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PubMed2002

Conservation of translation initiation sites based on dinucleotide frequency and codon usage in Escherichia coli K-12 (W3110): non-random distribution of A/T-rich sequences immediately upstream of the translation initiation codon.

Dinucleotide frequencies are useful for characterizing consensus elements as a minimum unit of nucleotide sequence because the neighborhood relations of nucleotide sequences are reflected in dinucleotides. Using a consensus score based on dinucleotide frequencies and intra-species codon usage heterogeneity, denoted by the Z1 parameter, we report the relationship between nucleotide conservation at the translation initiation sites of genes in the Escherichia coli K-12 genome (W3110) and codon usage in its downstream genes. Significant positive correlations were obtained in three regions centered at -13, -4, and +7, which correspond to the Shine-Dalgarno element, the A + T element immediately upstream of the translation initiation site, and the downstream box, respectively.

Base Sequence↗

PubMed2000

Compositional pressure and translational selection determine codon usage in the extremely GC-poor unicellular eukaryote Entamoeba histolytica.

It is widely accepted that the compositional pressure is the only factor shaping codon usage in unicellular species displaying extremely biased genomic compositions. This seems to be the case in the prokaryotes Mycoplasma capricolum, Rickettsia prowasekii and Borrelia burgdorferi (GC-poor), and in Micrococcus luteus (GC-rich). However, in the GC-poor unicellular eukaryotes Dictyostelium discoideum and Plasmodium falciparum, there is evidence that selection, acting at the level of translation, influences codon choices. This is a twofold intriguing finding, since (1) the genomic GC levels of the above mentioned eukaryotes are lower than the GC% of any studied bacteria, and (2) bacteria usually have larger effective population sizes than eukaryotes, and hence natural selection is expected to overcome more efficiently the randomizing effects of genetic drift among prokaryotes than among eukaryotes. In order to gain a new insight about this problem, we analysed the patterns of codon preferences of the nuclear genes of Entamoeba histolytica, a unicellular eukaryote characterised by an extremely AT-rich genome (GC = 25%). The overall codon usage is strongly biased towards A and T in the third codon positions, and among the presumed highly expressed sequences, there is an increased relative usage of a subset of codons, many of which are C-ending. Since an increase in C in third codon positions is 'against' the compositional bias, we conclude that codon usage in E. histolytica, as happens in D. discoideum and P. falciparum, is the result of an equilibrium between compositional pressure and selection. These findings raise the question of why strongly compositionally biased eukaryotic cells may be more sensitive to the (presumed) slight differences among synonymous codons than compositionally biased bacteria.

Animals↗

PubMed2001

Influence of intercodon and base frequencies on codon usage in filarial parasites.

Base frequency, codon usage, and intercodon identity were analyzed in five filarial parasite species representing five Onchocercidae genera. Wucheria bancrofti, Brugia malayi, Onchocerca volvulus, Acanthocheilonema viteae, and Dirofilaria immitis gene sequences were downloaded from NCBI, and analysis was performed using locally designed computer programs and other freely available applications. A clear sequence bias was observed among the nematode species examined. At the nucleotide level, AT basepairs were present in gene sequences at higher frequencies than GC. In addition, codons ending in A or T were used proportionately more than those with G or C in the third-codon position. In addition, the amino acids used most often corresponded to codons ending in AT basepairs. Intercodon base proportion was biased in that A was found most often at N4, second only to T in certain specific cases. Since all of these sequence biases were observed in a relatively consistent fashion among all of the organisms studied, we conclude that sequence bias is a genetic characteristic, which is associated with multiple filarial genera.

Animals↗

PubMed1985

Significance of nucleotide sequence alignments: a method for random sequence permutation that preserves dinucleotide and codon usage.

The similarity of two nucleotide sequences is often expressed in terms of evolutionary distance, a measure of the amount of change needed to transform one sequence into the other. Given two sequences with a small distance between them, can their similarity be explained by their base composition alone? The nucleotide order of these sequences contributes to their similarity if the distance is much smaller than their average permutation distance, which is obtained by calculating the distances for many random permutations of these sequences. To determine whether their similarity can be explained by their dinucleotide and codon usage, random sequences must be chosen from the set of permuted sequences that preserve dinucleotide and codon usage. The problem of choosing random dinucleotide and codon-preserving permutations can be expressed in the language of graph theory as the problem of generating random Eulerian walks on a directed multigraph. An efficient algorithm for generating such walks is described. This algorithm can be used to choose random sequence permutations that preserve (1) dinucleotide usage, (2) dinucleotide and trinucleotide usage, or (3) dinucleotide and codon usage. For example, the similarity of two 60-nucleotide DNA segments from the human beta-1 interferon gene (nucleotides 196-255 and 499-558) is not just the result of their nonrandom dinucleotide and codon usage.

Base Sequence↗

PubMed2001

Intron length and codon usage.

The correlation was shown between the length of introns and the codon usage of the coding sequences of the corresponding genes, which in some cases can be related to the level of gene expression. The link is positive in the unicellular organisms, i.e., genes with the longer introns show the higher bias of codon usage. It is most pronounced in baker's yeast, where it is definitely related to the level of gene expression--genes with the higher level of expression have the longer introns. The correlation is inverted in multicellular organisms as compared to unicellular ones. Some organisms, however, do not show the link. The presence or absence of the link does not seem to be related to the GC percent of the coding sequences.

Animals↗

PubMed1999

The positive relationship between codon usage bias and translation initiation AUG context in Saccharomyces cerevisiae.

The relationship between the codon usage bias and the sequence context surrounding the AUG translation initiation codon was examined in 211 Saccharomyces cerevisiae mRNA sequences. The codon usage bias and the number of matches to optimal AUG context, (A/U)A(A/C)AA(A/C)AUGUC(U/C), for translation initiation showed a positive relationship, indicating that these two factors are evolutionally under the similar natural selection constraint at the translation level. A new index (AUGCAI = AUG Context Adaptation Index) for the measure of optimal AUG context was devised, and the importance of each position of AUG context was also examined.

Base Sequence↗

PubMed1989

Nucleic acid composition, codon usage, and the rate of synonymous substitution in protein-coding genes.

Based on the rates of synonymous substitution in 42 protein-coding gene pairs from rat and human, a correlation is shown to exist between the frequency of the nucleotides in all positions of the codon and the synonymous substitution rate. The correlation coefficients were positive for A and T and negative for C and G. This means that AT-rich genes accumulate more synonymous substitutions than GC-rich genes. Biased patterns of mutation could not account for this phenomenon. Thus, the variation in synonymous substitution rates and the resulting unequal codon usage must be the consequence of selection against A and T in synonymous positions. Most of the variation in rates of synonymous substitution can be explained by the nucleotide composition in synonymous positions. Codon-anticodon interactions, dinucleotide frequencies, and contextual factors influence neither the rates of synonymous substitution nor codon usage. Interestingly, the nucleotide in the second position of codons (always a nonsynonymous position) was found to affect the rate of synonymous substitution. This finding links the rate of nonsynonymous substitution with the synonymous rate. Consequently, highly conservative proteins are expected to be encoded by genes that evolve slowly in terms of synonymous substitutions, and are consequently highly biased in their codon usage.

Animals↗

PubMed2001

Translational selection shapes codon usage in the GC-rich genome of Chlamydomonas reinhardtii.

In unicellular species codon usage is determined by mutational biases and natural selection. Among prokaryotes, the influence of these factors is different if the genome is skewed towards AT or GC, since in AT-rich organisms translational selection is absent. On the other hand, in AT-rich unicellular eukaryotes the two factors are present. In order to understand if GC-rich genomes display a similar behavior, the case of Chlamydomonas reinhardtii was studied. Since we found that translational selection strongly influences codon usage in this species, we conclude that there is not a common pattern among unicellular organisms.

AT Rich Sequence↗

PubMed1999

Codon usage as a tool to predict the cellular location of eukaryotic ribosomal proteins and aminoacyl-tRNA synthetases.

In spite of many efforts, the prediction of the location of proteins in eukaryotic cells (cytoplasm, mitochondrion or chloroplast) is still far from straightforward. In some cases (e.g. ribosomal proteins and aminoacyl-tRNA synthetases) both the cytoplasmic proteins and their organellar counterparts are encoded by the nuclear genome. A factorial correspondence analysis of the codon usage in yeast and Caenorhabditis elegans shows that the codon usage of those nuclear genes encoding ribosomal proteins or aminoacyl-tRNA synthetases is markedly different, depending on the final location of the proteins (cytoplasmic or mitochondrial). As a consequence, the location of such proteins-whose sequences are now frequently determined by systematic genomic sequencing-can be easily and quickly predicted. A WWW interface has been developed, aimed at providing a user-friendly tool for codon usage pattern analysis. It is available from http://www.genetique.uvsq.fr/afc.html

Amino Acyl-tRNA Synthetases↗

PubMed2000

High-level periplasmic expression in Escherichia coli using a eukaryotic signal peptide: importance of codon usage at the 5' end of the coding sequence.

We investigated the ability of signal peptides of eukaryotic origin (human, mouse, and yeast) to efficiently direct model proteins to the Escherichia coli periplasm. These were compared against a well-characterized prokaryotic signal peptide-OmpA. Surprisingly, eukaryotic signal peptides can work very efficiently in E. coli, but require optimization of codon usage by codon-based mutagenesis of the signal peptide coding region. Analysis of the 5' of periplasmic and cytoplasmic E. coli genes shows some codon usage differences.

Amino Acid Sequence↗

PubMed2000

Synthesis of a new Cre recombinase gene based on optimal codon usage for mammalian systems.

The origin of the Cre recombinase gene is bacteriophage P1, and thus the codon usages are different from in mammals. In order to adapt this codon usage for mammals, we synthesized a "mammalian Cre recombinase gene" and examined its expression in Chinese hamster ovarian tumor (CHO) cells. Significant increases in protein production as well as mRNA levels were observed. When the recombination efficiency was compared using CHO cell transfectants having a cDNA containing loxP sites, the "mammalian Cre recombinase gene" recombined the loxP sites much more efficiently than the wild-type Cre recombinase gene.

Amino Acid Sequence↗

PubMed1987

Codon usage in Homo sapiens: evidence for a coding pattern on the non-coding strand and evolutionary implications of dinucleotide discrimination.

This study reports the analysis of codon usage in 35 complete Homo sapiens genes. Both codon frequency and inter-codon interference exhibit patterns of evolutionary interest. There is a significant positive correlation between the frequency with which a given codon is used and the frequency with which its complement is used. Since the frequency of appearance of the complementary codon on the coding strand is equal to the frequency of appearance of the original codon on the non-coding strand, in the same phase, the non-coding strand is found to resemble the coding strand in triplet composition. The same effect has been observed in Escherichia coli. This preference for the use of certain complementary triplets as codons suggests that the evolution of the use of the genetic code depended to some extent upon the double-stranded nature of the coding material. In addition, the effect of discrimination against the use of two dinucleotides, CpG and UpA, is observed in codon usage and also in adjacent codon interference. Codons beginning with G, or A, are unlikely to be preceded by codons ending in C, or U, respectively. Consideration of codon assignment in the genetic code together with the observed CpG infrequency suggests that the evolution of the code may have been influenced by conditions in which the use of CpG dinucleotides was unfavorable. The infrequent use of UpA dinucleotides can be explained as the result of frameshift mutation during gene evolution.

Base Sequence↗

PubMed1999

Recent selection on synonymous codon usage in Drosophila.

Evidence from a variety of sources indicates that selection has influenced synonymous codon usage in Drosophila. It has generally been difficult, however, to distinguish selection that acted in the distant past from ongoing selection. However, under a neutral model, polymorphisms usually reflect more recent mutations than fixed differences between species and may, therefore, be useful for inferring recent selection. If the ancestral state is preferred, selection should shift the frequency distribution of derived states/site toward lower values; if the ancestral is unpreferred, selection should increase the number of derived states/site. Polymorphisms were classified as ancestrally preferred or unpreferred for several genes of D. simulans and D. melanogaster. A computer simulation of coalescence was employed to derive the expected frequency distributions of derived states/site under various modifications of the Wright-Fisher neutral model, and distributions of test statistics (t and Mann-Whitney U) were derived by appropriate sampling. One-tailed tests were applied to transformed frequency data to assess whether the two frequency distributions deviated from neutral expectations in the direction predicted by selection on codon usage. Several genes from D. simulans appear to be subject to recent selection on synonymous codons, including one gene with low codon bias, esterase-6. Selection may also be acting in D. melanogaster.

Animals↗

PubMed1998

Replicational and transcriptional selection on codon usage in Borrelia burgdorferi.

With more than 10 fully sequenced, publicly available prokaryotic genomes, it is now becoming possible to gain useful insights into genome evolution. Before the genome era, many evolutionary processes were evaluated from limited data sets and evolutionary models were constructed on the basis of small amounts of evidence. In this paper, I show that genes on the Borrelia burgdorferi genome have two separate, distinct, and significantly different codon usages, depending on whether the gene is transcribed on the leading or lagging strand of replication. Asymmetrical replication is the major source of codon usage variation. Replicational selection is responsible for the higher number of genes on the leading strands, and transcriptional selection appears to be responsible for the enrichment of highly expressed genes on these strands. Replicational-transcriptional selection, therefore, has an influence on the codon usage of a gene. This is a new paradigm of codon selection in prokaryotes.

Borrelia burgdorferi Group↗

PubMed1997

Growth rate-optimised tRNA abundance and codon usage.

The abundance of different tRNAs in Escherichia coli at different growth rates correlates strongly with the usage of the corresponding cognate codons. On the assumption that the investment in the translation system is optimised to provide a maximal growth rate, the relationship between tRNA levels and codon usage can be predicted. When the complications due to different degeneracies and different association rate constants for the different tRNA-codon combinations are accounted for, recent data from the literature indicate that the predicted relations hold up very well: the tRNA levels correlate with codon frequencies in a way that would support a maximal growth rate. The relations can also be used to predict the association rate constant between an A-site codon and the cognate ternary complex. In the cases where they can be compared, the results agree reasonably well with experimental results from the literature.

Cell Division↗

PubMed1986

Structural organization and unusual codon usage in the DNA polymerase gene from herpes simplex virus type 1.

We have analyzed the protein and nucleic acid sequences of the DNA polymerase from herpes simplex virus type 1 (HSV-1) to provide insight into the expression and possible structure of this enzyme. Extensive similarity between the amino acid sequence and that of the Epstein Barr virus DNA polymerase is reported. We describe probable structural similarities between these proteins and the use of these similarities to define structural and functional domains within the polymerase. Analysis of base composition and codon usage reveals that several genes from HSV-1, including DNA polymerase, exhibit a strong preference for guanine or cytosine at the third codon position. This preference may result from the high guanine + cytosine content of the virus and produces a highly restricted codon usage, different from that of the host cell. Consequences of the unusual codon usage for viral expression include the potential for extensive mRNA secondary structure.

Amino Acid Sequence↗

PubMed2001

Correlation between sequence conservation of the 5' untranslated region and codon usage bias in Mus musculus genes.

The codon adaptation index (CAI) values of all protein-coding sequences of the full-length cDNA libraries of Mus musculus were computed based on the RIKEN mouse full-length cDNA library. We have also computed the extent of consensus in flanking sequences of the initiator ATG codon based on the 'relative entropy' values of respective nucleotide positions (from -20 to +12 bp relative to the initiator ATG codon) for each group of genes classified by CAI values. With regard to the two nucleotides positions (-3 and +4) known to be highly conserved in Kozak's consensus sequence, a clear correlation between CAI values and relative entropy values was observed at position -3 but this was not significant at position +4, although a significant correlation was found at position -1 of the consensus sequence. Further, although no correlation was observed at any additional positions, relative entropy values were very high at positions -4, -6, and -8 in genes with high CAI values. These findings suggest that the extent of conservation in the flanking sequence of the initiator ATG codon including Kozak's consensus sequence was an important factor in modulation of the translation efficiency as well as synonymous codon usage bias particularly in highly expressed genes.

5' Untranslated Regions↗

PubMed1996

Codon usage limitation in the expression of HIV-1 envelope glycoprotein.

BACKGROUND: The expression of both the env and gag gene products of human immunodeficiency virus type 1 (HIV-1) is known to be limited by cis elements in the viral RNA that impede egress from the nucleus and reduce the efficiency of translation. Identifying these elements has proven difficult, as they appear to be disseminated throughout the viral genome. RESULTS: Here, we report that selective codon usage appears to account for a substantial fraction of the inefficiency of viral protein synthesis, independent of any effect on improved nuclear export. The codon usage effect is not specific to transcripts of HIV-1 origin. Re-engineering the coding sequence of a model protein (Thy-1) with the most prevalent HIV-1 codons significantly impairs Thy-1 expression, whereas altering the coding sequence of the jellyfish green fluorescent protein gene to conform to the favored codons of highly expressed human proteins results in a substantial increase in expression efficiency. CONCLUSIONS: Codon-usage effects are a major impediment to the efficient expression of HIV-1 genes. Although mammalian genes do not show as profound a bias as do Escherichia coli genes, other proteins that are poorly expressed in mammalian cells can benefit from codon re-engineering.

Animals↗