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PubMed1994

Contrasting patterns of evolutionary divergence within the Acinetobacter calcoaceticus pca operon.

The six enzymes required for catabolism of protocatechuate to succinate and acetylCoA are encoded by the pca genes in the Gram-bacterium, Acinetobacter calcoaceticus. The clustered A. calcoaceticus cat genes encode an analogous set of enzymes associated with the metabolic dissimilation of catechol. The nucleotide (nt) sequences of pcaIJFB and pcaK, reported here, complete evidence showing that all of the pca structural genes are tightly grouped in the order pcaIJFBDKCHG within a single operon. The pcaIJF region is nearly identical in nt sequence to the A. calcoaceticus catIDJF region which exhibits a G+C content and a codon usage pattern exceptional for A. calcoaceticus. In contrast, pcaD, pcaC, pcaH and pcaG have diverged substantially from their evolutionary counterparts in the cat region; all of these divergent genes exhibit G+C contents and codon usage patterns that are typical for A. calcoaceticus. The pcaIJF and catIJF regions are known to exchange DNA sequence information, and this property may have contributed to their nt sequence conservation. The pcaK gene has no counterpart among known cat genes. The deduced amino-acid sequence of PcaK indicates that it may be a transmembrane protein associated with transport.

Acetyl Coenzyme A↗
PubMed1997

On the informational content of overlapping genes in prokaryotic and eukaryotic viruses.

In genetic language a peculiar arrangement of biological information is provided by overlapping genes in which the same region of DNA can code for functionally unrelated messages. In this work, the informational content of overlapping genes belonging to prokaryotic and eukaryotic viruses was analyzed. Using information theory indices, we identified in the regions of overlap a first pattern, exhibiting a more uniform base composition and more severe constraints in base ordering with respect to the nonoverlapping regions. This pattern was found to be peculiar to coliphage, avian hepatitis B virus, human lentivirus, and plant luteovirus families. A second pattern, characterized by the occurrence of similar compositional constraints in both types of coding regions, was found to be limited to plant tymoviruses. At the level of codon usage, a low degree of correlation between overlapping and nonoverlapping coding regions characterized the first pattern, whereas a close link was found in tymoviruses, indicating a fine adaptation of the overlapping frame to the original codon choice of the virus. As a result of codon usage correlation analysis, deductions concerning the origin and evolution of several overlapping frames were also proposed. Comparison of amino acid composition revealed an increased frequency of amino acid residues with a high level of degeneracy (arginine, leucine, and serine) in the proteins encoded by overlapping genes; this peculiar feature of overlapping genes can be viewed as a way with which they may expand their coding ability and gain new, specialized functions.

Amino Acid Sequence↗
PubMed1999

Translation in Bacillus subtilis: roles and trends of initiation and termination, insights from a genome analysis.

We analysed the Bacillus subtilis protein coding sequences termini, and compared it to other genomes. The analysis focused on signals, com-positional biases of nucleotides, oligonucleotides, codons and amino acids and mRNA secondary structure. AUG is the preferred start codon in all genomes, independent of their G+C content, and seems to induce less stable mRNA structures. However, it is not conserved between homologous genes neither is it preferred in highly expressed genes. In B.subtilis the ribosome binding site is very strong. We found that downstream boxes do not seem to exist either in Escherichia coli or in B.subtilis. UAA stop codon usage is correlated with the G+C content and is strongly selected in highly expressed genes. We found less stable mRNA structures at both termini, which we related to mRNA-ribosome and mRNA-release-factor interactions. This pattern seems to impose a peculiar A-rich nucleotide and codon usage bias in these regions. Finally the analysis of all proteins from B.subtilis revealed a similar amino acid bias near both termini of proteins consisting of over-representation of hydrophilic residues. This bias near the stop codon is partially release-factor specific.

Algorithms↗
PubMed1994

The nuclear genomes of African and American trypanosomes are strikingly different.

We have investigated the compositional distributions of exons and their different codon positions, as well as the codon usage and amino-acid (aa) composition of the nuclear genomes of the African and American trypanosomes Trypanosoma brucei and T. cruzi. Very large differences between the two species were found in all the properties investigated. The most striking differences concern the compositional distributions of third codon positions and the extremely large nucleotide divergence of third codon position for homologous genes encoding proteins that are highly conserved in their aa sequences. Moreover, if coding sequences from each species are divided into two groups according to the GC levels in third codon positions, very different codon usages and aa compositions are found. This indicates a compositional compartmentalization in both genomes which had previously been detected in T. brucei (and T. equiperdum) by compositional fractionation.

Animals↗
PubMed1989

Evolution of chromosome bands: molecular ecology of noncoding DNA.

Giemsa dark bands, G-bands, are a derived chromatin character that evolved along the chromosomes of early chordates. They are facultative heterochromatin reflecting acquisition of a late replication mechanism to repress tissue-specific genes. Subsequently, R-bands, the primitive chromatin state, became directionally GC rich as evidenced by Q-banding of mammalian and avian chromosomes. Contrary to predictions from the neutral mutation theory, noncoding DNA is positionally constrained along the banding pattern with short interspersed repeats in R-bands and long interspersed repeats in G-bands. Chromosomes seem dynamically stable: the banding pattern and gene arrangement along several human and murine autosomes has remained constant for 100 million years, whereas much of the noncoding DNA, especially retroposons, has changed. Several coding sequence attributes and probably mutation rates are determined more by where a gene lives than by what it does. R-band exons in homeotherms but not G-band exons have directionally acquired GC-rich wobble bases and the corresponding codon usage: CpG islands in mammals are specific to R-band exons, exons not facultatively heterochromatinized, and are independent of the tissue expression pattern of the gene. The dynamic organization of noncoding DNA suggests a feedback loop that could influence codon usage and stabilize the chromosome's chromatin pattern: DNA sequences determine affinities of----proteins that together form----a chromatin that modulates----rate constants for DNA modification that determine----DNA sequences. Theories of hierarchical selection and molecular ecology show how selection can act on Darwinian units of noncoding DNA at the genome level thus creating positionally constrained DNA and contributing minimal genetic load at the individual level.

Base Sequence↗
PubMed2000

Increased expression and immunogenicity of sequence-modified human immunodeficiency virus type 1 gag gene.

A major challenge for the next generation of human immunodeficiency virus (HIV) vaccines is the induction of potent, broad, and durable cellular immune responses. The structural protein Gag is highly conserved among the HIV type 1 (HIV-1) gene products and is believed to be an important target for the host cell-mediated immune control of the virus during natural infection. Expression of Gag proteins for vaccines has been hampered by the fact that its expression is dependent on the HIV Rev protein and the Rev-responsive element, the latter located on the env transcript. Moreover, the HIV genome employs suboptimal codon usage, which further contributes to the low expression efficiency of viral proteins. In order to achieve high-level Rev-independent expression of the Gag protein, the sequences encoding HIV-1(SF2) p55(Gag) were modified extensively. First, the viral codons were changed to conform to the codon usage of highly expressed human genes, and second, the residual inhibitory sequences were removed. The resulting modified gag gene showed increases in p55(Gag) protein expression to levels that ranged from 322- to 966-fold greater than that for the native gene after transient expression of 293 cells. Additional constructs that contained the modified gag in combination with modified protease coding sequences were made, and these showed high-level Rev-independent expression of p55(Gag) and its cleavage products. Density gradient analysis and electron microscopy further demonstrated that the modified gag and gag protease genes efficiently expressed particles with the density and morphology expected for HIV virus-like particles. Mice immunized with DNA plasmids containing the modified gag showed Gag-specific antibody and CD8(+) cytotoxic T-lymphocyte (CTL) responses that were inducible at doses of input DNA 100-fold lower than those associated with plasmids containing the native gag gene. Most importantly, four of four rhesus monkeys that received two or three immunizations with modified gag plasmid DNA demonstrated substantial Gag-specific CTL responses. These results highlight the useful application of modified gag expression cassettes for increasing the potency of DNA and other gene delivery vaccine approaches against HIV.

AIDS Vaccines↗
PubMedDate not supplied

Genetics of lactobacilli: plasmids and gene expression.

This paper reviews the present knowledge of the structure and properties of small (< 5 kb) plasmids present in Lactobacillus spp. The data show that plasmids from Lactobacillus spp., like many plasmids from other Gram-positive bacteria, display a modular organization and replicate by a mechanism of rolling circle replication. Structurally, plasmids from lactobacilli are closely related to plasmids from other Gram-positive bacteria. They contain elements (plus- and minus origin of replication, element(s) for control of plasmid replication, mobilization function) showing extensive similarity to analogous elements in plasmids from these other organisms. It is believed that lactobacilli have acquired such elements by intra- and/or intergenic transfer mechanisms. The first part of the review is concluded with a description of plasmid vectors with a Lactobacillus replicon and integrative vectors, including data concerning their structural and segregational stability. In the second part of this review we describe the progress that has been made during the last few years in identifying and characterizing elements that control expression of genetic information in lactobacilli. Based on the sequence of eleven identified and twenty presumed promoters, some preliminary conclusions can be drawn regarding the structure of Lactobacillus promoters. A typical Lactobacillus promoter shows significant similarity to promoters from E. coli and B. subtilis. An analysis of published sequences of seventy genes indicates that the region encompassing the translation start codon AUG also shows extensive similarity to that of E. coli and B. subtilis. Codon usage of Lactobacillus genes is not random and shows interspecies as well as intraspecies heterogeneity. Interspecies differences may, in part, be explained by differences in G+C content of different lactobacilli. Differences in gene expression levels can, to a large extent, account for intraspecies differences of codon usage bias. Finally, we review the knowledge that has become available concerning protein secretion and heterologous gene expression in lactobacilli. This part is concluded with a compilation of data on the expression in Lactobacillus of heterologous genes under the control of their own promoter or under control of a Lactobacillus promoter.

Bacillus subtilis↗
PubMed1989

Evidence that mutation patterns vary among Drosophila transposable elements.

In Drosophila melanogaster, codon usage in the open reading frames (ORFs) of transposable elements (TEs) differs greatly from that in other ORFs. In addition, while the ORFs from a single element are similar, there is considerable variation among elements. In the TE ORFs there are no indications of selection for the codons prevalent in the other D. melanogaster genes, but rather codon usage can be succinctly summarized in terms of the base composition at silent sites. We suggest that the particular silent site base composition of each TE is determined by an individual pattern of mutation. In many of the TEs there is an ORF encoding a protein with homology to reverse transcriptase; the amino acid sequences of these are quite divergent, and so it is possible that each of these incorporates certain mismatched bases at different frequencies during replication.

Animals↗
PubMed1997

Analyses of frameshifting at UUU-pyrimidine sites.

Others have recently shown that the UUU phenylalanine codon is highly frameshift-prone in the 3'(rightward) direction at pyrimidine 3'contexts. Here, several approaches are used to analyze frameshifting at such sites. The four permutations of the UUU/C (phenylalanine) and CGG/U (arginine) codon pairs were examined because they vary greatly in their expected frameshifting tendencies. Furthermore, these synonymous sites allow direct tests of the idea that codon usage can control frameshifting. Frameshifting was measured for these dicodons embedded within each of two broader contexts: the Escherichia coli prfB (RF2 gene) programmed frameshift site and a 'normal' message site. The principal difference between these contexts is that the programmed frameshift contains a purine-rich sequence upstream of the slippery site that can base pair with the 3'end of 16 S rRNA (the anti-Shine-Dalgarno) to enhance frameshifting. In both contexts frameshift frequencies are highest if the slippery tRNAPhe is capable of stable base pairing in the shifted reading frame. This requirement is less stringent in the RF2 context, as if the Shine-Dalgarno interaction can help stabilize a quasi-stable rephased tRNA:message complex. It was previously shown that frameshifting in RF2 occurs more frequently if the codon 3'to the slippery site is read by a rare tRNA. Consistent with that earlier work, in the RF2 context frameshifting occurs substantially more frequently if the arginine codon is CGG, which is read by a rare tRNA. In contrast, in the 'normal' context frameshifting is only slightly greater at CGG than at CGU. It is suggested that the Shine-Dalgarno-like interaction elevates frameshifting specifically during the pause prior to translation of the second codon, which makes frameshifting exquisitely sensitive to the rate of translation of that codon. In both contexts frameshifting increases in a mutant strain that fails to modify tRNA base A37, which is 3'of the anticodon. Thus, those base modifications may limit frameshifting at UUU codons. Finally, statistical analyses show that UUU Ynn dicodons are extremely rare in E.coli genes that have highly biased codon usage.

Arginine↗
PubMed1999

ISSD Version 2.0: taxonomic range extended.

Two more organisms from different taxonomic groups were added to a new version of the Integrated Sequence-Structure Database (ISSD). ISSD serves as an integrated source of sequence and structure information for the analysis of correlations between mRNA synonymous codon usage and three-dimensional structure of the encoded proteins. ISSD now holds 88 non-homologous Escherichia coli proteins and 25 yeast Saccharomyces cerevisiae proteins in addition to the expanded set of mammalian proteins, which includes 166 proteins (107 in ISSD Version 1.0). Comparison of ISSD sequences with organism-specific codon usage data derived from CUTG database shows that it is a representative subset of the GenBank coding sequences data. Preliminary results of the statistical analysis confirm that sequence-structure correlations observed by us earlier are also present in the upgraded ISSD (Version 2.0), including bacterial and yeast proteins. The ISSD Version 2.0 release includes an improved Web-based data search and retrieval system and is accessible via URL http://www.protein.bio.msu.su/issd/. ISSD can be also accessed at ExPASy, URL http://www.expasy.ch/swissmod/swiss-model.htm l

Animals↗
PubMed1992

Computer-aided gene design.

A computer program, which runs on MS-DOS personal computers, is described that assists in the design of synthetic genes coding for proteins. The goal of the program is the design of a gene which (i) contains as many unique restriction sites as possible and (ii) uses a specific codon usage. The gene designed according to the criteria above is (i) suitable for 'modular mutagenesis' experiments and (ii) optimized for expression. The program 'reverse-translates' protein sequences into degenerated DNA sequences, generates a map of potential restriction sites and locates sequence positions where unique restriction sites can be accommodated. The nucleic acid sequence is then 'refined' according to a specific codon usage to remove any degeneration. Unique restriction sites, if potentially present, can be 'forced' into the degenerated nucleic acid sequence by using 'priority codes' assigned to different restriction sequences.

Amino Acid Sequence↗
PubMed1996

Transgenic barley expressing a protein-engineered, thermostable (1,3-1,4)-beta-glucanase during germination.

The codon usage of a hybrid bacterial gene encoding a thermostable (1,3-1,4)-beta-glucanase was modified to match that of the barley (1,3-1,4)-beta-glucanase isoenzyme EII gene. Both the modified and unmodified bacterial genes were fused to a DNA segment encoding the barley high-pI alpha-amylase signal peptide downstream of the barley (1,3-1,4)-beta-glucanase isoenzyme EII gene promoter. When introduced into barley aleurone protoplasts, the bacterial gene with adapted codon usage directed synthesis of heat stable (1,3-1,4)-beta-glucanase, whereas activity of the heterologous enzyme was not detectable when protoplasts were transfected with the unmodified gene. In a different expression plasmid, the codon modified bacterial gene was cloned downstream of the barley high-pI alpha-amylase gene promoter and signal peptide coding region. This expression cassette was introduced into immature barley embryos together with plasmids carrying the bar and the uidA genes. Green, fertile plants were regenerated and approximately 75% of grains harvested from primary transformants synthesized thermostable (1,3-1,4)-beta-glucanase during germination. All three trans genes were detected in 17 progenies from a homozygous T1 plant.

Amino Acid Sequence↗
PubMed1993

Codon preference in corynebacteria.

The codon usage (CU) of 34 genes from the closely related species, Brevibacterium lactofermentum and Corynebacterium glutamicum (BLCG), was analysed and compared with that of 23 genes from other Brevibacterium and Corynebacterium species. The G+C content of the BLCG genes ranged from 50 to 62%. A wider range was found in other corynebacterial genes (25-71%). The G+C contents of non-coding regions in glutamic acid bacteria are lower than those of the coding regions and both values are lower than the G+C content of ribosomal RNA (rRNA) sequences, suggesting an unusual biased mutation pressure. The CU and synonymous codon usage (SCU) analysis showed several common characteristics among the sequenced corynebacterial genes, consistent with the close relatedness of B. lactofermentum and C. glutamicum. A subset of 25 preferred codons were deduced from the presumably highly expressed genes and they encode most of the amino acid (aa) residues of the BLCG group. An analysis of the effective number of codons (Nc) was carried out in order to check the GC3s (G+C content at the silent third position of sense codons) dependence of the CU in corynebacteria. Nc values showed differences between the BLCG group and other corynebacterial sequences. A comparison of the most used codons for each aa showed a stronger similarity to Streptomyces than to Escherichia coli. The CU/SCU tables of corynebacteria are useful for identification of protein-coding regions, including start codons when they are uncertain, and for designing oligodeoxyribonucleotide probes from an aa sequence.

Base Sequence↗
PubMed1993

Low codon bias and high rates of synonymous substitution in Drosophila hydei and D. melanogaster histone genes.

We have evaluated codon usage bias in Drosophila histone genes and have obtained the nucleotide sequence of a 5,161-bp D. hydei histone gene repeat unit. This repeat contains genes for all five histone proteins (H1, H2a, H2b, H3, and H4) and differs from the previously reported one by a second EcoRI site. These D. hydei repeats have been aligned to each other and to the 5.0-kb (i.e., long) and 4.8-kb (i.e., short) histone repeat types from D. melanogaster. In each species, base composition at synonymous sites is similar to the average genomic composition and approaches that in the small intergenic spacers of the histone gene repeats. Accumulation of synonymous changes at synonymous sites after the species diverged is quite high. Both of these features are consistent with the relatively low codon usage bias observed in these genes when compared with other Drosophila genes. Thus, the generalization that abundantly expressed genes in Drosophila have high codon bias and low rates of silent substitution does not hold for the histone genes.

Animals↗
PubMed1991

msDNA of bacteria.

The msDNA-retron element represents the first prokaryotic member of the large and diverse retroelement family found in many eukaryotic genomes (Table II). This prokaryotic retroelement exists as a single copy element in the chromosome of two different bacterial groups: the common soil microbe M. xanthus and the enteric bacterium E. coli. It encodes an RT similar to the polymerases found in retroviruses, containing most of the strictly conserved amino acids found in all RTs. The RT is responsible for the production of an unusual extrachromosomal RNA-DNA molecule known as msDNA. Each composed of a short single strand of RNA and a short single strand of DNA, msDNAs vary considerably in their primary nucleotide sequences, but all share certain secondary structural features, including the unique 2',5' branch linkage that joins the 5' end of the DNA chain to the 2' position of an internal guanosine residue of the RNA strand. It is proposed that msDNA is synthesized by reverse transcription of a precursor RNA transcribed from a region of the retron containing the genes msr (encoding the RNA portion) and msd (encoding the DNA portion) and the ORF (encoding the RT). The precursor RNA transcript folds into a stable secondary structure that serves as both the primer and the template for the synthesis of msDNA. The msDNA-retron elements of E. coli are found in less than 10% of all strains observed, are heterogeneous in nature, and have an atypical aminoacid codon usage for this species, suggesting that this element was transmitted to E. coli by some other source. The presence of directly repeated 26-base-pair sequences flanking the junctions of the Ec67-retron of E. coli also suggests that it may be a mobile element. However, the msDNA-retrons of M. xanthus appear to be as old as other genes native to this species, based on codon-usage data for the RT genes and the fact that every strain of M. xanthus appears to have the same type of msDNA. If the msDNA-retron element originated with the myxobacteria, it would place the existence of retrons before the appearance of eukaryotic cells, suggesting that the bacterial element is perhaps the ancestral gene from which eukaryotic retroviruses and other retroelements evolved.(ABSTRACT TRUNCATED AT 400 WORDS)

Base Sequence↗
PubMed1999

Synonymous codon choices in the extremely GC-poor genome of Plasmodium falciparum: compositional constraints and translational selection.

We have analyzed the patterns of synonymous codon preferences of the nuclear genes of Plasmodium falciparum, a unicellular parasite characterized by an extremely GC-poor genome. When all genes are considered, codon usage is strongly biased toward A and T in third codon positions, as expected, but multivariate statistical analysis detects a major trend among genes. At one end genes display codon choices determined mainly by the extreme genome composition of this parasite, and very probably their expression level is low. At the other end a few genes exhibit an increased relative usage of a particular subset of codons, many of which are C-ending. Since the majority of these few genes is putatively highly expressed, we postulate that the increased C-ending codons are translationally optimal. In conclusion, while codon usage of the majority of P. falciparum genes is determined mainly by compositional constraints, a small number of genes exhibit translational selection.

Animals↗
PubMed1990

Genetic code 1990. Outlook.

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

Anaerobiosis↗
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↗