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PubMed1988

Possible evolution of splice-junction signals in eukaryotic genes from stop codons.

Splice-junction sequence signals are strongly conserved structural components of eukaryotic genes. These sequences border exon/intron junctions and aid in the process of removing introns by the RNA splicing machinery. Although substantial research has been undertaken to understand the mechanism of splicing, little is known about the origin and evolution of these splice signal sequences. Based on the previously published theory that the primitive genes evolved in pieces from primordial genetic sequences to avoid the interfering stop codons, a "stop-codon walk" mechanism is proposed in this paper to have assisted in the evolution of coding genes. This mechanism predicts the presence of stop codons in splice-junction signals inside the introns. Evidence of the consistent presence of stop codons in the splice-junction signals, in a position where they are expected, is shown by the analysis of codon statistics in these signal sequences in the GenBank databank. The results suggest that the splice-junction signals may have evolved from stop codons as a consequence of a selective pressure to avoid stop codons during the original evolution of coding genes. They also suggest that other splice signals within the introns, such as the branch-point sequence, may have evolved from stop codons for similar reasons.

Biological Evolution↗

PubMed1997

The atypical codon usage of the plant psbA gene may be the remnant of an ancestral bias.

The psbA gene of the chloroplast genome has a codon usage that is unusual for plant chloroplast genes. In the present study the evolutionary status of this codon usage is tested by reconstructing putative ancestral psbA sequences to determine the pattern of change in codon bias during angiosperm divergence. It is shown that the codon biases of the ancestral genes are much stronger than all extant flowering plant psbA genes. This is related to previous work that demonstrated a significant increase in synonymous substitution in psbA relative to other chloroplast genes. It is suggested, based on the two lines of evidence, that the codon bias of this gene currently is not being maintained by selection. Rather, the atypical codon bias simply may be a remnant of an ancestral codon bias that now is being degraded by the mutation bias of the chloroplast genome, in other words, that the psbA gene is not at equilibrium. A model for the evolution of selective pressure on the codon usage of plant chloroplast genes is discussed.

Base Sequence↗

PubMed2004

Phylogenetic artifacts can be caused by leucine, serine, and arginine codon usage heterogeneity: dinoflagellate plastid origins as a case study.

Phylogenetic analyses of first and second codon positions (DNA1 + 2 analysis) and amino acid sequences (protein analysis) are often thought to provide similar estimates of deep-level phylogeny. However, here we report a novel artifact influencing DNA level phylogenetic inference of protein-coding genes introduced by codon usage heterogeneity that causes significant incongruities between DNA1 + 2 and protein analyses. DNA1 + 2 analyses of plastid-encoded psbA genes (encoding of photosystem II D1 proteins) strongly suggest a relationship between haptophyte plastids and typical (peridinin-containing) dinoflagellate plastids. The psbA genes from haptophytes and a subset of the peridinin-type plastids display similar codon usage patterns for Leu, Ser, and Arg, which are each encoded by two separated codon sets that differ at first or first plus second codon positions. Our detailed analyses clearly indicate that these unusual preferences shared by haptophyte and some peridinin-type plastid genes are largely responsible for their strong affinity in DNA analyses. In particular, almost all of the support from DNA level analyses for the monophyly of haptophyte and peridinin-type plastids is lost when the codons corresponding to constant Leu, Ser, and Arg amino acids are excluded, suggesting that this signal comes from rapidly evolving synonymous substitutions, rather than from substitutions that result in amino acid changes. Indeed, protein maximum-likelihood analyses of concatenated PsaA and PsbA amino acid sequences indicate that, although 19' hexanoyloxyfucoxanthin-type (19' HNOF-type) plastids in dinoflagellates group with haptophyte plastids, peridinin-type plastids group weakly with those of stramenopiles. Consequently our results cast doubt on the single origin of peridinin-type and 19' HNOF-type plastids in dinoflagellates previously suggested on the basis of psaA and psbA concatenated gene phylogenetic analyses. We suggest that codon usage heterogeneity could be a more general problem for DNA level analyses of protein-coding genes, even when third codon positions are excluded.

Animals↗

PubMed2005

An empirical examination of the utility of codon-substitution models in phylogeny reconstruction.

Models of codon substitution have been commonly used to compare protein-coding DNA sequences and are particularly effective in detecting signals of natural selection acting on the protein. Their utility in reconstructing molecular phylogenies and in dating species divergences has not been explored. Codon models naturally accommodate synonymous and nonsynonymous substitutions, which occur at very different rates and may be informative for recent and ancient divergences, respectively. Thus codon models may be expected to make an efficient use of phylogenetic information in protein-coding DNA sequences. Here we applied codon models to 106 protein-coding genes from eight yeast species to reconstruct phylogenies using the maximum likelihood method, in comparison with nucleotide- and amino acid-based analyses. The results appeared to confirm that expectation. Nucleotide-based analysis, under simplistic substitution models, were efficient in recovering recent divergences whereas amino acid-based analysis performed better at recovering deep divergences. Codon models appeared to combine the advantages of amino acid and nucleotide data and had good performance at recovering both recent and deep divergences. Estimation of relative species divergence times using amino acid and codon models suggested that translation of gene sequences into proteins led to information loss of from 30% for deep nodes to 66% for recent nodes. Although computational burden makes codon models unfeasible for tree search in large data sets, we suggest that they may be useful for comparing candidate trees. Nucleotide models that accommodate the differences in evolutionary dynamics at the three codon positions also performed well, at much less computational cost. We discuss the relationship between a model's fit to data and its utility in phylogeny reconstruction and caution against use of overly complex substitution models.

Classification↗

PubMed2000

Animal products and K-ras codon 12 and 13 mutations in colon carcinomas.

K-ras gene mutations (codons 12 and 13) were determined by PCR-based mutant allele-specific amplification (MASA) in tumour tissue of 185 colon cancer patients: 36% harboured mutations, of which 82% were located in codon 12. High intakes of animal protein, calcium and poultry were differently associated with codon 12 and 13 mutations: odds ratios (OR) and 95% confidence intervals (95% CI) for codon 12 versus codon 13 were 9.0 (2.0-42), 4.1 (1.4-12) and 15 (1.4-160), respectively. In case-control comparisons, high intakes of animal protein and calcium were positively associated with colon tumours harbouring codon 12 mutations [for animal protein per 17 g, OR (95% CI) = 1.5 (1.0-2.1); for calcium per 459 mg, 1.2 (0.9-1.6)], while inverse associations were observed for tumours with K-ras mutations in codon 13 [for animal protein 0.4 (0.2-1.0); for calcium 0.6 (0. 3-1.2)]. Transition and transversion mutations were not differently associated with these dietary factors. These data suggest a different dietary aetiology of colon tumours harbouring K-ras codon 12 and 13 mutations.

Adult↗

PubMed1994

Synonymous codon usage in Drosophila melanogaster: natural selection and translational accuracy.

I present evidence that natural selection biases synonymous codon usage to enhance the accuracy of protein synthesis in Drosophila melanogaster. Since the fitness cost of a translational misincorporation will depend on how the amino acid substitution affects protein function, selection for translational accuracy predicts an association between codon usage in DNA and functional constraint at the protein level. The frequency of preferred codons is significantly higher at codons conserved for amino acids than at nonconserved codons in 38 genes compared between D. melanogaster and Drosophila virilis or Drosophila pseudoobscura (Z = 5.93, P < 10(-6)). Preferred codon usage is also significantly higher in putative zinc-finger and homeodomain regions than in the rest of 28 D. melanogaster transcription factor encoding genes (Z = 8.38, P < 10(-6)). Mutational alternatives (within-gene differences in mutation rates, amino acid changes altering codon preference states, and doublet mutations at adjacent bases) do not appear to explain this association between synonymous codon usage and amino acid constraint.

Animals↗

PubMed2005

No evidence for tissue-specific adaptation of synonymous codon usage in humans.

It has been proposed that the synonymous codon usage of human tissue-specific genes was under selective pressure to modulate the expression of proteins by codon-mediated translational control (Plotkin, J. B., H. Robins, and A. J. Levine. 2004. Tissue-specific codon usage and the expression of human genes. Proc. Natl. Acad. Sci. USA 101:12588-12591.) To test this model, we analyzed by internal correspondence analysis the codon usage of 2,126 human tissue-specific genes expressed in 18 different tissues. We confirm that synonymous codon usage differs significantly between the tissues. However, the effect is very weak: the variability of synonymous codon usage between tissues represents only 2.3% of the total codon usage variability. Moreover, this variability is directly linked to isochore-scale (>100 kb) variability of GC-content that affect both coding and introns or intergenic regions. This demonstrates that variations of synonymous codon usage between tissue-specific genes expressed in different tissues are due to regional variations of substitution patterns and not to translational selection.

Base Composition↗

PubMed1985

Codon-defined ribosomal pausing in Escherichia coli detected by using the pyrE attenuator to probe the coupling between transcription and translation.

This communication describes an assay for the relative translation efficiency of individual codons which makes use of the pyrE attenuator to probe the coupling between transcription and translation at the end of an artificial leader peptide. By cloning of short synthetic DNA fragments the codons to be tested were placed in the middle of the leader peptide and the downstream transcription of a pyrE"lacZ gene was monitored by measuring beta-galactosidase activity. The substitution, one by one, of three AGG codons for arginine with three CGT codons for the same amino acid residue was found to cause a two fold increase per codon of transcription over the pyrE attenuator, such that an eight fold higher frequency of pyrE expression was seen when all three AGG codons were replaced by CGT codons. No such effect of codon composition was observed, when the cells were grown with a low UTP pool which causes a reduction of the mRNA chain growth rate.

Base Sequence↗

PubMed1988

The AGG codon is translated slowly in E. coli even at very low expression levels.

Data are presented which indicate that AGG codons for arginine are translated significantly more slowly than the CGU codons for the same amino acid even when their expression level from the probe is very low. The two types of codons were inserted (three in tandem) on a multicopy plasmid in an artificial leader peptide gene in front of the pyrE attenuator where the frequency of transcription termination is regulated by the degree of coupling between transcription and translation. Transcription of the operon is initiated from the lac-promoter dependent on the concentration of the lac-operon inducer IPTG. At all induction levels it was found that the frequency of transcription past the pyrE attenuator was approximately nine times lower when the AGG codons were present in the leader than with CGT codons present. This shows that AGG codons decouple translation from transcription in the pyrE attenuator region even when the concentration of this codon is not increased significantly relative to that in the unperturbed wild type strain. Thus the results indicate that AGG codons are always slowly translated in Escherichia coli.

Adenine↗

PubMed1999

An extra tRNAGly(U*CU) found in ascidian mitochondria responsible for decoding non-universal codons AGA/AGG as glycine.

Amino acid assignments of metazoan mitochondrial codons AGA/AGG are known to vary among animal species; arginine in Cnidaria, serine in invertebrates and stop in vertebrates. We recently found that in the mitochondria of the ascidian Halocynthia roretzi these codons are exceptionally used for glycine, and postulated that they are probably decoded by a tRNA(UCU). In order to verify this notion unambig-uously, we determined the complete RNA sequence of the mitochondrial tRNA(UCU) presumed to decode codons AGA/AGG in the ascidian mitochondria, and found it to have an unidentified U derivative at the anticodon first position. We then identified the amino acids attached to the tRNA(U*CU), as well as to the conventional tRNAGly(UCC) with an unmodified U34, in vivo. The results clearly demonstrated that glycine was attached to both tRNAs. Since no other tRNA capable of decoding codons AGA/AGG has been found in the mitochondrial genome, it is most probable that this tRNA(U*CU) does actually translate codons AGA/AGG as glycine in vivo. Sequencing of tRNASer(GCU), which is thought to recognize only codons AGU/AGC, revealed that it has an unmodified guanosine at position 34, as is the case with vertebrate mitochondrial tRNASer(GCU) for codons AGA/AGG. It was thus concluded that in the ascidian, codons AGU/AGC are read as serine by tRNASer(GCU), whereas AGA/AGG are read as glycine by an extra tRNAGly(U*CU). The possible origin of this unorthodox genetic code is discussed.

Animals↗

PubMed2000

Optimizing heterologous expression in dictyostelium: importance of 5' codon adaptation.

Expression of heterologous proteins in Dictyostelium discoideum presents unique research opportunities, such as the functional analysis of complex human glycoproteins after random mutagenesis. In one study, human chorionic gonadotropin (hCG) and human follicle stimulating hormone were expressed in Dictyostelium. During the course of these experiments, we also investigated the role of codon usage and of the DNA sequence upstream of the ATG start codon. The Dictyostelium genome has a higher AT content than the human, resulting in a different codon preference. The hCG-beta gene contains three clusters with infrequently used codons that were changed to codons that are preferred by Dictyostelium. The results reported here show that optimizing the first 5-17 codons of the hCG gene contributes to 4- to 5-fold increased expression levels, but that further optimization has no significant effect. These observations suggest that optimal codon usage contributes to ribosome stabilization, but does not play an important role during the elongation phase of translation. Furthermore, adapting the 5'-sequence of the hCG gene to the Dictyostelium 'Kozak'-like sequence increased expression levels approximately 1.5-fold. Thus, using both codon optimization and 'Kozak' adaptation, a 6- to 8-fold increase in expression levels could be obtained for hCG.

Amino Acid Sequence↗

PubMed2000

Intercodon dinucleotides affect codon choice in plant genes.

In this work, 710 CDSs corresponding to over 290 000 codons equally distributed between Brassica napus, Arabidopsis thaliana, Lycopersicon esculentum, Nicotiana tabacum, Pisum sativum, Glycine max, Oryza sativa, Triticum aestivum, Hordeum vulgare and Zea mays were considered. For each amino acid, synonymous codon choice was determined in the presence of A, G, C or T as the initial nucleotide of the subsequent triplet; data were statistically analysed under the hypothesis of an independent assortment of codons. In 33.4% of cases, a frequency significantly (P: = 0.01) different from that expected was recorded. This was mainly due to a pervasive intercodon TpA and CpG deficiency. As a general rule, intercodon TpAs and CpGs were preferably replaced by CpAs and TpGs, respectively. In several instances, codon frequencies were also modified to avoid homotetramer and homotrimer formation, to reduce intercodon ApCs downstream (1,2) GG or AG dinucleotides, as well as to increase GpA or ApG intercodons under certain contexts. Since TpA, CpG and homotetra(tri)mer deficiency directly or indirectly accounted for 77% of significant variation in the codon frequency, it can be concluded that codon usage mirrors precise needs at the DNA structure level. Plant species exhibited a phylogenetically-related adaptation to structural constraints. Codon usage flexibility was reflected in strikingly different arrays of optimum codons for probe design.

Base Composition↗

PubMed2006

Codon usage bias and tRNA over-expression in Buchnera aphidicola after aromatic amino acid nutritional stress on its host Acyrthosiphon pisum.

Codon usage bias and relative abundances of tRNA isoacceptors were analysed in the obligate intracellular symbiotic bacterium, Buchnera aphidicola from the aphid Acyrthosiphon pisum, using a dedicated 35mer oligonucleotide microarray. Buchnera is archetypal of organisms living with minimal metabolic requirements and presents a reduced genome with high-evolutionary rate. Codonusage in Buchnera has been overcome by the high mutational bias towards AT bases. However, several lines of evidence for codon usage selection are given here. A significant correlation was found between tRNA relative abundances and codon composition of Buchnera genes. A significant codon usage bias was found for the choice of rare codons in Buchnera: C-ending codons are preferred in highly expressed genes, whereas G-ending codons are avoided. This bias is not explained by GC skew in the bacteria and might correspond to a selection for perfect matching between codon-anticodon pairs for some essential amino acids in Buchnera proteins. Nutritional stress applied to the aphid host induced a significant overexpression of most of the tRNA isoacceptors in bacteria. Although, molecular regulation of the tRNA operons in Buchnera was not investigated, a correlation between relative expression levels and organization in transcription unit was found in the genome of Buchnera.

Animals↗

PubMed2002

Hill-Robertson interference is a minor determinant of variations in codon bias across Drosophila melanogaster and Caenorhabditis elegans genomes.

According to population genetics models, genomic regions with lower crossing-over rates are expected to experience less effective selection because of Hill-Robertson interference (HRi). The effect of genetic linkage is thought to be particularly important for a selection of weak intensity such as selection affecting codon usage. Consistent with this model, codon bias correlates positively with recombination rate in Drosophila melanogaster and Caenorhabditis elegans. However, in these species, the G+C content of both noncoding DNA and synonymous sites correlates positively with recombination, which suggests that mutation patterns and recombination are associated. To remove this effect of mutation patterns on codon bias, we used the synonymous sites of lowly expressed genes that are expected to be effectively neutral sites. We measured the differences between codon biases of highly expressed genes and their lowly expressed neighbors. In D. melanogaster we find that HRi weakly reduces selection on codon usage of genes located in regions of very low recombination; but these genes only comprise 4% of the total. In C. elegans we do not find any evidence for the effect of recombination on selection for codon bias. Computer simulations indicate that HRi poorly enhances codon bias if the local recombination rate is greater than the mutation rate. This prediction of the model is consistent with our data and with the current estimate of the mutation rate in D. melanogaster. The case of C. elegans, which is highly self-fertilizing, is discussed. Our results suggest that HRi is a minor determinant of variations in codon bias across the genome.

Animals↗

PubMed1996

Introns and reading frames: correlation between splicing sites and their codon positions.

Computer analyses of the entire GenBank database were conducted to examine correlation between splicing sites and codon positions in reading frames. Intron insertion patterns (i.e., splicing site locations with respect to codon positions) have been analyzed for all of the 74 codons of all the eukaryote taxonomic groups: primates, rodents mammals, vertebrates, invertebrates, and plants. We found that reading frames are interrupted by an intron at a codon boundary (as opposed to the middle of a codon) significantly more often than expected. This observation is consistent with the exon shuffling hypothesis, because exons that end at codon boundaries can be concatenated without causing a frame shift and thus are evolutionarily advantageous. On the other hand, when introns interrupt at the middles of codons, they exist in between the first and second bases much more frequently than between the second and third bases, despite the fact that boundaries between the first and second bases of codons are generally far more important than those between the second and third bases. The reason for this is not clear and yet to be explained. We also show that the length of an exon is a multiple of 3 more frequently than expected. Furthermore, the total length of two consecutive exons is also more frequently a multiple of 3. All the observations above are consistent with results recently published by Long, Rosenberg, and Gilbert (1995).

Algorithms↗

PubMed1996

Codon usage in the Mycobacterium tuberculosis complex.

The usage of alternative synonymous codons in Mycobacterium tuberculosis (and M. bovis) genes has been investigated. This species is a member of the high-G+C Gram-positive bacteria, with a genomic G+C content around 65 mol%. This G+C-richness is reflected in a strong bias towards C- and G-ending codons for every amino acid: overall, the G+C content at the third positions of codons is 83%. However, there is significant variation in codon usage patterns among genes, which appears to be associated with gene expression level. From the variation among genes, putative optimal codons were identified for 15 amino acids. The degree of bias towards optimal codons in an M. tuberculosis gene is correlated with that in homologues from Escherichia coli and Bacillus subtilis. The set of selectively favoured codons seems to be quite highly conserved between M. tuberculosis and another high-G+C Gram-positive bacterium, Corynebacterium glutamicum, even though the genome and overall codon usage of the latter are much less G+C-rich.

Bacillus subtilis↗

PubMed1993

Codon usage patterns in chromosomal and retrotransposon genes of the mosquito Anopheles gambiae.

Codon usage was compiled for fourteen chromosomal genes and four retrotransposons from the mosquito Anopheles gambiae. Variation exists among chromosomal genes in the degree of bias. The genes showing the highest bias are probably most highly expressed. In these genes, the base composition at the third codon position is much richer in G + C than is the overall coding sequence. Thus, codon usage is biased toward G- or C-ending codons. Codon usage in each retrotransposon is quite different, not only from chromosomal genes but also from the other retrotransposons. Codon usage comparisons among homologous genes from An. gambiae and two other Dipterans, the yellow fever mosquito Aedes aegypti and the fruitfly Drosophila melanogaster, show that while there are similarities, particularly between An. gambiae and D. melanogaster in the preference for G- and C-ending codons, each species has evolved a distinct pattern of codon usage.

Animals↗

PubMed1997

Evidence of rare codon clusters within Escherichia coli coding regions.

It is known that there is a high occurrence of rare codons at the start of coding region. Here it is shown that although the remainder of the gene is likely to contain a relatively low number of rare codons, rare and non-rare codons do not form a random sequence. It is apparent that throughout the coding region there is a higher than expected number of rare codon clusters. For example once a rare codon has occurred there is a greater chance than expected of the next six codons containing another rare codon. This non-random distribution implies that rare codons may have an as yet unidentified biological role.

Base Sequence↗