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PubMed2003

A common periodic table of codons and amino acids.

A periodic table of codons has been designed where the codons are in regular locations. The table has four fields (16 places in each) one with each of the four nucleotides (A, U, G, C) in the central codon position. Thus, AAA (lysine), UUU (phenylalanine), GGG (glycine), and CCC (proline) were placed into the corners of the fields as the main codons (and amino acids) of the fields. They were connected to each other by six axes. The resulting nucleic acid periodic table showed perfect axial symmetry for codons. The corresponding amino acid table also displaced periodicity regarding the biochemical properties (charge and hydropathy) of the 20 amino acids and the position of the stop signals. The table emphasizes the importance of the central nucleotide in the codons and predicts that purines control the charge while pyrimidines determine the polarity of the amino acids. This prediction was experimentally tested.

Algorithms↗

PubMed1988

Mistranslation in IGF-1 during over-expression of the protein in Escherichia coli using a synthetic gene containing low frequency codons.

Partial misincorporation of Lys for Arg has been observed for the Arg residues of IGF-1 when the molecule is expressed in Escherichia coli using a synthetic gene with the low frequency AGA codon encoding all six Arg residues and yeast preferred codons encoding the remaining residues. The Lys for Arg substitution at these residues could not be detected when a gene containing E. coli preferred codons, with the codon CGT coding for all Arg residues, was used for the expression of the protein. Similarly, no misincorporation of Lys for Arg could be detected when a gene containing Escherichia coli preferred codons at all positions, except for an AGA codon at Arg (36), was utilized.

Amino Acid Sequence↗

PubMed1990

Codon discrimination due to presence of abundant non-cognate competitive tRNA.

It has been thought that preferential use of synonymous codons provides high efficiency and fidelity of protein synthesis through specific codon-anticodon interactions. In yeast genes, some codon boxes seem to prefer a codon which is unsuited for its cognate anticodon. Now, we propose that codon usage biases may arise due to presence of abundant non-cognate competitive tRNA capable of misreading a codon by C-U or G-U pairing in the middle position.

Codon↗

PubMed1986

Effect of distribution of unfavourable codons on the maximum rate of gene expression by an heterologous organism.

We have analysed theoretically the effect of the relative position of unfavourable codons on the maximum level of synthesis of foreign proteins in E. coli. We predict that the occurrence of such codons scattered in the corresponding genes has little effect. In contrast, clustering (in our terminology indicating directly adjacent codons) of unfavourable codons is predicted to dramatically reduce the maximum level of protein synthesis. The context effect would explain the reduction of expression level for a chloramphenicol acetyl transferase gene modified by Robinson et al. (1984), which contains 4 contiguous unfavourable codons. As an example, we predict that due to the different downstream contexts of unfavourable codons in the alpha 1 and beta interferon genes, the maximum level of synthesis in E. coli for these proteins will be different.

Acetyltransferases↗

PubMed2003

Effects of codon-optimization on protein expression by the human herpesvirus 6 and 7 U51 open reading frame.

Codon-optimization refers to the alteration of gene sequences, to make codon usage match the available tRNA pool within the cell/species of interest. Codon-optimization has emerged as a powerful tool to increase protein expression by genes from small RNA and DNA viruses, which commonly contain overlapping reading frames as well as structural elements that are embedded within coding regions; these features are not widespread among large DNA viruses. We therefore examined whether codon-optimization might influence protein expression from a herpesvirus gene. We focused on the U51 gene from human herpesviruses-6 and -7, which was cloned in both native and codon-optimized form, with an N-terminal HA epitope tag to allow protein detection. Codon-optimization was associated with a profound (10-100 fold) increase in U51 expression in human (293A, HSG, K562) or hamster (CHO) cell lines, suggesting this may represent a valuable tool to facilitate functional studies on recalcitrant herpesvirus genes. Finally, it is postulated that the suboptimal expression of native U51 may reflect a regulatory mechanism that controls viral gene expression.

Animals↗

PubMed2003

Positioning of mRNA codons with respect to 18S rRNA at the P and E sites of human ribosome.

Positioning of each nucleotide of the E site and the P site bound codons with respect to the 18S rRNA on the human ribosome was studied by cross-linking with mRNA analogs, derivatives of the hexaribonucleotide UUUGUU (comprising Phe and Val codons) that carried a perfluorophenylazide group on the second or the third uracil, and a derivative of the dodecaribonucleotide UUAGUAUUUAUU with a similar group on the guanine residue. The location of the modified nucleotides at any mRNA position from -3 to +3 (position +1 corresponds to the 5' nucleotide of the P site bound codon) was adjusted by the cognate tRNAs. A modified uridine at positions from -1 to +3 cross-linked to nucleotide G1207 of the 18S rRNA, and to nucleotide G961 when it was in position -2. A modified guanosine cross-linked to nucleotide G1207 if it was in position -3 of the mRNA. These data indicate that nucleotide G961 of the 18S rRNA is close only to mRNA positions -3 and -2, while G1207 is in the vicinity of positions from -3 to +3. The latter suggests that there is a sharp turn between the P and E site bound codons that brings nucleotide G1207 of the 18S rRNA close to each nucleotide of these codons. This correlates well with X-ray crystallographic data on bacterial ribosomes, indicating existence of a sharp turn between the P site and E site bound codons near a conserved nucleotide G926 of the 16S rRNA (corresponding to G1207 in 18S rRNA) close to helix 23b containing the conserved nucleotide 693 of the 16S rRNA (corresponding exactly to G961 of the 18S rRNA).

Codon↗

PubMedDate not supplied

Generation of protein isoform diversity by alternative initiation of translation at non-AUG codons.

The use of several translation initiation codons in a single mRNA, by expressing several proteins from a single gene, contributes to the generation of protein diversity. A small, yet growing, number of mammalian mRNAs initiate translation from a non-AUG codon, in addition to initiating at a downstream in-frame AUG codon. Translation initiation on such mRNAs results in the synthesis of proteins harbouring different amino terminal domains potentially conferring on these isoforms distinct functions. Use of non-AUG codons appears to be governed by several features, including the sequence context and the secondary structure surrounding the codon. Selection of the downstream initiation codon can occur by leaky scanning of the 43S ribosomal subunit, internal entry of ribosome or ribosomal shunting. The biological significance of non-AUG alternative initiation is demonstrated by the different subcellular localisations and/or distinct biological functions of the isoforms translated from the single mRNA as illustrated by the two main angiogenic factor genes encoding the fibroblast growth factor 2 (FGF2) and the vascular endothelial growth factor (VEGF). Consequently, the regulation of alternative initiation of translation might have a crucial role for the biological function of the gene product.

Animals↗

PubMed1996

The translational stop signal: codon with a context, or extended factor recognition element?

Wide ranging studies of the readthrough of translational stop codons within the last 25 years have suggested that the stop codon might be only part of the molecular signature for recognition of the termination signal. Such studies do not distinguish between effects on suppression and effects on termination, and so we have used a number of different approaches to deduce whether the stop signal is a codon with a context or an extended factor recognition element. A data base of natural termination sites from a wide range of organisms (148 organisms, approximately 40,000 sequences) shows a very marked bias in the bases surrounding the stop codon in the genes for all organisms examined, with the most dramatic bias in the base following the codon (+4). The nature of this base determines the efficiency of the stop signal in vivo, and in Escherichia coli this is reinforced by overexpressing the stimulatory factor, release factor 3. Strong signals, defined by their high relative rates of selecting the decoding release factors, are enhanced whereas weak signals respond relatively poorly. Site-directed cross-linking from the +1, and bases up to +6 but not beyond make close contact with the bacterial release factor-2. The translational stop signal is deduced to be an extended factor recognition sequence with a core element, rather than simply a factor recognition triplet codon influenced by context.

Base Sequence↗

PubMed2002

Hypothetical clues suggesting that 'AU' and 'UA' were the first 'beginning' and 'end' codons: is their ancient polymerase extant present as a protein domain fossil in reverse transcriptase and telomerase?

Tryptophan and cysteine are excluded from the histones, except histone H3, presumably to decrease premature terminations, since the first two letters of their codons are the same as that of the termination codon UGA. Though tyrosine codon also begins with 'UG', any mutation in tyrosine codon causing premature termination is corrected more professionally by the suppressor tRNA system. Given this background, a hypothetical model for the first replication is proposed. The first termination codon is 'UA' and the first initiation codon is 'AU', in 'UAU' centred RNA rings, which are replicated both clockwise and counter-clockwise. Replication of these would result in the formation of palindromic strands, which may have led to the formation of palindromic sequences in the genome, such as those forming hairpin loops. Their polymerase may be extant in reverse transcriptase (RT), because of tendencies to 'turn the corner' and to form 'hairpin loops', when RT is used for DNA synthesis in vitro. The catalytic subunit of telomerase hTERT in close contact to its RNA template may be another site to find this ancient 'polymerase'.

Codon↗

PubMed2000

DNA sequence analysis of the complete mitochondrial genome of the green alga Scenedesmus obliquus: evidence for UAG being a leucine and UCA being a non-sense codon.

The complete DNA sequence of the mitochondrial genome of the chlorophyceen alga Scenedesmus obliquus was determined. The circular genome of 42781bp contains a basic set of 13 mitochondrial genes, which are conserved among plant or algal chondriomes. In addition, two scrambled rRNA and 27 tRNA genes are present, together with four intronic sequences (group I and II) and five open reading frames (ORFs), which show no significant homology to other ORFs from organellar genomes. The comparison with deduced amino acid sequences from 13 conserved mitochondrial genes gives rise to the conclusion that two deviations from the standard genetic code must be present in S. obliquus mitochondria: (i) UAG codes for leucine as was already found in some other algal mitochondria; (ii) UCA is a stop codon, which seems unique for mitochondrial genomes. This was supported by our finding that a tRNA-Leu gene possesses a UCA anticodon and by a missing tRNA-serine, able to decode the UCA codon. Consistent with these data is the absence of any UCA codon from conserved mitochondrial ORFs. This codon occurs only close to the end of all ORFs, while UAA or UGA codons are found at some distance from any conserved ORF. Codon changes by RNA editing can be excluded, since RT-PCR analysis does not reveal any evidence for post-transcriptional RNA modifications of the primary transcript.

Algal Proteins↗

PubMed2001

Gene expressivity is the main factor in dictating the codon usage variation among the genes in Pseudomonas aeruginosa.

Codon usage biases of all DNA sequences (length greater than or equal to 300 bp) from the complete genome of Pseudomonas aeruginosa have been analyzed. As P. aeruginosa is a GC-rich organism, G and/or C are expected to predominate in their codons. Overall codon usage data analysis indicates that indeed codons ending in G and/or C are predominant in this organism. But multivariate statistical analysis indicates that there is a single major trend in the codon usage variation among the genes in this organism, which has a strong negative correlation with the expressivities of the genes. The majority of the lowly expressed genes are scattered towards the positive end of the major axis whereas the highly expressed genes are clustered towards the negative end. This is the first report where the prokaryotic organism having highly skewed base composition is dictated mainly by translational selection, though some other factors such as the lengths of the genes as well as the hydrophobicity of genes also influence the codon usage variation among the genes in this organism in a minor way.

Codon↗

PubMed1997

The involucrin gene of the tree shrew: recent repeat additions and the relocation of cysteine codons.

The coding region of the involucrin gene of Tupaia glis has been cloned and sequenced. It resembles the involucrin coding region of other non-anthropoid mammals in possessing a segment of related, short tandem repeats at a defined location, but in Tupaia, there has been recent serial duplication of a repeat into which a cysteine codon had earlier been introduced. As a result of the duplication, there is a total of as many as six cysteine codons in the segment of repeats, a number larger than for any other species yet examined. In Ratttus there has been a comparable but independent addition of cysteine codons, and both Tupaia and Rattus have eliminated an otherwise conserved cysteine codon 75 located close to but outside the segment of repeats. In Tupaia, this elimination probably occurred by gene conversion. Also independently, the gene of Canis has added cysteine codons to the segment of repeats but has not yet lost cysteine 75. It is proposed that the gain and the loss of cysteine codons are parts of a multi-stage program of cysteine relocation.

Animals↗

PubMed1999

Translation-coupled violation of Parity Rule 2 in human genes is not the cause of heterogeneity of the DNA G+C content of third codon position.

The genome of higher eukaryotes consists of genes having a widely heterogeneous base composition at the third codon position. Ubiquitous variability of the DNA base composition has the following two aspects: intragenomic heterogeneity of the G+C content and the amino-acid-specific translation-coupled biases from the Parity Rule 2 (PR2). PR2 is an intrastrand rule where A = T and G = C are expected if there is no bias in mutation and selection between the two complementary strands of DNA. To examine whether or not the biases from PR2 are responsible for the wide heterogeneity of the DNA G+C content in human, the third codon position of 846 human genes was analyzed. Genes were separated into six groups according to their G+C content of the third codon position, and each group was examined for the translation-coupled PR2 biases in the nucleotide composition of the third codon position for two- and four-codon amino acids. The results show that genes in the different G+C content groups have similar PR2 biases, indicating that the intragenomic heterogeneity of the G+C content is not correlated with translation-coupled biases from the PR2. Therefore, the heterogeneity of the G+C content is likely to be determined by some other mechanism (e.g. locally variable directional mutation pressures) than amino-acid-specific selections for the codon preference.

Base Composition↗

PubMed1996

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

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

Animals↗

PubMed2002

Synonymous codon usage bias and the expression of human glucocerebrosidase in the methylotrophic yeast, Pichia pastoris.

The lysosomal hydrolase glucocerebrosidase catalyzes the penultimate step in the breakdown of membrane glycosphingolipids. An inherited deficiency in this enzyme leads to the onset of Gaucher disease, the most common lysosomal storage disorder. Exogenous sources of this protein are required for biochemical and biophysical investigations and enzyme replacement therapy of Gaucher disease. Heterologous expression of glucocerebrosidase has been successful in mammalian and insect cell lines and although its use in enzyme replacement therapy of Gaucher disease has proven efficacious, current production levels limit the availability of the enzyme. Initial attempts to express human glucocerebrosidase using the methylotrophic yeast Pichia pastoris had limited success, despite significant levels of transcription. Using fragments of the glucocerebrosidase cDNA fused to the luciferase cDNA as a translational read-through reporter, the impact of synonymous codon usage bias on protein expression in P. pastoris was examined. A table of preferred codons was determined for P. pastoris and the codon usage of a 186-bp fragment of the glucocerebrosidase gene was optimized to that of the P. pastoris preferred set. A second construct with altered G+C content but no codon optimization was created for comparison. While the native glucocerebrosidase coding region limited luciferase activity to baseline levels, the codon optimized and G+C altered constructs increased luciferase activity 10.6- and 7.5-fold, respectively. Optimized G+C content, regardless of corresponding codon optimization, appears to be the major contributor to increased translational efficiency in this heterologous expression host.

Amino Acid Sequence↗

PubMed2002

Does the prion protein gene 129 codon polymorphism influence sleep? Evidence from a fatal familial insomnia kindred.

OBJECTIVE: Experimental and clinical evidence in prion diseases suggests that the prion protein gene (PRNP) plays a role in regulating sleep. METHODS: Seventeen healthy individuals belonging to a single fatal familial insomnia pedigree, 8 carriers and 9 non-carriers of the PRNP codon 178 mutation, underwent polysomnography and spectral electroencephalographic (EEG) analysis. All were also characterized with regard to the codon 129 polymorphism on both PRNP alleles. RESULTS: PRNP codon 129 polymorphism exhibited influences on sleep-EEG activities. In particular, spindle frequency band power and balance between delta and spindle activity were found to correlate with the genotype of PRNP codon 129, irrespective of the mutation at codon 178. CONCLUSIONS: Our data suggest that PRNP codon 129 polymorphism may also affect sleep in the healthy population and warrant further studies in the general population and other sleep disorders.

Adult↗

PubMed1996

Codon usage in Cryptosporidium parvum differs from that in other Eimeriorina.

Codon usage of Crytosporidium parvum was compared with those of other Eimeriorina Toxoplasma gondii and Eimeria tenella and revealed a biased use of synonymous codons with a preference for NNU (40.0%) and NNA (33.4%). There was no close resemblance of the codon usage of C. parvum to T. gondii (correlation coefficient, r = 0.14) or E. tenella (r = 0.14) but it was similar to Entamoeba histolytica (r = 0.75) and Plasmodium falciparum (r = 0.5). Analysis of the codon usage in homologous gene sequences (actin, beta-tubulin) also failed to reveal a close relationship between C. parvum and T. gondii or E. tenella. The low usage codons in C. parvum were most frequently used codons in T. gondii and E. tenella. These observations are consistent with 18S rRNA sequence analysis which shows no close relationship of Cryptosporidium with other Eimeriorina (Sarcocystis, Toxoplasma and Eimeria) and questions the validity of the current classification of C. parvum.

Actins↗

PubMed1988

Influence of duplexes 3' to the mRNA initiation codon on the efficiency of monosome formation.

The structural features of mRNA molecules that determine their relative translational rates are at present poorly defined. An early and potentially rate-limiting step in this process is the assembly of an intact 80S ribosome at the translational initiation codon. It is generally assumed that the efficiency of this reaction is controlled by structures in the 5' nontranslated region and in the immediate proximity of the AUG initiation codon. In this paper, we present an assay of initial monosome formation and measure the effects of hybridizing mRNA to complementary DNA fragments on the efficiency of this reaction. This hybridization serves to block specific regions of the mRNA from sequence-specific and intramolecular (secondary structure) interactions. We find that cDNAs that block the 5' nontranslated region, the initiation codon, or regions immediately 3' to the initiation codon markedly inhibit 80S ribosome attachment. These results are consistent with previous studies by ourselves and others which suggest that the introduction of secondary structures into this region can result in decreased translational efficiency. In addition, however, we note that cDNAs that hybridize to segments of the coding region significant distances (as many as several hundred bases) 3' to the initiation codon can also inhibit initial ribosome binding. This effect appears to be limited to duplexes within the mRNA coding region since a cDNA hybridizing exclusively within the 3' nontranslated region does not inhibit, and may actually stimulate, monosome formation. The results of this monosome formation assay therefore suggest that mRNA structures remote from the 5' terminus and initiation codon may also be important in determining the efficiency of translational initiation.

Anisomycin↗