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PubMed2006

[Codon usage of Chinese hamster ovary cells.].

BACKGROUND: To investigate the optimal codons of dihydrofolate reductase (dhfr) minus Chinese hamster ovary cells (CHO dhfr-). METHODS: A cDNA library of CHO dhfr- containing high abundence mRNA was constructed and protein-coding sequences were obtained after identification and analysis. Codon frequence of CHO dhf- was compared with that of Chinese hamster in CUTG database. Then codon usage variation among cDNA was investigated using correspondence analysis (COA). RESULTS: Fifty qualified cDNAs from CHO dhfr- were selected, which encodes proteins of high abundence. Comparing with the codon frequence of Chinese hamster, the highest frequence of synonymous codons for amino acids in CHO dhfr- cells were the same as Chinese hamster except that of Arg and Pro. This method of COA identifies the first main factor which can account for the largest fractions (14.7%) of variation among cDNAs. Twenty-two synonymous codons were identified as the optimal codons of CHO cell. CONCLUSION: CHO dhfr- cell has its own optimal codons, it is suggested that codon bias is one of reasons for functional diversity of different mammal cells and it is an effective stratagy to modification of the codon usage of the foreign gene according to the optimal codons of CHO dhfr- to increase the production of foreign gene.

Animals↗
PubMed1995

Synonymous substitution-rate constants in Escherichia coli and Salmonella typhimurium and their relationship to gene expression and selection pressure.

Based on the differences in synonymous codon use between E. coli and S. typhimurium, the synonymous substitution rates can be estimated. In contrast to previous studies on the substitution rates in these two organisms, we use a kinetic model that explicitly takes the selection bias into account. The selection pressure on synonymous codons for a particular amino acid can be calculated from the observed codon bias. This offers a unique opportunity to study systematically the relationship between substitution-rate constants and selection pressure. The results indicate that the codon bias in these organisms is determined by a mutation-selection balance rather than by stabilizing selection. A best fit to the data implies that the mutation rate constant increases about threefold in genes at low expression levels relative to those that are highly expressed.

Base Sequence↗
PubMed2000

A test of translational selection at 'silent' sites in the human genome: base composition comparisons in alternatively spliced genes.

Natural selection appears to discriminate among synonymous codons to enhance translational efficiency in a wide range of prokaryotes and eukaryotes. Codon bias is strongly related to gene expression levels in these species. In addition, between-gene variation in silent DNA divergence is inversely correlated with codon bias. However, in mammals, between-gene comparisons are complicated by distinctive nucleotide-content bias (isochores) throughout the genome. In this study, we attempted to identify translational selection by analyzing the DNA sequences of alternatively spliced genes in humans and in Drosophila melanogaster. Among codons in an alternatively spliced gene, those in constitutively expressed exons are translated more often than those in alternatively spliced exons. Thus, translational selection should act more strongly to bias codon usage and reduce silent divergence in constitutive than in alternative exons. By controlling for regional forces affecting base-composition evolution, this within-gene comparison makes it possible to detect codon selection at synonymous sites in mammals. We found that GC-ending codons are more abundant in constitutive than alternatively spliced exons in both Drosophila and humans. Contrary to our expectation, however, silent DNA divergence between mammalian species is higher in constitutive than in alternative exons.

Alternative Splicing↗
PubMedDate not supplied

[Regularities of the nucleotide sequence at the 5'-end of the codon in Escherichia coli genes].

The frequencies of occurrence of nucleotides at the 5' side of codons have been determined in highly and weakly expressed genes from E. coli. Significant constraints on the nucleotide 5' to some codons were found in highly expressed genes. Certain rules of synonymous codon usage depending on the amino acid 3' of the codon were established. E. g., codon possessing quanosine in the third position (NNG) are preferred over NNA if the next amino acid is lysine (P less than 10(-5)). On the other hand, rules of synonymous codon usage in relation to 5' flanking nucleotide were found. For example, when coding for aspartic acid, GAC codon is preferred over GAU (P less than 0.001) if uridine is 5' to codon and on the contrary GAU is favoured (P less than 0.0001) if quanosine is at the 5' side of aspartic acid codon. These rules can be used in the chemical synthesis of genes designed for expression in E. coli.

Base Sequence↗
PubMedDate not supplied

Codon equilibrium I: Testing for homogeneous equilibrium.

We present theoretical considerations that suggest that synonymous-codon usage might be expected to be close to an equilibrium distribution given a very homogeneous process of silent substitution. By homogeneous we mean that substitution depends only on the two bases involved, so that 12 base-substitution rates completely describe the silent substitution process. We have developed a method of statistically testing for such homogeneous equilibrium and applied it to reported data on the codon usages of different classes of organisms. Weakly expressed bacterial sequences and both mammalian and nonmammalian eukaryotic sequences deviate significantly from a random pattern of codon usage, in the direction of homogeneous equilibrium. On the other hand, highly expressed bacterial sequences do not exhibit homogeneous equilibrium, which may be correlated with recent experimental results showing that they are optimized to accept the most abundant tRNAs. To examine the effect of amino acid replacements on the homogeneous model of silent substitution, we divided the amino acids with degenerate codes into two classes, those with high mutabilities and those with low, and performed the same analysis on bacterial and eukaryotic data sets. The codon sets of the highly mutable class of amino acids are not further from homogeneous equilibrium than are the codon sets of the class with low mutabilities. We also found for the eukaryotic data that these independent classes of codon sets show very similar equilibrium patterns. The various results suggest a high level of uniformity in the process of silent fixation in the different synonymous-codon sets, especially in eukaryotes.

Amino Acid Sequence↗
PubMed1994

Codon use and the rate of divergence of land plant chloroplast genes.

Codon fitnesses for chloroplast genes were estimated using the relative synonymous codon use of psbA, which has a different pattern of codon use than other chloroplast genes and is the major translation product of the chloroplast. These estimates were used to calculate the codon adaptation index (CAI) of chloroplast genes from Marchantia polymorpha, Nicotiana tabacum, and Chlamydomonas reinhardtii. The genes with the highest CAI values in M. polymorpha correspond to those that are expressed at the highest levels. The rate of divergence between M. polymorpha and both C. reinhardtii and N. tabacum is inversely related to the CAI value of the M. polymorpha gene. The data suggest that selection is acting on the synonymous codon use of the highly expressed genes of the M. polymorpha chloroplast genome. The data set is inconclusive about N. tabacum genes, but, as there is a weaker correspondence between CAI value and expression level, it suggests that selection is not operating in this lineage.

Animals↗
PubMed1991

Essential factors determining codon usage in ubiquitin genes.

Ubiquitin is ubiquitous in all eukaryotes and its amino acid sequence shows extreme conservation. Ubiquitin genes comprise direct repeats of the ubiquitin coding unit with no spacers. The nucleotide sequences coding for 13 ubiquitin genes from 11 species reported so far have been compiled and analyzed. The G + C content of codon third base reveals a positive linear correlation with the genome G + C content of the corresponding species. The slope strongly suggests that the overall G + C content of codons of polyubiquitin genes clearly reflects the genome G + C content by AT/GC substitutions at the codon third position. The G + C content of ubiquitin codon third base also shows a positive linear correlation with the overall G + C content of coding regions of compiled genes, indicating the codon choices among synonymous codons reflect the average codon usage pattern of corresponding species. On the other hand, the monoubiquitin gene, which is different from the polyubiquitin gene in gene organization, gene expression, and function of the encoding protein, shows a different codon usage pattern compared with that of the polyubiquitin gene. From comparisons of the levels of synonymous substitutions among ubiquitin repeats and the homology of the amino acid sequence of the tail of monomeric ubiquitin genes, we propose that the molecular evolution of ubiquitin genes occurred as follows: Plural primitive ubiquitin sequences were dispersed on genome in ancestral eukaryotes. Some of them situated in a particular environment fused with the tail sequence to produce monomeric ubiquitin genes that were maintained across species. After divergence of species, polyubiquitin genes were formed by duplication of the other primitive ubiquitin sequences on different chromosomes. Differences in the environments in which ubiquitin genes are embedded reflect the differences in codon choice and in gene expression pattern between poly- and monomeric ubiquitin genes.

Amino Acid Sequence↗
PubMed1999

Protein-coding regions prediction combining similarity searches and conservative evolutionary properties of protein-coding sequences.

The gene identification procedure in a completely new gene with no good homology with protein sequences can be a very complex task. In order to identify the protein-coding region, a new method, 'SYNCOD', based on the analysis of conservative evolutionary properties of coding regions, has been realized. This program is able to identify and use the coding region homologies of the non-annotated (unknown) protein-coding sequences already present in the nucleotide sequence databases by using the alignment produced by BLASTN. The ratio of number mismatches resulting in synonymous codons to the number of mismatches resulting in non-synonymous codons is estimated for each open reading frame. Monte Carlo simulations are then used to estimate the significance of the ratio deviation from random behavior. The SYNCOD program has been tested on generated random sequences and on different control sets. The high accuracy of predicting protein-coding regions (the correlation coefficient, CC, varies from 0.67 to 0.79) and the high specificity (the portion of wrong exons, WE, varies from 0.06 to 0.07) have proved to be important features of the suggested approach. The SYNCOD program is resident on the ITBA-CNR Web Server and can be used via the Internet (URL: www.itba.mi.cnr.it/webgene).

Algorithms↗
PubMed1996

Unbiased estimation of symmetrical directional mutation pressure from protein-coding DNA.

The most generally applicable procedure for obtaining estimates of the symmetrical, or strandnonspecific, directional mutation pressure (microD) on protein-coding DNA sequences is to determine the G+C content at synonymous codon sites (Psyn), and to divide Psyn by twice the arithmetic mean of the G+C content at synonymous codon sites of a large number of randomly generated, synonymously coding DNA sequences (Psyn). Unfortunately, the original procedure yields biased estimates of Psyn and microD and is computationally expensive. We here present a fast procedure for estimating unbiased microD values. The procedure employs direct calculation of Psyn (approximately Psyn) and two normalization procedures, one for Psyn < or = Psyn and another for Psyn > or = Psyn. The normalization removes a bias sometimes caused by codons specifying arginine, asparagine, isoleucine, and leucine. Consequently, comparison of protein-coding genes that are translated using different genetic codes is facilitated.

Animals↗
PubMed1986

Codon usage in yeast: cluster analysis clearly differentiates highly and lowly expressed genes.

Codon usage data has been compiled for 110 yeast genes. Cluster analysis on relative synonymous codon usage revealed two distinct groups of genes. One group corresponds to highly expressed genes, and has much more extreme synonymous codon preference. The pattern of codon usage observed is consistent with that expected if a need to match abundant tRNAs, and intermediacy of tRNA-mRNA interaction energies are important selective constraints. Thus codon usage in the highly expressed group shows a higher correlation with tRNA abundance, a greater degree of third base pyrimidine bias, and a lesser tendency to the A+T richness which is characteristic of the yeast genome. The cluster analysis can be used to predict the likely level of gene expression of any gene, and identifies the pattern of codon usage likely to yield optimal gene expression in yeast.

Base Composition↗
PubMed2005

Modelling of translation of human protein disulfide isomerase in Escherichia coli-A case study of gene optimisation.

Recombinant human protein disulfide isomerase (PDI) was expressed in vivo in Escherichia coli using a non-optimised gene sequence and an optimised sequence with four 5' codons substituted by synonymous codons that take less time to translate. The optimisation resulted in a 2-fold increase of total PDI concentration and by successive optimisation with expression at low temperature in a 10-fold increase of the amount of soluble PDI in comparison with the original wild-type construct. The improvement can be due to a faster clearing of the ribosome binding site on the mRNA, elevating the translation initiation rate and resulting in higher ribosome loading and better ribosome protection of the PDI mRNA against endonucleolytic cleavage by RNase. This hypothesis was supported by a novel computer simulation model of E. coli translational ribosome traffic based upon the stochastic Gillespie algorithm. The study indicates the applicability of such models in optimisation of recombinant protein sequences.

Computer Simulation↗
PubMed2001

Cloning and expression of the external-glycoprotein gene mutant from HIV-2 in the methylotrophic yeast Pichia pastoris and identification of the glycoprotein.

To achieve high-level expression of HIV-2(ROD) external glycoprotein gp105 in Pichia pastoris, the gp105 gene mutant tP1, with the 5' non-functional region of the gp105 gene removed, was obtained by PCR amplification and was cloned into secreted expression vector pHILS1. The His(+)Mut(s) recombinant P. pastoris strain was screened by PCR and induced by methanol. SDS/PAGE and Western-blot analyses showed that mutation of the low-usage codon AGG into synonymous codon CGA and the introduction of the optimal codon TTC made P. pastoris overexpress tP1, an 85 kDa heterologous glycoprotein that was secreted into the medium and recognized specifically by HIV-2 polyclonal antibody. The recombinant strain GS115/tP1 had excellent genetic stability in terms of the properties of growth and expression of gp105, and seven out of 58 recombinant stains with a yield of 29% were selected to be used for further purification of gp105.

Blotting, Western↗
PubMed1988

Codon usage in Pseudomonas aeruginosa.

We have generated a codon usage table for Pseudomonas aeruginosa. Codon usage in P. aeruginosa is extremely biased. In contrast to E. coli and yeast, P. aeruginosa preferentially uses those codons within a synonymous codon group with the strongest predicted codon-anticodon interaction. We were unable to correlate a particular codon usage pattern with predicted levels of mRNA expressivity. The choice of a third base reflects the high guanine plus cytosine content of the P. aeruginosa genome (67.2%) and cytosine is the preferred nucleotide for the third codon position.

Bacteriophages↗
PubMed2003

HGT-DB: a database of putative horizontally transferred genes in prokaryotic complete genomes.

The Horizontal Gene Transfer DataBase (HGT-DB) is a genomic database that includes statistical parameters such as G+C content, codon and amino-acid usage, as well as information about which genes deviate in these parameters for prokaryotic complete genomes. Under the hypothesis that genes from distantly related species have different nucleotide compositions, these deviated genes may have been acquired by horizontal gene transfer. The current version of the database contains 88 bacterial and archaeal complete genomes, including multiple chromosomes and strains. For each genome, the database provides statistical parameters for all the genes, as well as averages and standard deviations of G+C content, codon usage, relative synonymous codon usage and amino-acid content. It also provides information about correspondence analyses of the codon usage, plus lists of extraneous group of genes in terms of G+C content and lists of putatively acquired genes. With this information, researchers can explore the G+C content and codon usage of a gene when they find incongruities in sequence-based phylogenetic trees. A search engine that allows searches for gene names or keywords for a specific organism is also available. HGT-DB is freely accessible at http://www.fut.es/~debb/HGT.

Amino Acids↗
PubMed2000

Two human gene families display preferences for different nucleotides and have distinct codon usage patterns.

Analysis of base composition has proven important for functional gene analysis. By comparing base composition and codon usage between two specific human gene families we were able to show a highly conserved nucleotide distribution among the members of one gene family and a significant difference between the two families. The two groups selected for analysis were the human factor H gene family, which represents six secreted human plasma proteins with functions in immune defense, and a class of four human zinc finger proteins, termed early growth response (EGR) proteins, which represent DNA-binding transcription factors. The nucleotide distribution of each gene family is distinct: members of the factor H gene family represent AT-rich genes, displaying an overall AT nucleotide content of 62.8% and a particular preference for A nucleotides (33.9%). In contrast, the EGR genes are GC-rich (55.9%) and C nucleotides are used in 31.2%. This nucleotide difference affects codon usage among synonymous codons and is considered of biological significance, as it affects DNA stability. The codon preference is particularly high at codon position 3, where each family selects for codons which have the preferred nucleotide at this silent third position. At position 3, A nucleotides are preferred by factor H genes in 36.3% of the 2, 503 codons analyzed, compared to 10% of the 1,876 codons analyzed for the EGR family. In contrast, C nucleotides are used by the EGR family in 48.1%, compared to 16% of the triplets used by the factor H gene family. This comparison of two human gene families shows that nucleotide distribution and codon usage is not uniform within the human organism and the described differences most likely represent selection constraints between the polymorphic factor H and highly conserved EGR genes.

Base Composition↗
PubMed2005

What makes ribosome-mediated transcriptional attenuation sensitive to amino acid limitation?

Ribosome-mediated transcriptional attenuation mechanisms are commonly used to control amino acid biosynthetic operons in bacteria. The mRNA leader of such an operon contains an open reading frame with "regulatory" codons, cognate to the amino acid that is synthesized by the enzymes encoded by the operon. When the amino acid is in short supply, translation of the regulatory codons is slow, which allows transcription to continue into the structural genes of the operon. When amino acid supply is in excess, translation of regulatory codons is rapid, which leads to termination of transcription. We use a discrete master equation approach to formulate a probabilistic model for the positioning of the RNA polymerase and the ribosome in the attenuator leader sequence. The model describes how the current rate of amino acid supply compared to the demand in protein synthesis (signal) determines the expression of the amino acid biosynthetic operon (response). The focus of our analysis is on the sensitivity of operon expression to a change in the amino acid supply. We show that attenuation of transcription can be hyper-sensitive for two main reasons. The first is that its response depends on the outcome of a race between two multi-step mechanisms with synchronized starts: transcription of the leader of the operon, and translation of its regulatory codons. The relative change in the probability that transcription is aborted (attenuated) can therefore be much larger than the relative change in the time it takes for the ribosome to read a regulatory codon. The second is that the general usage frequencies of codons of the type used in attenuation control are small. A small percentage decrease in the rate of supply of the controlled amino acid can therefore lead to a much larger percentage decrease in the rate of reading a regulatory codon. We show that high sensitivity further requires a particular choice of regulatory codon among several synonymous codons for the same amino acid. We demonstrate the importance of a high fraction of regulatory codons in the control region. Finally, our integrated model explains how differences in leader sequence design of the trp and his operons of Escherichia coli and Salmonella typhimurium lead to high basal expression and low sensitivity in the former case, and to large dynamic range and high sensitivity in the latter. The model clarifies how mechanistic and systems biological aspects of the attenuation mechanism contribute to its overall sensitivity. It also explains structural differences between the leader sequences of the trp and his operons in terms of their different functions.

Journal Article↗
PubMed1981

Rapidly evolving mouse alpha-globin-related pseudo gene and its evolutionary history.

The nucleotide sequences of a mouse pseudo alpha-globin gene and two adult alpha-globin genes from mouse and rabbit were compared. A close examination of sequence differences among the three genes revealed that the mouse pseudo alpha-globin gene was derived from one of the mouse alpha-globin genes about 24 million years ago by gene duplication and lost its original function, presumably due to loss of both the intervening sequences or frameshift mutations that prevented production of a functional globin polypeptide, and eventually became an inactive gene about 17 million years ago. After this event, this gene evolved at a very high rate, approximately 1.9 times the rate of synonymous codon change in productive genes. This suggests the presence of functional constraints against synonymous codon changes in normally functioning genes and also suggests that the "nucleotide arrangements" serve almost no important functions beside protein coding ability in the greater part of this gene, except for a very limited number of nucleotides. A continuous stretch of the pseudo alpha-globin gene consisting of a third exon and a 5' half of the 3' noncoding region shows marked sequence homology to the alpha-globin gene, suggesting transfer from one of the globin or globin-like genes by recombination very recently.

Animals↗
PubMed1996

Non-random usage of 'degenerate' codons is related to protein three-dimensional structure.

We report an analysis of a novel sequence-structure database of mammalian proteins incorporating nucleotide sequences of the exon regions of their genes together with protein sequence and structural information. We find that synonymous codon families (i.e. coding the same residue) have non-random codon distribution frequencies between protein secondary structure types. Their structural preferences are related to the third, 'silent' nucleotide position in a codon. We also find that some synonymous codons show very different or even opposite structural preferences at the N- or C-termini of structure fragments, relative to those observed for their amino acid residues.

Animals↗