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PubMed2001

Seryl-tRNA synthetase is not responsible for the evolution of CUG codon reassignment in Candida albicans.

A number of Candida species translate the standard leucine-CUG codon as serine using a novel ser-tRNA(CAG). This tRNA, which has an unusual anticodon stem-loop structure, has been implicated in the evolution of this codon reassignment. However, such a sense codon reassignment might also require a change in the specificity of the cognate aminoacyl tRNA-synthetase, in this case the ser-tRNA synthetase. Here we describe the cloning and sequence analysis of the C. albicans seryl aminoacyl-tRNA synthetase (CaSerRS) gene (CaSES1). The predicted CaSerRS sequence shows a significant level of amino acid identity to SerRs from other organisms and fully complements a S. cerevisiae SerRS null strain without any apparent defect in growth rate. This suggests that the SerRS recognizes and charges S. cerevisiae ser-tRNAs with similar efficiency to that of the S. cerevisiae SerRS. Using an antibody raised against CaSerRS, we also demonstrate the presence of SerRS in a range of Candida spp. showing CUG codon reassignment. We conclude that the key element in CUG reassigment in Candida spp. is the tRNA that decodes the CUG codon rather than a SerRS structural change. The nucleotide sequence of the CaSES1 gene has been deposited at GenBank under Accession No. AF290915.

Amino Acid Sequence↗

PubMed1998

Codon 219 Lys allele of PRNP is not found in sporadic Creutzfeldt-Jakob disease.

The polymorphism at codon 219 of the prion protein gene (PRNP) was found in the general Japanese population with 6% allele frequency. Herein, we examined 85 cases of sporadic Creutzfeldt-Jakob disease (CJD) for the codon 219 polymorphism. The codon 219Glu/Lys heterozygous polymorphism was not found in these CJD cases. In addition, we examined 43 patients with dementia of non-CJD origin, and 4 were found to have the codon 219Glu/Lys heterozygous polymorphism with a similar allele frequency as in the general population. Thus, the codon 219Glu/Lys heterozygous polymorphism might be uniquely excluded from sporadic CJD.

Alanine↗

PubMed2002

Correlation of p21 gene codon 31 polymorphism and TNF-alpha gene polymorphism with nasopharyngeal carcinoma.

Background p21 (WAF1/CIP1) is a downstream protein from p53 and can arrest the cell cycle at the G1/S phase in response to signal from p53. The most frequently seen polymorphic site is at codon 31, where a base change from AGC to AGA causes an amino acid change from serine to arginine. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that is secreted from macrophages, and is related to a sequence of events in the response to inflammation and cancer formation. The TNF-alpha gene promoter -308 G/A polymorphism has been reported to be associated with some cancers. In this study, these polymorphisms were proposed to be a candidate genetic marker of nasopharyngeal carcinoma (NPC). The distribution was analyzed in 47 NPC patients and a control group of 119 healthy people. The association of the p21 codon 31 polymorphism with NPC was detected by polymerase chain reaction (PCR) and restriction analysis by Blp I endonuclease, and calculated by the chi-square test. The TNF-alpha gene promoter -308 G/A polymorphism was identified by Nco I endonuclease. The distribution of the gene p21 codon 31 polymorphisms showed no significant difference between the two groups. The serine form of p21 codon 31 was more prominent in smokers than nonsmokers among the NPC patients (P < 0.05). There was no significant difference in the distribution of TNF-alpha gene promoter -308 G/A polymorphism between control and cancer patients. The results indicate that the gene p21 codon 31 polymorphism and TNF-alpha promoter -308 polymorphism are not correlated with NPC. However, the difference between smokers and nonsmokers suggests that an environmental factor may be involved in association with the p21 gene in the formation of NPC.

Adult↗

PubMed2001

Donor-recipient incompatibility at CD31-codon 563 is a major risk factor for acute graft-versus-host disease after allogeneic bone marrow transplantation from a human leucocyte antigen-matched donor.

Disparities at minor histocompatibility antigens (mHA) are thought to be responsible for acute graft-versus-host disease (aGVHD) in patients receiving bone marrow transplantation (BMT) from a human leucocyte antigen (HLA)-matched donor. Although some mHA have been identified in humans, their role in aGVHD has not. Patients (n = 150) receiving a BMT from an HLA-matched donor were investigated for a correlation between aGVHD and donor/recipient incompatibility for seven polymorphisms previously proposed for mHA (HA-1, H-Y, CD31-codon 125, CD31-codon 563, HPA-1, HPA-3 and HPA-5). Only mismatch at CD31-codon 563 predicted grade II-IV aGVHD. The risk derived from CD31-codon 563 mismatch was the same as that derived from the use of bone marrow from an unrelated donor. We suggest that donor/recipient compatibility at CD31-codon 563 should be added to HLA-typing for donor selection and/or adjustment of aGVHD prophylaxis.

Acute Disease↗

PubMed1996

The prognostic significance of serum viral load, codon 215 reverse transcriptase mutation and CD4+ T cells on progression of HIV disease in a double-blind study of thymopentin.

OBJECTIVE: To determine in asymptomatic HIV-infected subjects the prognostic value of virion reverse transcriptase (RT) codon 215 mutation, serum HIV RNA level, CD4+ T-cell count and immune complex dissociated (ICD) p24 level. The retrospective evaluation of thymopentin treatment effect on subjects in high risk groups for progression was a secondary objective. PARTICIPANTS: Zidovudine (ZDV)-experienced asymptomatic HIV-infected subjects (n = 352) who had been enrolled in a 48-week placebo-controlled double-blind trial of thymopentin treatment were studied. METHODS: Post hoc analyses were conducted to determine which subjects at study entry were at greater risk for progression to AIDS-related complex (ARC), AIDS or death, and to determine the effect of treatment on these subjects. Four potential prognostic variables (virion RT codon 215 mutation, circulating HIV virion RNA copies, CD4+ T-cell count, and ICD p24) were evaluated by dichotomizing subjects for each variable based on the median of the observed values. CD4+ T-cell count was evaluated prospectively, whereas frozen samples were evaluated under blinded conditions for the other variables after the study was completed. RESULTS: The presence of the codon 215 mutation [P = 0.044; relative hazard (RH), 2.6], > or = 20,000 HIV RNA copies/ml (P = 0.002; RH, 5.5), and < 350 CD4+ cells 10(6)/l (P = 0.042; RH, 2.2) were prognostic factors, and > or = 30 pg/ml ICD p24 level (P = 0.52; RH, 1.4) was not a prognostic factor in predicting progression. Subjects were prestratified by previous ZDV use (< or = 6 or > 6 months). Across both strata thymopentin delayed treatment progression to ARC, AIDS, or death (P = 0.015; RH, 3.0). This effect was magnified in the ZDV-experienced subjects at greater risk, where thymopentin delayed progression compared to placebo in the presence of the codon 215 mutation (P = 0.007; RH, 10.1), > or = 20,000 RNA copies/ml (P = 0.012; RH, 8.9), and CD4+ T-cell count < 350 x 10(6)/l (P = 0.005; RH, 10.4). CONCLUSIONS: Codon 215 mutation, serum HIV RNA and CD4 T-cell count are independent predictors of progression in ZDV-experienced asymptomatic subjects. Furthermore, thymopentin delays HIV disease progression in the presence of a key ZDV resistance mutation as well as high viral load and low CD4+ T-cell counts.

Adjuvants, Immunologic↗

PubMed2005

High-level production of yeast (Schwanniomyces occidentalis) phytase in transgenic rice plants by a combination of signal sequence and codon modification of the phytase gene.

This study was designed to produce yeast (Schwanniomyces occidentalis) phytase in rice with a view to future applications in the animal feed industry. To achieve high-level production, chimeric genes with the secretory signal sequence of the rice chitinase-3 gene were constructed using either the original full-length or N-truncated yeast phytase gene, or a modified gene whose codon usage was changed to be more similar to that of rice, and then introduced into rice (Oryza sativa L.). When the original phytase genes were used, the phytase activity in the leaves of transgenic rice was of the same level as in wild-type plants, whose mean value was 0.039 U/g fresh weight (g-FW) (1 U of activity was defined as 1 micromol P released per min at 37 degrees C). In contrast, the enzyme activity was increased markedly when codon-modified phytase genes were introduced: up to 4.6 U/g-FW of leaves for full-length codon-modified phytase, and 10.6 U/g-FW for truncated codon-modified phytase. A decrease in the optimum temperature and thermal stability was observed in the truncated heterologous enzyme, suggesting that the N-terminal region plays an important role in enzymatic properties. In contrast, the optimum temperature and pH of full-length heterologous phytase were indistinguishable from those of the benchmark yeast phytase, although the heterologous enzyme was less glycosylated. Full-length heterologous phytase in leaf extract showed extreme stability. These results indicate that codon modification, combined with the use of a secretory signal sequence, can be used to produce substantial amounts of yeast phytase, and possibly any phytases from various organisms, in an active and stable form.

Journal Article↗

PubMed1997

Severe upper gastrointestinal polyposis associated with sparse colonic polyposis in a familial adenomatous polyposis family with an APC mutation at codon 1520.

BACKGROUND: Familial adenomatous polyposis usually results in colonic polyposis with hundreds to thousands of polyps, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and variable extracolonic features. Recent reports indicate that patients with distal mutations between codons 1445 and 1578 do not express CHRPE and have a high incidence of desmoid tumours. PATIENTS: The family studied has an unusual phenotype of sparse colonic polyposis but profuse upper gastrointestinal polyposis. Affected subjects do not have CHRPE. METHODS: The protein truncation test followed by sequencing identified a 2 base pair deletion at codon 1520 in the APC gene. This results in a frameshift creating a stop codon 13 codons downstream. RESULTS: This family demonstrates that sparse colonic polyposis but severe upper tract polyposis may be associated with mutations between codons 1445 and 1578. CONCLUSIONS: Study of duodenal and colonic polyps in further cases with mutations in this region is warranted. Such mutations may preferentially cause duodenal adenomas and desmoid tumours as somatic mutations in these tumours also occur in this region, unlike colorectal tumours where somatic mutations occur more proximally. This study emphasises the importance of screening the upper gastrointestinal tract even when the colonic disease is mild.

Adenomatous Polyposis Coli↗

PubMed1996

Insulin sensitivity and body weight changes in young white carriers of the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor gene.

Recently, a missense mutation replacing tryptophan with arginine at codon 64 of the beta 3-adrenergic receptor gene was shown to be associated with insulin resistance in nondiabetic subjects and to an earlier onset of NIDDM in Pima Indians. We studied whether the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor gene in a cohort of young healthy Danes was associated with high birth weight, accelerated weight gain during childhood and adolescence, present obesity, or impaired insulin sensitivity. The protocol included 380 unrelated white subjects in whom insulin sensitivity and secretion were measured during a combined intravenous glucose and tolbutamide tolerance test. A number of biochemical and anthropometric characteristics were determined for each subject. The subjects were genotyped for the codon 64 polymorphism by applying polymerase chain reaction restriction fragment-length polymorphism screening with the use of endonuclease BstN1. The allelic frequency of the mutated allele was 7% (95% CI: 5-10%), and it was similar in obese and nonobese subjects. The beta 3-adrenergic receptor gene variant was not related to birth weight or weight gain during childhood or adolescence. In its heterozygous form, the gene variant was not associated with an altered insulin sensitivity index (SI) or other features of the insulin resistance syndrome (BMI, blood pressure, fasting serum lipid levels, or fasting serum fibrinolytic variables). Three homozygous carriers of the polymorphism were identified, and each had a significantly higher BMI (27.4 +/- 1.3 vs. 23.5 +/- 3.7 kg/m2 [mean +/- SD]; P = 0.032), lower SI [4.9 +/- 2.9 vs. 15.4 +/- 9.0 10(-5) x (min x pmol/l)-1; P = 0.013], and higher fasting serum C-peptide (730 +/- 155 vs. 471 +/- 158 pmol/l; P = 0.016) than the wild-type carriers. The homozygous carriers also had significantly higher levels of fasting serum triglyceride (P = 0.042) and serum LDL cholesterol (P = 0.013). When adjustments were made for age, sex, BMI, and VO2max in a multiple regression analysis, a significantly negative association was found between homozygosity for the codon 64 variant and the SI (P = 0.009). We conclude that in young healthy Danes, the homozygous form but not the heterozygous form of the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor may be associated with obesity and, independent of BMI, with a low SI. Since only three homozygous carriers were identified among 380 subjects, the results must be interpreted with caution, and studies of larger population samples are needed.

Adult↗

PubMed2001

Polymorphism at codon 469 of the intercellular adhesion molecule-1 locus is associated with protection against severe gastrointestinal complications in Henoch-Schönlein purpura.

OBJECTIVE: Henoch-Schonlein purpura (HSP) is a small sized vasculitis affecting mainly children. Intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms have recently been implicated in the susceptibility to some vasculitides. To further investigate the clinical implication of ICAM-1 polymorphisms in HSP, we examined their potential association and influence in the development of severe complications in an unselected series of patients with HSP. METHODS: Fifty-two patients, of which 41 were children, were diagnosed with HSP using classification criteria of Michel, et al at the Hospital Xeral-Calde (Lugo, Spain); 129 ethnically matched controls were included. Patients had at least one year of followup. Patients and controls were genotyped by allelic oligonucleotide techniques for ICAM-I polymorphism at codon 241 and 469. RESULTS: The frequency distribution of the alleles and genotypes for each ICAM-1 polymorphism did not show significant differences between HSP patients and controls. Also, no differences between patients with or without renal manifestations were found. However, the frequency of the codon 469 K/E genotype was significantly decreased in patients without severe gastrointestinal manifestations compared to those with them (22.29 vs 65%, OR 0.1, p = 0.02, after correction for age, sex, and disease duration). None of the 11 adults exhibited the R/G genotype at codon 241 compared with 7 of 41 children (OR 0.0, 95% CI 0.0-2.9, p = 0.14). Patients with the R/G genotype were associated with low incidence of renal manifestations and none developed permanent renal involvement (renal sequelae); however, this finding did not achieve statistical significance. CONCLUSION: ICAM-1 polymorphisms alone are not associated with development of HSP, but patients not carrying the codon 469 K/E genotype are at decreased risk of developing severe gastrointestinal complications. The R/G polymorphism at codon 241 may reduce the risk of renal sequelae in the development of HSP in adulthood.

Adolescent↗

PubMed2001

p53 codon 72 polymorphism and rheumatoid arthritis.

OBJECTIVE: To investigate whether the p53 codon 72 polymorphism is associated with susceptibility to rheumatoid arthritis (RA) and its clinical features. METHODS: A polymerase chain reaction of genomic DNA-restriction fragment length polymorphism was used to determine genotypes of the p53 codon 72 in 114 patients with RA and 114 healthy controls. Clinical/serological manifestations were analyzed in each patient and correlated with the genotypes. RESULTS: The genotype distribution of the p53 codon 72 did not differ between patients with RA and controls (Arg/Arg, Arg/Pro, Pro/Pro genotypes 38, 58, 18 vs 37, 60, 17 controls, respectively; chi-square = 0.08, 2 df, p = 0.96). No significant difference was found in allele frequencies between the groups. Clinically there was no significant difference in age at onset, functional class, physician's global assessment, ESR, CRP, RF titer, extraarticular and cervical spine involvement, frequencies of joint operation, and admission in RA patients according to the p53 codon 72 genotypes. However, the number of patients within each group was extremely small, for example only 5 patients with cervical spine involvement. No firm conclusions could safely be reached about clinical manifestations from this study. CONCLUSION: No association was found between the p53 codon 72 polymorphism and RA. Studies are needed to clarify the role of the p53 polymorphism in the pathogenesis of RA.

Adolescent↗

PubMed2002

XPD codon 751 polymorphism, metabolism genes, smoking, and bladder cancer risk.

Cigarette smoking is the main risk factor for bladder cancer, accounting for at least 50% of bladder cancer in men. Cigarette smoke is a rich source of arylamines, which are detoxified by the NAT2 enzyme and activated by the NAT1 enzyme to highly reactive species that can form bulky adducts on DNA. DNA damage from such adducts is mainly repaired by the nucleotide excision repair pathway, in which the XPD protein functions in opening the DNA helix. We hypothesized that an XPD codon 751 polymorphism (Lys-to-Gln amino acid change) could affect the repair of smoking-induced DNA damage and could be associated with bladder-cancer risk. We also hypothesized that allelic variants of the NAT1 and NAT2 genes might modify the effect of the XPD codon 751 polymorphism on smoking-associated bladder-cancer risk. We determined the XPD codon 751 genotype for 228 bladder-cancer cases and 210 controls who were frequency-matched to cases by age, sex, and ethnicity, and we used our previously published data on the NAT1 and NAT2 genotypes for these same individuals (J. A. Taylor et al., Cancer Res., 58: 3603-3610, 1998). We found a slight decrease in risk for the XPD codon 751 Gln/Gln genotype (adjusted odds ratio: 0.8; 95% confidence interval: 0.4-1.3) compared with subjects with the Lys/Lys or Lys/Gln genotypes. The analysis with smoking showed that smokers with the Lys/Lys or Lys/Gln genotypes were twice as likely to have bladder cancer than smokers with the Gln/Gln genotype (test of interaction P = 0.03). The combined presence of the NAT1/NAT2 high-risk genotype and the XPD Lys/Lys or Lys/Gln genotypes ignoring smoking had an odds ratio that was only slightly higher than expected, assuming no genotype-genotype interaction (P = 0.52). We found little evidence for a gene-gene-exposure, three-way interaction among the XPD codon 751 genotype, smoking, and the NAT1/NAT2 genotype.

Aged↗

PubMed2004

p53 codon 72 polymorphic variants, loss of allele-specific transcription, and human papilloma virus 16 and/or 18 E6 messenger RNA expression in squamous cell carcinomas of the head and neck.

A polymorphism at codon 72 of the human tumor suppressor p53 determines translation into either arginine or proline. Yet, the impact of this amino acid variability on the risk to develop malignant tumors, particularly carcinomas associated with human papilloma virus (HPV) infections, remains unresolved because of contradictory results. To address a potential correlation between the different genotypes and the manifestation of squamous cell carcinomas of the head and neck (SCCHN), we determined the p53 codon 72 in 193 healthy subjects and 122 unselected SCCHN with known HPV status. Furthermore, loss of allele-specific transcription was analyzed in p53 codon 72 heterozygous (Arg/Pro) SCCHN and correlated with HPV 16 and/or 18 E6 transcript expression. We found a moderately increased risk (odds ratio, 1.86; 95% confidence interval, 1.0-3.3) for individuals with germ line heterozygosity to develop SCC of the pharynx. On the other hand, p53 codon 72 polymorphic variants, most notably the Arg/Arg genotype, showed no association with the presence of HPV 16 and/or 18 E6 transcript. Moreover, there was no evidence for HPV-driven selection in SCCHN with allele-specific loss of transcription. Our data suggest that the p53 codon 72 polymorphism has a minor impact on the development of SCCHN.

Adult↗

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↗

PubMed1995

Somatic APC and K-ras codon 12 mutations in periampullary adenomas and carcinomas from familial adenomatous polyposis patients.

Periampullary adenomas in the duodenum of Familial Adenomatous Polyposis (FAP) patients are among the most frequent and clinically important extracolonic neoplasms in FAP. The purpose of this study was to characterize the frequency and nature of somatic adenomatous polyposis coli (APC) gene and K-ras codon 12 mutations in periampullary adenomas and carcinomas in FAP. These molecular changes have been shown to be important during the early stages of colorectal carcinogenesis. DNA was prepared from endoscopic periampullary biopsies and paraffin blocks from 49 FAP patients. Of 143 samples, 77 were histologically normal, 29 were biopsies from small periampullary adenomas, 29 biopsies were from 19 large adenomas and eight samples were from periampullary cancers. APC mutations in the mutation cluster region and K-ras codon 12 mutations were detected by polymerase chain reaction based techniques. Somatic APC mutations consisting of deletions at codons 1464 and 1465 were detected in one small and two large periampullary adenomas. Loss of heterozygosity was seen in one periampullary carcinoma. K-ras codon 12 mutations were detected in seven of 19 large periampullary adenomas and in one of eight periampullary carcinomas. These data suggest that K-ras codon 12 mutations may be important during periampullary tumorigenesis in FAP but somatic APC mutations in the mutation cluster region are infrequent. Local environmental factors in the duodenum may contribute to differences in the molecular changes which occur during the adenoma-to-carcinoma sequence in periampullary compared to colonic tumorigenesis.

Adenoma↗

PubMed2026

Molecular dynamics simulations of positively selected codons in FcγRI reveal novel biochemical binding properties.

FcγRI is a high-affinity receptor for IgG, associated with autoimmune disease pathology and determines clinical responses to antibody-based immunotherapies. FcγRI has a complex evolutionary history that is not fully understood, and to address this we explored signatures of positive selection in the receptor's functional gene, FCGR1A, using codon-based selection tests on aligned 1-1 orthologous sequences from placental mammals (n = 32). Signatures of positive selection have occurred at several locations within the gene, with two sites (H148 (M2a ω 0.997 & M8 ω = 0.993)) and (W149 (M2a ω = 0.999 & M8 ω = 1.000)) exhibiting highest posterior probabilities, suggesting strong evidence of positive selection; these positions are known to form one of the FcγRI-IgG binding interfaces. We employed ancestral reconstruction to statistically infer prior codon sequences at these sites and identified ancestral H148P and W149R codons at different nodes in the phylogeny. Employing molecular dynamics simulations, we determined how evolutionary changes at these sites may have influenced the binding of FcγRI-IgG of modern-day Homo sapiens. Measuring RMSD, free energy, radius of gyration, hydrogen bond formation, and analyzing free energy landscapes, we demonstrate that structural instability between mutant structures vs the WT counterpart; however, overall binding potential increases at position 148, yet decreases at 149 in potential. H148P protonation at physiological pH remains similar, yet during acidotic calculations, protonation is likely reduced, with predicted reduction in affinity for IgG. While ancestral W149R substitutions demonstrate an implication for electron conjugation. Examining key sites at this binding FcγRI-IgG interface, our data demonstrate that these two codons have evolved in humans to be relatively insensitive to shifts in pH promoting a more stable interaction with the Fc portion of IgG during diseases that promote acidosis.

Receptors, IgG↗

PubMed2000

Quadruplet codons: implications for code expansion and the specification of translation step size.

One of the requirements for engineering expansion of the genetic code is a unique codon which is available for specifying the new amino acid. The potential of the quadruplet UAGA in Escherichia coli to specify a single amino acid residue in the presence of a mutant tRNA(Leu) molecule containing the extra nucleotide, U, at position 33.5 of its anticodon loop has been examined. With this mRNA-tRNA combination and at least partial inactivation of release factor 1, the UAGA quadruplet specifies a leucine residue with an efficiency of 13 to 26 %. The decoding properties of tRNA(Leu) with U at position 33.5 of its eight-membered anticodon loop, and a counterpart with A at position 33.5, strongly suggest that in both cases their anticodon loop bases stack in alternative conformations. The identity of the codon immediately 5' of the UAGA quadruplet influences the efficiency of quadruplet translation via the properties of its cognate tRNA. When there is the potential for the anticodon of this tRNA to dissociate from pairing with its codon and to re-pair to mRNA at a nearby 3' closely matched codon, the efficiency of quadruplet translation at UAGA is reduced. Evidence is presented which suggests that when there is a purine base at position 32 of this 5' flanking tRNA, it influences decoding of the UAGA quadruplet.

Amino Acid Sequence↗

PubMed2025

Assessment of mRNA Decay and Calculation of Codon Occurrence to mRNA Stability Correlation Coefficients after 5-EU Metabolic Labeling.

mRNA translation and decay are tightly connected. This chapter describes a method to assess the influence of each codon identity on mRNA stability in cultured cells. The technique involves metabolic labeling of the nascent mRNAs by addition of the nucleoside analog 5-ethynyluridine (5-EU), purification of the RNA at different time-points after chase of the 5-EU, then biotinylation with Click chemistry, pull-down, and sequencing. The transcripts' half-lives are calculated from the expression level of each mRNA at the different time-points. Finally, the method describes the calculation of the Codon occurrence to mRNA Stability correlation Coefficient, or CSC, as a correlation between the codon occurrence in a transcript and the transcript half-life, for each codon.

RNA Stability↗

PubMed2005

A model of protein translation including codon bias, nonsense errors, and ribosome recycling.

We present and analyse a model of protein translation at the scale of an individual messenger RNA (mRNA) transcript. The model we develop is unique in that it incorporates the phenomena of ribosome recycling and nonsense errors. The model conceptualizes translation as a probabilistic wave of ribosome occupancy traveling down a heterogeneous medium, the mRNA transcript. Our results show that the heterogeneity of the codon translation rates along the mRNA results in short-scale spikes and dips in the wave. Nonsense errors attenuate this wave on a longer scale while ribosome recycling reinforces it. We find that the combination of nonsense errors and codon usage bias can have a large effect on the probability that a ribosome will completely translate a transcript. We also elucidate how these forces interact with ribosome recycling to determine the overall translation rate of an mRNA transcript. We derive a simple cost function for nonsense errors using our model and apply this function to the yeast (Saccharomyces cervisiae) genome. Using this function we are able to detect position dependent selection on codon bias which correlates with gene expression levels as predicted a priori. These results indirectly validate our underlying model assumptions and confirm that nonsense errors can play an important role in shaping codon usage bias.

Animals↗