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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↗
PubMed1998

Malaria parasites contain two identical copies of an elongation factor 1 alpha gene.

Elongation factor 1alpha (EF-1alpha) is an abundant protein in eukaryotic cells, involved chiefly in translation of mRNA on the ribosomes, and is frequently encoded by more than one gene. Here we show the presence of two identical copies of the EF-1alpha gene in the genome of three malaria parasites, Plasmodium knowlesi, P. berghei and P. falciparum. They are organized in a head-to-head orientation and both genes are expressed in a stage specific manner at a high level, indicating that the small intergenic region contains either two strong promoters or a single bidirectional one. Both genes are expressed at the same time during erythrocytic development of the parasite. This expression pattern and the 100% similarity of the two genes excludes the possibility that the duplicated genes developed in accordance to the different types of ribosomes in Plasmodium. It is more likely that the duplication reflects a gene dosage effect. Comparison of codon usage in the Cdc2-related kinase genes (CRK2) of Plasmodium, which are expressed at a very low level, with the EF-1alpha genes indicates the existence of a codon bias for highly expressed genes, as has been shown in other organisms.

Amino Acid Sequence↗
PubMed2006

Long-term evolution and functional diversification in the members of the nucleophosmin/nucleoplasmin family of nuclear chaperones.

The proper assembly of basic proteins with nucleic acids is a reaction that must be facilitated to prevent protein aggregation and formation of nonspecific nucleoprotein complexes. The proteins that mediate this orderly protein assembly are generally termed molecular (or nuclear) chaperones. The nucleophosmin/nucleoplasmin (NPM) family of molecular chaperones encompasses members ubiquitously expressed in many somatic tissues (NPM1 and -3) or specific to oocytes and eggs (NPM2). The study of this family of molecular chaperones has experienced a renewed interest in the past few years. However, there is a lack of information regarding the molecular evolution of these proteins. This work represents the first attempt to characterize the long-term evolution followed by the members of this family. Our analysis shows that there is extensive silent divergence at the nucleotide level suggesting that this family has been subject to strong purifying selection at the protein level. In contrast to NPM1 and NPM-like proteins in invertebrates, NPM2 and NPM3 have a polyphyletic origin. Furthermore, the presence of selection for high frequencies of acidic residues as well as the existence of higher levels of codon bias was detected at the C-terminal ends, which can be ascribed to the critical role played by these residues in constituting the acidic tracts and to the preferred codon usage for phosphorylatable amino acids at these regions.

Animals↗
PubMed1999

Selection at the wobble position of codons read by the same tRNA in Saccharomyces cerevisiae.

The transfer RNA gene complement of Saccharomyces cerevisiae was utilized for a whole-genome analysis of the deviation from a neutral usage of pyrimidine-ending cognate codons, that is, codons read by a single tRNA species having either inosine or guanosine as the first anticodon base. Mutational pressure at the wobble position was estimated from the base composition of the noncoding portion of the yeast genome. The selective pressure for translational efficiency was inferred from the degree of codon adaptation to tRNA gene redundancy and from mRNA abundance data derived from yeast transcriptome analysis. Amino acid conservation in orthologous comparisons with wholly sequenced microbial genomes was used to estimate translational accuracy requirements. A close correspondence was observed between the usage of wobble position pyrimidines and the frequency predicted by mutational bias. However, in the case of four cognate pairs (Gly: ggu/ggc; Asn: aau/aac; Phe: uuu/uuc; Tyr: uau/ uac) all read by guanosine-starting anticodons, we found evidence for a strong selective pressure driven by translational efficiency. Only for the glycine pair, wobble pyrimidine choice also appears to fulfill a translational accuracy requirement. Wobble pyrimidine selection is strictly related to the number of hydrogen bonds formed by alternative cognate codons: whenever a different number of hydrogen bonds can be formed at the wobble position, there is selection against six- or nine-hydrogen-bonded codon-anticodon pairs. Our results indicate that an intrinsic codon preference, critically dependent on the stability of codon-anticodon interaction and mainly reflecting selection for the optimization of translational efficiency, is built into the translational apparatus.

Codon↗
PubMed1991

B cell development regulated by gene rearrangement: arrest of maturation by membrane-bound D mu protein and selection of DH element reading frames.

In productively rearranged murine VH-DH-JH genes (encoding immunoglobulin heavy chain variable regions), the DH elements are preferentially used in one particular reading frame (RF1), although the recombination breakpoints at the DH-JH border vary. Despite this variability, the bias of RF usage is not due to cellular selection by antigen but is quantitatively established at the stage of DH-JH rearrangement: RF3 is counterselected on the basis of stop codons. RF2 allows the expression of a truncated mu chain (D mu protein) from most DH-JH joints. Using B cells in which the membrane exon of the mu chain is disrupted by homologous recombination on one of the two homologous chromosomes, we obtain evidence that membrane-bound D mu signals arrest of differentiation, presumably by preventing VH-DHJH joining. In addition to RF3 and RF2 counterselection, promotion of DH-JH joining in areas of sequence homology further enforces RF1 usage.

Amino Acid Sequence↗
PubMed1998

Rate variation of DNA sequence evolution in the Drosophila lineages.

Rate constancy of DNA sequence evolution was examined for three species of Drosophila, using two samples: the published sequences of eight genes from regions of the normal recombination rates and new data of the four AS-C (ac, sc, l'sc and ase) and ci genes. The AS-C and ci genes were chosen because these genes are located in the regions of very reduced recombination in Drosophila melanogaster and their locations remain unchanged throughout the entire lineages involved, yielding less effect of ancestral polymorphism in the study of rate constancy. The synonymous substitution pattern of the three lineages was found to be erratic in both samples. The dispersion index for replacement substitution was relatively high for the per, G6pd and ac genes. A significant heterogeneity was found in the number of synonymous substitutions in the three lineages between the two samples of genes with different recombination rates. This is partly due to a lack of the lineage effect in the D. melanogaster and Drosophila simulans lineages in the AS-C and ci genes in contrast to Akashi's observation of genes in regions of normal recombination. The higher codon bias in Drosophila yakuba as compared with D. melanogaster and D. simulans was observed in the four AS-C genes, which suggests change(s) in action of natural selection involved in codon usage on these genes. Fluctuating selection intensity may also be responsible for the observed locus-lineage interaction effects in synonymous substitution.

Animals↗
PubMed1987

Nucleotide sequence of cDNA encoding the small subunit of ribulose-1,5-bisphosphate carboxylase from maize.

We have cloned a full length cDNA for the small subunit of ribulose-1,5-bisphosphate carboxylase from C4 monocot maize, determined the complete nucleotide sequence of this cDNA and deduced its amino acid sequence. The cDNA insert included 513 bp of the coding region, and 65 and 252 nucleotides of the 5' and 3' untranslated regions, respectively. The transit and mature peptides have, respectively, 47 and 123 amino acids. Comparison with the small subunit genes from other plants revealed that the maize small subunit is similar to the wheat one, there being 73% homology between the transit peptides and 64% between the mature proteins. This indicates that there is no noteworthy difference between the C3 and C4 small subunit structures. Extreme codon bias was observed for this gene, and similar codon preferences are observed for other proteins highly expressed in maize leaf, light harvesting chlorophyll binding protein and phosphoenolpyruvate carboxylase. The results indicate that preferential codon usage for highly expressed genes occurs in maize leaf.

Amino Acid Sequence↗
PubMed2005

Context-dependent codon bias and messenger RNA longevity in the yeast transcriptome.

Context-dependent codon bias and its relationship with messenger RNA (mRNA) longevity was examined in 4,648 mRNA transcripts of the Saccharomyces cerevisiae transcriptome for which mRNA half-lives have been empirically determined. Surprisingly, rare codon usage (codons used <13 times per 1,000 codons in the genome) increased with mRNA half-life. However, it is shown that this pattern was not due to preference for rare codon use within codon families containing both rare and nonrare codons. Rather, the pattern was due to an increase in the frequency of amino acids encoded solely by rare codons, and a decrease in the frequency of amino acids never encoded by rare codons, with mRNA half-life. When standardized by open reading frame length, the use of consecutive rare codons was also positively correlated with mRNA half-life. There was negative correlation between the usage of synonymous A|T dinucleotides spanning codon boundaries and mRNA half-life, despite the fact that the frequency of AT dinucleotide usage overall, and AT dinucleotide usage at other codon position contexts (e.g., 1-2, 2-3, or 3|1 total), was not correlated with mRNA half-life. The use of A|T dinucleotides at synonymous dicodon boundaries could potentially allow for more efficient 3'-5' degradation by endonucleolytic cleavage.

Codon↗
PubMed2004

Modulation of base-specific mutation and recombination rates enables functional adaptation within the context of the genetic code.

The persistence of life requires populations to adapt at a rate commensurate with the dynamics of their environment. Successful populations that inhabit highly variable environments have evolved mechanisms to increase the likelihood of successful adaptation. We introduce a 64 x 64 matrix to quantify base-specific mutation potential, analyzing four different replicative systems, error-prone PCR, mouse antibodies, a nematode, and Drosophila. Mutational tendencies are correlated with the structural evolution of proteins. In systems under strong selective pressure, mutational biases are shown to favor the adaptive search of space, either by base mutation or by recombination. Such adaptability is discussed within the context of the genetic code at the levels of replication and codon usage.

Adaptation, Biological↗
PubMed1999

The causes of synonymous rate variation in the rodent genome. Can substitution rates be used to estimate the sex bias in mutation rate?

Miyata et al. have suggested that the male-to-female mutation rate ratio (alpha) can be estimated by comparing the neutral substitution rates of X-linked (X), Y-linked (Y), and autosomal (A) genes. Rodent silent site X/A comparisons provide very different estimates from X/Y comparisons. We examine three explanations for this discrepancy: (1) statistical biases and artifacts, (2) nonneutral evolution, and (3) differences in mutation rate per germline replication. By estimating errors and using a variety of methodologies, we tentatively reject explanation 1. Our analyses of patterns of codon usage, synonymous rates, and nonsynonymous rates suggest that silent sites in rodents are evolving neutrally, and we can therefore reject explanation 2. We find both base composition and methylation differences between the different sets of chromosomes, a result consistent with explanation 3, but these differences do not appear to explain the observed discrepancies in estimates of alpha. Our finding of significantly low synonymous substitution rates in genomically imprinted genes suggests a link between hemizygous expression and an adaptive reduction in the mutation rate, which is consistent with explanation 3. Therefore our results provide circumstantial evidence in favor of the hypothesis that the discrepancies in estimates of alpha are due to differences in the mutation rate per germline replication between different parts of the genome. This explanation violates a critical assumption of the method of Miyata et al., and hence we suggest that estimates of alpha, obtained using this method, need to be treated with caution.

Animals↗
PubMed1996

Asymmetric substitution patterns in the two DNA strands of bacteria.

Analyses of the genomes of three prokaryotes, Escherichia coli, Bacillus subtilis, and Haemophilus influenzae, revealed a new type of genomic compartmentalization of base frequencies. There was a departure from intrastrand equifrequency between A and T or between C and G, showing that the substitution patterns of the two strands of DNA were asymmetric. The positions of the boundaries between these compartments were found to coincide with the origin and terminus of chromosome replication, and there were more A-T and C-G deviations in intergenic regions and third codon positions, suggesting that a mutational bias was responsible for this asymmetry. The strand asymmetry was found to be due to a difference in base compositions of transcripts in the leading and lagging strands. This difference is sufficient to affect codon usage, but it is small compared to the effects of gene expressivity and amino-acid composition.

Bacillus subtilis↗
PubMed1999

Enhanced evolvability in immunoglobulin V genes under somatic hypermutation.

Darwinian theory requires that mutations be produced in a nonanticipatory manner; it is nonetheless consistent to suggest that mutations that have repeatedly led to nonviable phenotypes would be introduced less frequently than others-if under appropriate genetic control. Immunoglobulins produced during infection acquire point mutations that are subsequently selected for improved binding to the eliciting antigen. We and others have speculated that an enhancement of mutability in the complementarity-determining regions (CDR; where mutations have a greater chance of being advantageous) and/or decrement of mutability in the framework regions (FR; where mutations are more likely to be lethal) may be accomplished by differential codon usage in concert with the known sequence specificity of the hypermutation mechanism. We have examined 115 nonproductively rearranged human Ig sequences. The mutation patterns in these unexpressed genes are unselected and therefore directly reflect inherent mutation biases. Using a chi2 test, we have shown that the number of mutations in the CDRs is significantly higher than the number of mutations found in the FRs, providing direct evidence for the hypothesis that mutations are preferentially targeted into the CDRs.

Arthritis↗
PubMed2005

Alternative codon usage of PRRS virus ORF5 gene increases eucaryotic expression of GP(5) glycoprotein and improves immune response in challenged pigs.

Pigs exposed to GP(5) protein of PRRSV by means of DNA immunization develop specific neutralizing and protecting antibodies. Herein, we report on the consequences of codon bias, and on the favorable outcome of the systematic replacement of native codons of PRRSV ORF5 gene with codons chosen to reflect more closely the codon preference of highly expressed mammalian genes. Therefore, a synthetic PRRSV ORF5 gene (synORF5) was constructed in which 134 nucleotide substitutions were made in comparison to wild-type gene (wtORF5), such that 59% (119) of wild-type codons were replaced with known preferable codons in mammalian cells. In vitro expression in mammalian cells of synORF5 was considerably increased comparatively to wtORF5, following infection with tetracycline inducible replication-defective human adenoviral vectors (hAdVs). After challenge inoculation, SPF pigs vaccinated twice with recombinant hAdV/synORF5 developed earlier and higher antibody titers, including virus neutralizing antibodies to GP(5) than pigs vaccinated with hAdV/wtORF5. Data obtained from animal inoculation studies suggest direct correlation between expression levels of immunogenic structural viral proteins and immune response.

Animals↗
PubMed1996

Co-variation of tRNA abundance and codon usage in Escherichia coli at different growth rates.

We have used two-dimensional polyacrylamide gel electrophoresis to fractionate tRNAs from Escherichia coli. A sufficiently high degree of resolution was obtained for 44 out of 46 tRNA species in E. coli to be resolved into individual electrophoretic components. These isolated components were identified by hybridization to tRNA-specific oligonucleotide probes. Systematic measurements of the abundance of each individual tRNA isoacceptor in E. coli, grown at rates varying from 0.4 to 2.5 doublings per hour, were made with the aid of this electrophoretic protocol. We find that there is a biased distribution of the tRNA abundance at all growth rates, and that this can be roughly correlated with the values of codon frequencies in the mRNA pools calculated for bacteria growing at different rates. The tRNA species cognate to abundant codons increase in concentration as the growth rate increases but not as dramatically as might be anticipated. The levels of most of the tRNA isoacceptors cognate to less abundant codons remain unchanged with increasing growth rates. The result of these changes in tRNA abundance is that the relative increase in the amounts of major tRNA species in the bacteria growing at the fastest growth rates is more modest than previous estimates from this laboratory suggested. Furthermore, a systematic error in previous estimates of ribosomal RNA content of the bacteria has been detected. This will account for the quantitative discrepancies between the previous and the present data for tRNA abundance.

Base Sequence↗
PubMed2005

Codon utilization, DNA landscaping and fractal analysis in bacteriophage phi(adh).

The bacteriophage phi(adh) has a low G+C content and encodes its protein products using a restricted number of the codons, which it could theoretically use. Investigated were (i) the restricted codon usage by determining codon indices and codon distances for various genes and ORFs, (ii) distribution of purines and pyrimidines on the two strands of the double-stranded genome and within all genes and ORFs, and (iii) nucleotide positional bias within the genome. The genes and ORFs can be clustered into four groups, based on codon distance analysis. The genome landscape showed that the plus strand was more purine-rich than the negative one and that the only area of the genome where the landscape was located in the pyrimidine-rich region was at the start of the sequence which was also the only region of the genome where ORFs were found on the negative strand. The nucleotide composition of the genome, examined by fractal analysis showed little, if any, DNA positional bias, as opposed to overall compositional bias with a self-similarity profile. The ORFs showed a bias in favour of purines on the coding strand.

Amino Acids↗
PubMed1994

Codon usage in Kluyveromyces lactis and in yeast cytochrome c-encoding genes.

Codon usage (CU) in Kluyveromyces lactis has been studied. Comparison of CU in highly and lowly expressed genes reveals the existence of 21 optimal codons; 18 of them are also optimal in other yeasts like Saccharomyces cerevisiae or Candida albicans. Codon bias index (CBI) values have been recalculated with reference to the assignment of optimal codons in K. lactis and compared to those previously reported in the literature taking as reference the optimal codons from S. cerevisiae. A new index, the intrinsic codon deviation index (ICDI), is proposed to estimate codon bias of genes from species in which optimal codons are not known; its correlation with other index values, like CBI or effective number of codons (Nc), is high. A comparative analysis of CU in six cytochrome-c-encoding genes (CYC) from five yeasts is also presented and the differences found in the codon bias of these genes are discussed in relation to the metabolic type to which the corresponding yeasts belong. Codon bias in the CYC from K. lactis and S. cerevisiae is correlated to mRNA levels.

Amino Acids↗
PubMed2006

Revisiting the directional mutation pressure theory: the analysis of a particular genomic structure in Leishmania major.

This paper reports the existence of a significant negative correlation between GC12 and GC3 in the recently sequenced genome of Leishmania major. This result contradicts the previous evidence that the compositional correlations between codon positions are universal. Moreover, it challenges the interpretation of the GC12 vs. GC3 linear regression slope as the relative neutrality of GC12, within the framework of the directional mutation pressure theory [Sueoka, N., 1988. Directional mutational pressure and neutral molecular evolution. P Natl Acad Sci USA 85, 2653-2657.]. The analysis of the codon usage pattern for L. major shows that codon choice is most likely influenced by both mutation pressure and translational selection. Dinucleotide frequencies were also analysed; our results do not support the existence of an unusual neighbour-dependent mutation bias in this genome. We developed two evolutionary models that could explain the origin of the negative GC12/GC3 correlation. The first model is based on the effect of translational selection on the GC3 the second one is based on a potential mutation bias combined with purifying selection at the amino-acid level. Both models predict a negative GC12/GC3 correlation at the equilibrium. The potential implications of these results for this aspect of the directional mutation pressure theory are discussed. We conclude that the particular case of L. major should lead to a careful reevaluation of several hypotheses of this theory. The origin of the negative GC12/GC3 correlation remains for now an open question.

Animals↗
PubMed1998

Complete sequence of the amphioxus (Branchiostoma lanceolatum) mitochondrial genome: relations to vertebrates.

The complete nucleotide sequence of the mitochondrial DNA of the amphioxus Branchiostoma lanceolatum has been determined. This mitochondrial genome is small (15 076 bp) because of the short size of the two rRNA genes and the tRNA genes. In addition, this genome contains a very short non-coding region (57 bp) with no sequence reminiscent of a control region. The organisation of the coding genes, as well as of the two rRNA genes, is identical to that of the sea lamprey. Some differences in the repartition of the tRNA genes occur when compared to the lamprey. The mitochondrial codon usage of the amphioxus is reminiscent of that of urochordates since the AGA codon is read as a glycine and not as a stop codon as in vertebrates. Moreover, the base composition at the wobble positions of the codon is strongly biased toward guanine. Altogether, these data clearly emphasise the close relationships between amphioxus and vertebrates, and reinforce the notion that prochordates may be viewed as the brother group of vertebrates.

Animals↗