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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↗
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↗
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↗
PubMed1988

Codon usage patterns in Escherichia coli, Bacillus subtilis, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Drosophila melanogaster and Homo sapiens; a review of the considerable within-species diversity.

The genetic code is degenerate, but alternative synonymous codons are generally not used with equal frequency. Since the pioneering work of Grantham's group it has been apparent that genes from one species often share similarities in codon frequency; under the "genome hypothesis" there is a species-specific pattern to codon usage. However, it has become clear that in most species there are also considerable differences among genes. Multivariate analyses have revealed that in each species so far examined there is a single major trend in codon usage among genes, usually from highly biased to more nearly even usage of synonymous codons. Thus, to represent the codon usage pattern of an organism it is not sufficient to sum over all genes as this conceals the underlying heterogeneity. Rather, it is necessary to describe the trend among genes seen in that species. We illustrate these trends for six species where codon usage has been examined in detail, by presenting the pooled codon usage for the 10% of genes at either end of the major trend. Closely-related organisms have similar patterns of codon usage, and so the six species in Table 1 are representative of wider groups. For example, with respect to codon usage, Salmonella typhimurium closely resembles E. coli, while all mammalian species so far examined (principally mouse, rat and cow) largely resemble humans.

Amino Acids↗
PubMed1994

The use of logistic models for the analysis of codon frequencies of DNA sequences in terms of explanatory variables.

The development of the regressive logistic model applicable to the analysis of codon frequencies of DNA sequences in terms of explanatory variables is presented. A codon is a triplet of nucleotides that code for an amino acid, and may be considered as a trivariate response (B1, B2, B3), where Bi (i = 1, 2, 3) is a categorical random variable with values A, C, G, T. The linear order of bases in the DNA and possible statistical dependence of the bases in a given codon make the regressive logistic model a suitable tool for the analysis of codon frequencies. A problem of structural zeros arises from the fact that the stopping codons (terminators) do not code for amino acids; this is solved by normalizing the likelihood function. Codon frequencies may also depend on the function of the gene and they are known to differ between genes of the same genome. Differences also occur between synonymous codons for the same amino acid. Thus, the use of covariates that differ between synonymous codons as well as covariates that are constant within codons of the same amino acid may be useful in explaining the frequencies. As an illustration, the method is applied to the human mitochondrial genome using the following as explanatory variables: (1) TSCORE, a measure of the number of single base mutations required for a given codon to become a terminator; (2) AARISK, an indicator of a codon's ability of changing by a single base substitution to triplets coding for amino acids with very different characteristics; (3) AVDIST, a measure of the typicality of the amino acid coded for by the triplets. The results indicate that models that incorporate dependency structure and covariates are to be preferred to either the models comprising covariates alone or dependency structure alone.

Amino Acid Sequence↗
PubMed1980

Nucleotide sequence divergence and functional constraint in mRNA evolution.

Comparison of about 50 pairs of homologous nucleotide sequences for different genes revealed that the substitutions between synonymous codons occurred at much higher rates than did amino acid substitutions. Furthermore, five pairs of mRNA sequences for different genes were compared in species that had diverged at the same time. The evolutionary rate of synonymous substitution was estimated to be 5.1 X 10(-9) per site per year on the average and is approximately constant among different genes. It also is suggested that this property would be suitable for a molecular clock to determine the evolutionary relationships and branching order of duplicated genes. Each functional block of the noncoding region evolves with a rate that is almost constant, regardless of the types of genes. The intervening sequence and the 5' portion of the 3' noncoding region show considerable divergence, the extent of which is almost comparable to that in the synonymous codon sites, whereas the other blocks consisting of the 5' noncoding region and the 3' portion of the 3' noncoding region are strongly conserved, showing approximatley half of the divergence of the synonymous sites. This strong sequence preservation might be due to the functional requirements for transcription and modification of mRNA.

Amino Acid Sequence↗
PubMed1985

Theory of degenerate coding and informational parameters of protein coding genes.

The theory of degenerate coding is presented in a way enabling further application to molecular biology. There are two kinds of redundancy of a degenerate code. The first is due to the excess in codon length and the second to the code degeneracy. If the code is asymmetrically degenerate, the second kind of redundancy can be profitable for control of error rate. This control can be performed just by selective synonymous codon usage. Utilisation of the genetic code is partially influenced by this theoretical possibility. In particular the degree of error protectivity is well correlated with deviation from equiprobability in synonymous codon usage. The biological significance of this fact is discussed.

Animals↗
PubMed1991

Codon usage in Aspergillus nidulans.

Synonymous codon usage in genes from the ascomycete (filamentous) fungus Aspergillus nidulans has been investigated. A total of 45 gene sequences has been analysed. Multivariate statistical analysis has been used to identify a single major trend among genes. At one end of this trend are lowly expressed genes, whereas at the other extreme lie genes known or expected to be highly expressed. The major trend is from nearly random codon usage (in the lowly expressed genes) to codon usage that is highly biased towards a set of 19-20 "optimal" codons. The G + C content of the A. nidulans genome is close to 50%, indicating little overall mutational bias, and so the codon usage of lowly expressed genes is as expected in the absence of selection pressure at silent sites. Most of the optimal codons are C- or G- ending, making highly expressed genes more G + C-rich at silent sites.

Aspergillus nidulans↗
PubMed1991

A Macintosh computer program for designing DNA sequences that code for specific peptides and proteins.

A computer program (PINCERS) is described for use in the design of synthetic genes and mixed-probe DNA sequences. A protein sequence is reverse translated with generation of synonymous codons at each position producing a degenerate sequence. In order to locate potential restriction enzyme sites, the degenerate sequence is searched with a library of restriction enzymes for sites that utilize any combination of synonymous codons. These sites are indicated in a map so that they may be incorporated into the synthetic gene sequence. The program allows the user to select the appropriate codon usage table for the organism of interest and then to set a threshold usage frequency below which codons are not generated. PINCERS may also be used to assist in planning the synthesis of mixed-probe DNA sequences for cross-hybridization experiments. It can identify regions of specified length with the protein sequence that have the least overall degeneracy, thereby minimizing the number of probes to be synthesized and, therefore, maximizing the concentration of a given probe sequence.

DNA↗
PubMedDate not supplied

Coevolution of codon usage and transfer RNA abundance.

The use of synonymous codons is strongly biased in the bacterium Escherichia coli and yeast, comprising both bias between codons recognized by the same transfer RNA and bias between groups of codons recognized by different synonymous tRNAs. A major determinant of the second sort of bias is tRNA content, codons recognized by abundant tRNAs being used more often than those recognised by rare tRNAs, particularly in highly expressed genes, probably owing to selection at the level of translation against codons recognized by rare tRNAs. Conversely, codon usage is likely to exert selection pressure on tRNA abundance. Here I develop a model for the coevolution of codon usage and tRNA abundance which explains why there are unequal abundances of synonymous tRNAs leading to biased usage between groups of codons recognized by them in unicellular organisms.

Biological Evolution↗
PubMed1995

Inferring weak selection from patterns of polymorphism and divergence at "silent" sites in Drosophila DNA.

Patterns of codon usage and "silent" DNA divergence suggest that natural selection discriminates among synonymous codons in Drosophila. "Preferred" codons are consistently found in higher frequencies within their synonymous families in Drosophila melanogaster genes. This suggests a simple model of silent DNA evolution where natural selection favors mutations from unpreferred to preferred codons (preferred changes). Changes in the opposite direction, from preferred to unpreferred synonymous codons (unpreferred changes), are selected against. Here, selection on synonymous DNA mutations is investigated by comparing the evolutionary dynamics of these two categories of silent DNA changes. Sequences from outgroups are used to determine the direction of synonymous DNA changes within and between D. melanogaster and Drosophila simulans for five genes. Population genetics theory shows that differences in the fitness effect of mutations can be inferred from the comparison of ratios of polymorphism to divergence. Unpreferred changes show a significantly higher ratio of polymorphism to divergence than preferred changes in the D. simulans lineage, confirming the action of selection at silent sites. An excess of unpreferred fixations in 28 genes suggests a relaxation of selection on synonymous mutations in D. melanogaster. Estimates of selection coefficients for synonymous mutations (3.6 < magnitude of Nes < 1.3) in D. simulans are consistent with the reduced efficacy of natural selection (magnitude of Nes < 1) in the three- to sixfold smaller effective population size of D. melanogaster. Synonymous DNA changes appear to be a prevalent class of weakly selected mutations in Drosophila.

Animals↗
PubMed1995

Polyketide synthase acyl carrier proteins from Streptomyces: expression in Escherichia coli, purification and partial characterisation.

Acyl carrier proteins (ACPs) of the type II polyketide synthases for the aromatic antibiotics actinorhodin, granaticin, frenolicin and oxytetracycline were expressed in Escherichia coli downstream of an inducible phage T7 promoter. For the act and otc genes, several of the first eight codons were changed to synonymous codons used in highly expressed E. coli genes. Correlated with these changes, the amounts of the act and otc ACPs purified from the recombinant E. coli cultures were an order of magnitude greater than for the gra and fren ACPs expressed from the unmodified genes. Electrospray mass spectrometry (ESMS) of the purified proteins confirmed their calculated M(r) based on the DNA sequences while also revealing that, in the act and gra ACP samples, some 2% and 30% of the holo-form of the protein was present (i.e., carrying the 4'-phosphopantetheine prosthetic group), with the remainder (and 100% of the otc and fren samples) being in the apo-form. Increasing incubation time post heat induction led to an increase in act holo-ACP. The recombinant act and gra ACPs could function in vitro as substrates for an S. coelicolor malonyl CoA:ACP acyl transferase, as measured by the coupling of a labelled malonyl unit to the ACP; their quantitative abilities to do so correlated with the proportions of deduced holo form in the two samples.

Acyl Carrier Protein↗
PubMed2026

Dietary arginine drives codon-dependent MHC class I translation and improves immunity in colon tumorigenesis and respiratory viral infection.

Amino acid levels fluctuate across diverse pathological conditions. Whether such amino acid modulations directly shape pathophysiology by regulating host gene expression remains unknown. We found that extracellular arginine restriction, observed in cancer and infection, represses specific arginine tRNAs-directly suppressing translation of major histocompatibility complex I (MHC class I) and antigen presentation. Arginine regulation of MHC class I was codon-usage dependent, as synonymous codon mutations prevented MHC class I modulation. Dietary arginine restriction impaired anti-viral immunity against influenza and SARS-CoV-2 and increased colon tumorigenesis. Conversely, increasing arginine availability via dietary supplementation or myeloid-specific arginase 1 deletion enhanced MHC class I protein levels, suppressed colon tumorigenesis, and improved viral infection outcomes. These disease-modulating effects were abolished in &#x3b2;2-microglobulin (B2m)-deficient mice. Thus, dietary modulation of a single amino acid critically influences codon-biased translation and MHC class I-mediated immunity to respiratory viral infections and cancer, revealing an unexpected mechanism and disease hazard for arginine deficiency and highlighting potential for amino acid-based translation modulation therapy.

Animals↗
PubMed1993

The rates of macromolecular chain elongation modulate the initiation frequencies for transcription and translation in Escherichia coli.

Here we show that most macromolecular biosynthesis reactions in growing bacteria are sub-saturated with substrate. The experiments should in part test predictions from a previously proposed model (Jensen & Pedersen 1990) which proposed a central role for the rates of the RNA and peptide chain elongation reactions in determining the concentration of initiation competent RNA polymerases and ribosomes and thereby the initiation frequencies for these reactions. We have shown that synthesis of ribosomal RNA and the concentration of ppGpp did not exhibit the normal inverse correlation under balanced growth conditions in batch cultures when the RNA chain elongation rate was limited by substrate supply. The RNA chain elongation rate for the polymerase transcribing lacZ mRNA was directly measured and found to be reduced by two-fold under conditions of high ppGpp levels. In the case of translation, we have shown that the peptide elongation rate varied at different types of codons and even among codons read by the same tRNA species. The faster translated codons probably have the highest cognate tRNA concentration and the highest affinity to the tRNA. Thus, the ribosome may operate close to saturation at some codons and be unsaturated at synonymous codons. Therefore, not only translation of the codons for the seven amino acids, whose biosynthesis is regulated by attenuation, but also a substantial fraction of the other translation reactions may be unsaturated. Recently, we have obtained results which indicate that also many ribosome binding sites are unsaturated with their substrate, i.e. with ribosomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacterial Proteins↗
PubMed1990

Nucleotide sequence of the Caulobacter crescentus flaF and flbT genes and an analysis of codon usage in organisms with G + C-rich genomes.

The Caulobacter crescentus flaFG region encodes trans-acting, regulatory factors that modulate flagellin synthesis during flagellum biogenesis. In this study, sequence analysis and experiments utilizing a promoterless cat gene demonstrated that the flaF and flbT genes have overlapping transcripts with the same orientation. In addition, the 5' ends of the flgL and flbA genes were located. A sequence resembling an Rho-factor-independent terminator was found in the 3' region of the flaF gene. This region was uniquely A + T-rich and the encoded mRNA contained an inverted repeat sequence which could form a stable stem-loop structure followed by nine U-residues. The codon usage of C. crescentus genes was examined and indicated a preference for specific codons from each of the synonymous codon groups. Furthermore, comparison to the codon usage of other organisms with G + C-rich genomes indicated a strong preference for the same codons preferred by C. crescentus.

Amino Acid Sequence↗
PubMed1990

Switches in species-specific codon preferences: the influence of mutation biases.

A model of synonymous codon usage is developed in which the most frequent codons are selectively advantageous because of their coadaptation with tRNA abundances. Random drift opposes the progress of this coevolution by pushing codon frequencies in the direction of the frequency that would result from mutation in the absence of selection. It is predicted that, within a certain range, an increased mutation bias away from an advantageous codon has little influence on its usage in highly expressed genes. However, a subsequent small increase in mutation bias over a critical range leads to a large reduction in the frequency of the codon. The switch in preference from one synonym to another is a sharp transition, with no stable intermediate state in which neither codon is advantageous. Codon usage patterns were compared among three related bacterial species of differing genomic G & C contents, Escherichia coli, Serratia marcescens, and Proteus vulgaris. It was found that although changes in mutation biases do not always result in switches in codon preferences, some switches have occurred in the direction of species-specific mutation biases. Fluctuating mutation biases may therefore be the main cause of differences between species in their codon preferences.

Amino Acids↗
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↗