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PubMed1997

Synthetic spider dragline silk proteins and their production in Escherichia coli.

Synthetic genes were designed to encode analogs of the two proteins of Nephila clavipes dragline silk, spidroins 1 and 2. The genes were constructed of tandem repeats of relatively long (more than 300 bp) DNA sequences assembled from synthetic oligonucleotides, and encoded proteins of high molecular mass (65-163 kDa). Both analogs were produced efficiently in Escherichia coli. The yield and homogeneity of the products of longer genes were limited by premature termination of synthesis, probably as a result of processivity errors in protein synthesis. Average termination rates were determined to be 1 in 1100 codons to 1 in 300 codons, depending on the length and synonymous codon choices of the gene. Both analog proteins could be induced to form stable aqueous solutions without denaturants. Circular dichroism spectra of the purified proteins in dilute solution resembled spectra of redissolved natural dragline silk in reflecting a largely disordered structure in water and more ordered structures in mixed solvents with methanol and trifluoroethanol.

Amino Acid Sequence↗
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↗
PubMed1997

Preferential codon usage and two types of repetitive motifs in the fibroin gene of the Chinese oak silkworm, Antheraea pernyi.

In this paper we describe the peculiar structures and preferential codon usage found in wild silkworm fibroin genes. We determined a 1350 bp nucleotide sequence from the Chinese oak silkworm, Antheraea pernyi. The deduced amino acid sequence was partitioned into thirteen polyalanine-containing repetitive motifs, which was one of the characteristics of Antheraea fibroins. Eleven of these arrays can be classified into two types of motifs depending on difference in amino acid sequences following polyalanine. Repetitive motifs structurally similar to those of A. pernyi were detected in a homologue of the Japanese oak silkworm, Antheraea yamamai. The most remarkable feature of this study was preferential codon usage, especially seen in alanine synonymous codons within both homologues of Antheraea: isocodon GCA most frequently occurred in alanine isocodons. In contrast, GCU isocodon was the most abundant in Bombyx mori fibroin heavy chain that lacks polyalanine arrays. This result strongly suggests different modes of selective constraint between the two types of fibroin gene. The similar finding that GCA isocodon was most frequent in two dragline silk sequences of the spider, Nephila clavipes, is consistent with our results because of the repetitive polyalanine-containing arrays seen in spider dragline silk.

Amino Acid Sequence↗
PubMed1996

Maximizing transcription efficiency causes codon usage bias.

The rate of protein synthesis depends on both the rate of initiation of translation and the rate of elongation of the peptide chain. The rate of initiation depends on the encountering rate between ribosomes and mRNA; this rate in turn depends on the concentration of ribosomes and mRNA. Thus, patterns of codon usage that increase transcriptional efficiency should increase mRNA concentration, which in turn would increase the initiation rate and the rate of protein synthesis. An optimality model of the transcriptional process is presented with the prediction that the most frequently used ribonucleotide at the third codon sites in mRNA molecules should be the same as the most abundant ribonucleotide at the third codon sites in mRNA molecules should be the same as the most abundant ribonucleotide in the cellular matrix where mRNA is transcribed. This prediction is supported by four kinds of evidence. First, A-ending codons are the most frequently used synonymous codons in mitochondria, where ATP is much more abundant than that of the three other ribonucleotides. Second, A-ending codons are more frequently used in mitochondrial genes than in nuclear genes. Third, protein genes from organisms with a high metabolic rate use more A-ending codons and have higher A content in their introns than those from organisms with a low metabolic rate.

Animals↗
PubMed2003

Nonrandom intragenic variations in patterns of codon bias implicate a sequential interplay between transitional genetic drift and functional amino acid selection.

Although most codon third bases appear to be functionless, the synonymous codons so defined exhibit a strikingly nonrandom distribution (codon bias) within human and other genes. To examine this phenomenon further, we generated a database of DNA sequences encoding human transmembrane cell-surface receptor proteins. Using this database we show here that the guanine and cytosine content of codon third bases (GC3) varies intragenically with the nature of the specified receptor domains (transmembrane > extracellular > intracellular domains; p < 0.001), the phenotype of the encoded amino acids (hydrophobic > hydrophilic > neutral amino acids; p < 0.001), and the receptor affiliation of the transmembrane (G-protein-coupled receptors > receptor tyrosine kinases; p < 0.001). Within gene regions specifying transmembrane domains, GC3 declines as domain functionality becomes redundant with increasing hydrophobicity (p < 0.001). Codons containing the second-base cytosine (XCZ, which encodes neutral amino acids) are selectively depleted of third-base adenine content (A3: XCA codons) when encoding transmembrane domain residues, consistent with positive selection for transitional mutation of XCG to XTG (which encodes hydrophobic amino acids) rather than to the synonymous XCA. Supporting this XCG --> XTG mechanism of codon bias, the G3:A3 ratio of codons specifying the transmembrane amino acid glycine (GGZ) is intermediate between that of its functional homolog alanine (GCZ) and that of hydrophobic valine (GTZ), even though the C3:T3 ratios are similar. Conversely, nearest-neighbor analysis of third bases 5' to codons specifying valine and leucine (CTZ) confirms a significant difference in C3:T3 but not G3:A3 ratios (i.e., C3/G1 --> T3/G1 > C3/A1; p < 0.001), consistent with the functionally advantageous retention of hydrophobic residues. These data raise the possibility that patterns of intragenic codon bias reflect a balance between negative and positive selection, suggesting in turn that analysis of codon third-base usage may help to predict the functional significance of encoded products.

Amino Acids↗
PubMed2002

Trends in codon and amino acid usage in Thermotoga maritima.

The usage of synonymous codons and the frequencies of amino acids were investigated in the complete genome of the bacterium Thermotoga maritima using a multivariate statistical approach. The GC3 content of each gene was the most prominent source of variation of codon usage. Surprisingly the usage of UGU and UGC (synonymous triplets coding for Cys, the least frequent amino acid in this species) was detected as the second most prominent source of variation. However, this result is probably an artifact due to the very low frequency of Cys together with the nonbiased composition of this genome. The third trend was related to the preferential usage of a subset of codons among highly expressed genes, and these triplets are presumed to be translationally optimal. Concerning the amino acid usage, the hydropathy level of each protein (and therefore the frequency of charged residues) was the main trend, while the second factor was related to the frequency of usage of the smaller residues, suggesting that the cell economy strongly influences the architecture of the proteins. The third axis of the analysis discriminated the usage of Phe, Tyr, Trp (aromatic residues) plus Cys, Met, and His. These six residues have in common the property of being the preferential targets of reactive oxygen species, and therefore the anaerobic condition of T. maritima is an important factor for the amino acid frequencies. Finally, the Cys content of each protein was the fourth trend.

Amino Acids↗
PubMed2004

The effect of expression levels on codon usage in Plasmodium falciparum.

The usage of alternative synonymous codons in the completely sequenced, extremely A+T-rich parasite Plasmodium falciparum was studied. Confirming previous studies obtained with less than 3% of the total genes recently described, we found that A- and U-ending triplets predominate but translational selection increases the frequency of a subset of codons in highly expressed genes. However, some new results come from the analysis of the complete sequence. First, there is more variation in GC3 than previously described; second, the effect of natural selection acting at the level of translation has been analysed with real expression data at 4 different stages and third, we found that highly expressed proteins increment the frequency of energetically less expensive amino acids. The implications of these results are discussed.

Animals↗
PubMed1987

Influence of the codon following the AUG initiation codon on the expression of a modified lacZ gene in Escherichia coli.

In a lacZ expression vector (pMC1403Plac), all 64 codons were introduced immediately 3' from the AUG initiation codon. The expression of the second codon variants was measured by immunoprecipitation of the plasmid-coded fusion proteins. A 15-fold difference in expression was found among the codon variants. No distinct correlation could be made with the level of tRNA corresponding to the codons and large differences were observed between synonymous codons that use the same tRNA. Therefore the effect of the second codon is likely to be due to the influence of its composing nucleotides, presumably on the structure of the ribosomal binding site. An analysis of the known sequences of a large number of Escherichia coli genes shows that the use of codons in the second position deviates strongly from the overall codon usage in E. coli. It is proposed that codon selection at the second position is not based on requirements of the gene product (a protein) but is determined by factors governing gene regulation at the initiation step of translation.

Base Sequence↗
PubMed2004

Comparing expression level-dependent features in codon usage with protein abundance: an analysis of 'predictive proteomics'.

Synonymous codon usage is a commonly used means for estimating gene expression levels of Escherichia coli genes and has also been used for predicting highly expressed genes for a number of prokaryotic genomes. By comparison of expression level-dependent features in codon usage with protein abundance data from two proteome studies of exponentially growing E. coli and Bacillus subtilis cells, we try to evaluate whether the implicit assumption of this approach can be confirmed with experimental data. Log-odds ratio scores are used to model differences in codon usage between highly expressed genes and genomic average. Using these, the strength and significance of expression level-dependent features in codon usage were determined for the genes of the Escherichia coli, Bacillus subtilis and Haemophilus influenzae genomes. The comparison of codon usage features with protein abundance data confirmed a relationship between these to be present, although exceptions to this, possibly related to functional context, were found. For species with expression level-dependent features in their codon usage, the applied methodology could be used to improve in silico simulations of the outcome of two-dimensional gel electrophoretic experiments.

Animals↗
PubMed1996

Specific replacement of consecutive AGG codons results in high-level expression of human cardiac troponin T in Escherichia coli.

The adult isoform of human cardiac troponin T (TnT) contains 288 amino acids, 14 of which (4.9%) are encoded by the rarely used arginine codons (12 AGG, 2 AGA) in Escherichia coli genes. To generate sufficient quantity of TnT protein for antibody production, we cloned the corresponding cDNA and expressed it in E. coli. A low-level expression of TnT that comprised only about 1% of total cell protein was initially observed with the use of the native cDNA. The existence of two pairs of consecutive AGG codons AGG(165) AGG(166) and AGG(215) AGG(216) in the cDNA was suspected to be the main cause for this low-level expression. These two pairs of consecutive AGG codons were successively replaced with the major synonymous codon CGT by site-directed mutagenesis. As suspected, a 10-fold increase in TnT expression was obtained when one pair of the rare arginine codons was replaced and a 40-fold increase was achieved when both pairs of the rare codons were replaced. Our finding demonstrates the importance of consecutive rare codons in the suppression of high-level expression of heterologous proteins in E. coli and suggests that in order to maximize protein expression, a similar approach may be taken with other genes which contain consecutive rare codons.

Adult↗
PubMed1990

Genetic code 1990. Outlook.

The genetic code is evolving as shown by 9 departures from the universal code: 6 of them are in mitochondria and 3 are in nuclear codes. We propose that these changes are preceded by disappearance of a codon from coding sequences in mRNA of an organism or organelle. The function of the codon that disappears is taken by other, synonymous codons, so that there is no change in amino acid sequences of proteins. The deleted codon then reappears with a new function. Wobble pairing between anticodons and codons has evolved, starting with a single UNN anticodon pairing with 4 codons. Directional mutation pressure affects codon usage and may produce codon reassignments, especially of stop codons. Selenocysteine is coded by UGA, which is also a stop codon, and this anomaly is discussed. The outlook for discovery of more changes in the code is favorable, and open reading frames should be compared with actual sequential analyses of protein molecules in this search.

Anaerobiosis↗
PubMed1989

On the rate of DNA sequence evolution in Drosophila.

Analysis of the rate of nucleotide substitution at silent sites in Drosophila genes reveals three main points. First, the silent rate varies (by a factor of two) among nuclear genes; it is inversely related to the degree of codon usage bias, and so selection among synonymous codons appears to constrain the rate of silent substitution in some genes. Second, mitochondrial genes may have evolved only as fast as nuclear genes with weak codon usage bias (and two times faster than nuclear genes with high codon usage bias); this is quite different from the situation in mammals where mitochondrial genes evolve approximately 5-10 times faster than nuclear genes. Third, the absolute rate of substitution at silent sites in nuclear genes in Drosophila is about three times higher than the average silent rate in mammals.

Animals↗
PubMed1991

Codon bias and gene expression.

The frequencies with which individual synonymous codons are used to code their cognate amino acids is quite variable from genome to genome and within genomes, from gene to gene. One particularly well documented codon bias is that associated with highly expressed genes in bacteria as well as in yeast; this is the so-called major codon bias. Here, it is suggested that the major codon bias is not an arrangement for regulating individual gene expression. Instead, the data suggest that this codon bias, which is correlated with a corresponding bias of tRNA abundance, is a global arrangement for optimizing the growth efficiency of cells. On the practical side, it is suggested that heterologous gene expression is not as sensitive to codon bias as previously thought, but that it is quite sensitive to other characteristics of the heterologous gene.

Codon↗
PubMed2001

Fidelity of replication of repetitive DNA in mutS and repair proficient Escherichia coli.

Replication fidelity is not constant among strains within a species or at all genetic loci within a genome. Altered fidelity of replication may affect patterns of pathogenesis and the evolution of these strains. We have been studying replication fidelity in Escherichia coli, both in laboratory attenuated strains and in food-borne pathogens. To understand the altered patterns of mutagenesis at the molecular level, we used a shuttle vector plasmid with a tRNA mutational marker gene which had been altered to include homopolymeric runs of five, seven and nine [G:C] pairs, as well as non-repetitive DNA. Replication of the plasmid in mutS strains resulted in a 20-fold increase in mutant progeny plasmids. The mutations were almost all (>90%) frameshift mutations, while base substitution mutations were rare. Most mutations were insertions or deletions of one or two [G:C] pairs in the longest homopolymeric runs. Larger deletions (5 to >70bp), also targeted to the repetitive sequence, were likewise common. Mutations increased exponentially with the length of the homopolymeric run. These patterns of mutation, including unexpectedly high levels in repair proficient strains, led to an examination of the E. coli K-12 genome for homopolymeric DNA. This sequence motif was found to be rare, particularly in genes and open reading frames. Amino acid homotrimers were found to avoid usage of homopolymeric codons, even when they are preferred among synonymous codons in E. coli. There appears to be active selection against tandem direct nucleotide repeats in the E. coli genome, correlated with the inability of the organism to accurately replicate such sequence.

Adenosine Triphosphatases↗
PubMed2005

Variation in the strength of selected codon usage bias among bacteria.

Among bacteria, many species have synonymous codon usage patterns that have been influenced by natural selection for those codons that are translated more accurately and/or efficiently. However, in other species selection appears to have been ineffective. Here, we introduce a population genetics-based model for quantifying the extent to which selection has been effective. The approach is applied to 80 phylogenetically diverse bacterial species for which whole genome sequences are available. The strength of selected codon usage bias, S, is found to vary substantially among species; in 30% of the genomes examined, there was no significant evidence that selection had been effective. Values of S are highly positively correlated with both the number of rRNA operons and the number of tRNA genes. These results are consistent with the hypothesis that species exposed to selection for rapid growth have more rRNA operons, more tRNA genes and more strongly selected codon usage bias. For example, Clostridium perfringens, the species with the highest value of S, can have a generation time as short as 7 min.

Bacteria↗
PubMedDate not supplied

Codon usage in Giardia lamblia.

A codon usage table for the intestinal parasite Giardia lamblia was generated by analysis of the nucleotide sequences of eight genes comprising 3,135 codons. Codon usage revealed a biased use of synonymous codons with a preference for NNC codons (42.1%). The codon usage of G. lamblia more closely resembles that of the prokaryote Halobacterium halobium (correlation coefficient r = 0.73) rather than that of other eukaryotic protozoans, i.e. Trypanosoma brucei (r = 0.434) and Plasmodium falciparum (r = -0.31). These observations are consistent with the view that G. lamblia represents the first line of descent from the ancestral cells that first took on eukaryotic features.

Animals↗
PubMed2000

Sequence diversity of Pseudomonas aeruginosa: impact on population structure and genome evolution.

Comparative sequencing of Pseudomonas aeruginosa genes oriC, citS, ampC, oprI, fliC, and pilA in 19 environmental and clinical isolates revealed the sequence diversity to be about 1 order of magnitude lower than in comparable housekeeping genes of Salmonella. In contrast to the low nucleotide substitution rate, the frequency of recombination among different P. aeruginosa genotypes was high, leading to the random association of alleles. The P. aeruginosa population consists of equivalent genotypes that form a net-like population structure. However, each genotype represents a cluster of closely related strains which retain their sequence signature in the conserved gene pool and carry a set of genotype-specific DNA blocks. The codon adaptation index, a quantitative measure of synonymous codon bias of genes, was found to be consistently high in the P. aeruginosa genome irrespective of the metabolic category and the abundance of the encoded gene product. Such uniformly high codon adaptation indices of 0.55 to 0.85 fit the ubiquitous lifestyle of P. aeruginosa.

Biological Evolution↗
PubMed1997

Codon bias evolution in Drosophila. Population genetics of mutation-selection drift.

Although non-random patterns of synonymous codon usage are a prominent feature in the genomes of many organisms, the relatives roles of mutational biases and natural selection in maintaining codon bias remain a contentious issue. In some species, patterns of codon bias and empirical findings on the biology of translation suggest 'major codon preference', a balance among mutation pressure, genetic drift, and weak selection in favor of translationally superior codons. Population genetics theory makes testable predictions to distinguish such a model from a strictly mutational model of codon bias. Major codon preference predicts two fitness classes of synonymous DNA changes: 'preferred' mutations from non-major to major codons and 'unpreferred' changes in the opposite direction. An extension of current statistical methods is employed to reveal differences in the within and between species dynamics of preferred and unpreferred silent mutations in Drosophila simulans. In this lineage, codon bias appears to be maintained under roughly equal magnitudes of natural selection and genetic drift. In the sibling species, D. melanogaster, however, a reduction in N(e)s, the product of effective population size and selection coefficient, appears to have allowed a genome-wide reduction in codon bias.

Animals↗