.

The fixation of weakly selected mutations can be greatly influenced by strong directional selection at linked loci. Here, I investigate a two-locus model in which weakly selected, reversible mutations occur at one locus and recurrent strong directional selection occurs at the other locus. This model is analogous to selection on codon usage at synonymous sites linked to nonsynonymous sites under strong directional selection. Two approximations obtained here describe the expected frequency of the weakly selected preferred alleles at equilibrium. These approximations, as well as simulation results, show that the level of codon bias declines with an increasing rate of substitution at the strongly selected locus, as expected from the well-understood theory that selection at one locus reduces the efficacy of selection at linked loci. These solutions are used to examine whether the negative correlation between codon bias and nonsynonymous substitution rates recently observed in Drosophila can be explained by this hitchhiking effect. It is shown that this observation can be reasonably well accounted for if a large fraction of the nonsynonymous substitutions on genes in the data set are driven by strong directional selection.

Alleles↗
PubMed1998

Specific correlations between relative synonymous codon usage and protein secondary structure.

We found significant species-specific correlations between the use of two synonymous codons and protein secondary structure units by comparing the three-dimensional structures of human and Escherichia coli proteins with their mRNA sequences. The correlations are not explained by codon-context, expression level, GC/AU content, or positional effects. The E. coli correlation is between Asn AAC and the C-terminal regions of beta-sheet segments; it may result from selection for translational accuracy, suggesting the hypothesis that downstream Asn residues are important for beta-sheet formation. The correlation in human proteins is between Asp GAU and the N termini of alpha-helices; it may be important for eukaryote-specific sequential, cotranslational folding. The kingdom-specific correlations may reflect kingdom-specific differences in translational mechanisms. The correlations may help identify residues that are important for secondary structure formation, be useful in secondary structure prediction algorithms, and have implications for recombinant gene expression.

Bacterial Proteins↗
PubMed2001

Synonymous codon usage, accuracy of translation, and gene length in Caenorhabditis elegans.

In many unicellular organisms, invertebrates, and plants, synonymous codon usage biases result from a coadaptation between codon usage and tRNAs abundance to optimize the efficiency of protein synthesis. However, it remains unclear whether natural selection acts at the level of the speed or the accuracy of mRNAs translation. Here we show that codon usage can improve the fidelity of protein synthesis in multicellular species. As predicted by the model of selection for translational accuracy, we find that the frequency of codons optimal for translation is significantly higher at codons encoding for conserved amino acids than at codons encoding for nonconserved amino acids in 548 genes compared between Caenorhabditis elegans and Homo sapiens. Although this model predicts that codon bias correlates positively with gene length, a negative correlation between codon bias and gene length has been observed in eukaryotes. This suggests that selection for fidelity of protein synthesis is not the main factor responsible for codon biases. The relationship between codon bias and gene length remains unexplained. Exploring the differences in gene expression process in eukaryotes and prokaryotes should provide new insights to understand this key question of codon usage.

Animals↗
PubMed2004

INCA: synonymous codon usage analysis and clustering by means of self-organizing map.

UNLABELLED: INteractive Codon usage Analysis (INCA) provides an array of features useful in analysis of synonymous codon usage in whole genomes. In addition to computing codon frequencies and several usage indices, such as 'codon bias', effective Nc and CAI, the primary strength of INCA has numerous options for the interactive graphical display of calculated values, thus allowing visual detection of various trends in codon usage. Finally, INCA includes a specific unsupervised neural network algorithm, the self-organizing map, used for gene clustering according to the preferred utilization of codons. AVAILABILITY: INCA is available for the Win32 platform and is free of charge for academic use. For details, visit the web page http://www.bioinfo-hr.org/inca or contact the author directly. SUPPLEMENTARY INFORMATION: Software is accompanied with a user manual and a short tutorial.

Algorithms↗
PubMed1996

Acute intermittent porphyria caused by defective splicing of porphobilinogen deaminase RNA: a synonymous codon mutation at -22 bp from the 5' splice site causes skipping of exon 3.

Acute intermittent porphyria (AIP) results from mutations in the porphobilinogen deaminase (PBG) gene. Three of 14 randomly selected, unrelated patients with the cross reacting immunological material (CRIM) negative form of AIP were found to have previously undescribed RNA splicing defects. Defective splicing of exons 12 and 13 was caused by a C-->G transversion at position -3 of the 3' splice site of intron 11 and a G-->A transition at the first position of intron 13, respectively. Defective splicing of exon 3 was associated with a synonymous codon mutation (CGC-->CGG, R28R) at position -22 from the 5' splice site. Our findings are consistent with previous reports indicating that about 15% of mutations in the PBG deaminase gene that cause AIP affect RNA splicing and add to the evidence that synonymous intraexonic codon mutations may cause disease.

Acute Disease↗
PubMed2004

The 'weighted sum of relative entropy': a new index for synonymous codon usage bias.

Shannon entropy from information theory has been applied to estimate the degree of deviation from equal usage of synonymous codons; however, previous attempts have failed to take into account all three aspects of amino acid usage, i.e. (i) the number of distinct amino acids, (ii) their relative frequencies, and (iii) their degree of codon degeneracy. A new index taking into account all of these aspects is proposed. The index, designated as the 'weighted sum of relative entropy' (E(w)), is defined as the sum of the relative entropy of each amino acid weighted by its relative frequency in the sequence. In this paper, we demonstrate that E(w) allows us to avoid some amino acid usage biases and can yield results contradictory to those obtained by previous methods.

Algorithms↗