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PubMed2025

Genetic Downregulation of Interleukin-6 Signaling, Coagulation Function, and Risk of Thromboembolic Disease.

BACKGROUND: Although genetic evidence supports IL-6 (interleukin-6) signaling inhibition as protective against atherosclerotic disease, its potential effects on thromboembolic outcomes are not well established. We conducted a Mendelian randomization analysis to investigate the association of genetically proxied IL-6 signaling inhibition with venous thromboembolism, cardioembolic stroke, and coagulation cascade protein levels. METHODS: IL-6 signaling inhibition was proxied using the rs2228145 IL6R missense variant, which impairs classical IL-6 signaling and lowers CRP (C-reactive protein) levels. Genetic associations with thromboembolic disease outcomes were obtained from genome-wide association studies of venous thromboembolism (81 190 cases) and cardioembolic stroke (10 804 cases). As atherosclerotic comparator traits, we included coronary artery disease (181 522 cases) and large-artery atherosclerotic stroke (6399 cases). Genetic associations with 35 coagulation cascade protein levels were obtained from the UK Biobank (n=6218) and deCODE cohorts (n=35 559). Mendelian randomization estimates were derived using the Wald ratio method, scaled per 1-unit decrease in natural log-transformed CRP levels. RESULTS: Genetically proxied IL-6 signaling inhibition was associated with increased risk of venous thromboembolism (odds ratio [OR], 1.31 [95% CI, 1.16-1.47], P=6.5×10-6) but not with cardioembolic stroke (OR, 1.25 [95% CI, 0.73-2.14], P=0.42). Conversely, protective associations were observed for both coronary artery disease and large-artery atherosclerotic stroke. Proteomic analyses demonstrated significant reductions in levels of 5 procoagulant and 7 anticoagulant or antifibrinolytic proteins. CONCLUSIONS: These findings suggest that IL-6 signaling inhibition dysregulates coagulation homeostasis and increases venous thromboembolism risk. Further experimental, translational, and epidemiologic studies are warranted to delineate underlying mechanisms and to evaluate thromboembolic safety in pharmacologic IL-6 signaling inhibition.

Humans↗
PubMed2026

Associations of genetically predicted interleukin-6 and tumor necrosis factor signaling pathways with mortality among persons with colorectal cancer: a two-sample Mendelian randomization.

BACKGROUND: Despite significant progress in identifying risk factors for colorectal cancer (CRC), factors influencing survival in people with CRC remain less understood. Pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) have been implicated in cancer progression and may influence CRC outcomes. We investigated associations between genetically predicted levels of IL-6 and TNF-α signaling pathways and mortality in people with CRC. METHODS: We conducted a two-sample Mendelian randomization (MR) analysis using cis-acting single nucleotide polymorphisms (SNPs) associated with soluble IL-6 receptor alpha (sIL6-RA) and IL-6 signal transducer gp130 (IL6ST), representing IL-6 signaling, and with TNF-α, and its soluble receptors (sTNF-R1, sTNF-R2). SNPs were obtained separately from two large genome-wide association studies (GWAS): deCODE and UK Biobank (UKB). The outcome was CRC-specific mortality among 16,964 CRC cases (4010 deaths) in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Analyses were stratified by tumor site and stage. The inverse variance weighted (IVW) method, incorporating a correlation matrix for dependent SNPs, was used for primary analyses. Because literature links TNF-α to CRC incidence, we additionally performed a simulation study to evaluate the potential impact of collider bias resulting from restricting analyses to CRC cases. RESULTS: Genetically predicted sIL6-RA was weakly positively associated with CRC-specific mortality (deCODE-SNPs (n = 13) HR per 1 SD increase: 1.06; 95% CI: 1.00-1.12; UKB-SNPs (n = 11) HR: 1.09; 95% CI: 1.02-1.17). Genetically proxied IL6ST levels showed no association with CRC-specific mortality in the overall sample (deCODE-SNPs (n = 19) HR: 1.04; 95% CI: 0.90-1.21; UKB-SNPs (n = 9) HR: 1.11; 95% CI: 0.87-2.42), while higher IL6ST levels were associated with increased mortality among patients with stage 2/3 disease (deCODE-SNPs (n = 19) HR: 1.45; 95% CI: 1.10-1.91; UKB-SNPs (n = 9) HR: 1.87; 95% CI: 1.22-2.89). No associations were observed for TNF-α, sTNF-R1, or sTNF-R2. Findings for all exposures were consistent across both GWAS datasets. Simulation analyses for TNF-α indicated collider bias was present but limited in magnitude. CONCLUSIONS: Our findings suggest that IL-6 signaling may play a role in CRC progression although of limited magnitude, whereas TNF-related pathways appear less relevant for prognosis.

Humans↗
PubMed2001

[The realm of mitochondrial genetics competence].

The paper discusses the main applications of achievements of mitochondrial genetics: human pathology (mitochondrial diseases, complex disease susceptibility genes) and population genetics (evolution of mankind, demographic history, and migration ways of populations). Awareness of the physiological properties of the well-known nucleotide sequences of mitochondrial DNA is ascertained to be a strategy for studying the functional organization of nuclear genome whose structure is all but completely decoded.

Genetic Predisposition to Disease↗
PubMed1986

Primordial reading of genetic information.

From the consideration of general features of the anticodon loop and stem in tRNA and the properties of present-day translation, we put forward a plausible scenario to explain the evolution of the genetic code from a highly ambiguous triplet code to the present refined decoding system. Our model based on the reading of the code suggests that the anticodon of primordial tRNA could adopt either the 3' or the 5' stacked conformation permitting the formation of the "best two out of three" base pairs, either the first and second codon position or the second and third. Progressive acquisition of precise structural constraint and the modification of bases in the anticodon loop would give way eventually to the less ambiguous "two out of three" reading mechanism having only the 3' stacked conformation. Further adjustments of base composition and modification leads inevitably to the present generalized code. In this way the primordial code encoding 4-8 amino acids or related derivates evolves smoothly to the present code having 20 amino acids.

Biological Evolution↗
PubMed1996

Mutations in yeast ribosomal proteins S28 and S4 affect the accuracy of translation and alter the sensitivity of the ribosomes to paromomycin.

Ribosomal proteins S12, S5 and S4 of Escherichia coli are essential for the control of translational accuracy. Their yeast equivalents, i.e., S28, S4 and S13, have also been implicated in this process. Using a poly(U)-dependent cell-free translation system, we determined the accuracy of translation and the sensitivity to antibiotic paromomycin of yeast ribosomes carrying mutant ribosomal proteins S28 and/or S4. Our results confirm by quantitative biochemical methods previous genetic data showing that proteins S28 and S4 are involved in the decoding activity of the ribosome and interact to control translational accuracy. We find that the suppressor mutation SUP44 in yeast S4, decreased the accuracy of translation. To examine the effect of mutant S28, we disrupted RPS28B and introduced in RPS28A the same substitutions that cause hyperaccurate translation or antibiotic resistance in bacteria. Three of these substitutions (Lys-62-->Asn, Thr or Gln) similarly increased translational accuracy in vitro or antibiotic resistance. In the presence of the SUP44 mutation, these substitutions partially reversed the decrease of translational accuracy caused by SUP44. However, the Lys-62-->Arg substitution decreased translational accuracy and caused antibiotic sensitivity both in nonsuppressor and in SUP44 haploids. These results establish the role of Lys-62 of S28 in optimizing translational accuracy and provide a more precise view of the functional role of two important ribosomal proteins.

Anti-Bacterial Agents↗
PubMed1996

Three, four or more: the translational stop signal at length.

Translational stop signals are defined in the genetic code as UAA, UAG and UGA, although the mechanism of their decoding via protein factors is clearly different from that of the other codons. There are strong biases in the upstream and downstream nucleotides surrounding stop codons. Experimental tests have shown that termination-signal strength is strongly influenced by the identity of the nucleotide immediately downstream of the codon (+4), with a correlation between the strength of this four-base signal and its occurrence at termination sites. The +4 nucleotide and other biases downstream of the stop codon may reflect sites of contact between the release factor and the mRNA, whereas upstream biases may be due to coding restrictions, with the release factor perhaps recognizing the final tRNA and the last two amino acids of the polypeptide undergoing synthesis. This means that the translational stop signal is probably larger than the triplet codon, but its exact length will be clearer when it is known which nucleotides are in direct contact with the release factor. Ultimately it will be defined exactly when a crystal structure of the release factor with its recognition substrate becomes available.

Codon, Terminator↗
PubMed1997

Beyond the wobble: the rule of conjugates.

A reexamination of the genetic code suggests a rule of conjugates which captures the observed quartet degeneracies without exception. Adenine is the conjugate of cytosine and uracil is the conjugate of guanine. Further analysis reveals that the rule of conjugates is a macrolevel manifestation of the molecular-level hydrogen-bonding and base-stacking interactions at the decoding site. This new perspective is of significance to evolutionary discussions of nucleic acid bases, genetic code, and interactions involving RNAs.

Adenine↗
PubMed1998

Multivariate behavioral genetic analysis of achievement and cognitive measures in reading-disabled and control twin pairs.

In recent years behavioral genetic studies have provided conclusive evidence that reading disability and related learning disorders, such as mathematics disability, are due at least in part to heritable factors (DeFries et al. 1987; Alarcón et al. 1997). Although the observed relationship between performance in these areas also may be due substantially to genetic influences (Light and DeFries 1995; Thompson et al. 1991), relatively few studies have examined the genetic and environmental etiology of this covariation in a multivariate framework. In the present study data from 196 identical (monozygotic; MZ) and 155 same-sex fraternal (dizygotic; DZ) twin pairs in which at least one member of each pair evidenced reading problems in school (reading disabled) were subjected to a multivariate behavioral genetic analysis. Structural equation models were fitted to twin data for verbal IQ (VIQ), phonological decoding ability (PHON), reading performance (READ), and mathematics performance (MATH) to assess the extent to which VIQ and PHON mediate the observed covariation between READ and MATH. Results suggest that VIQ and PHON account for most of the covariation between READ and MATH. Moreover, approximately 82% of the observed correlation between READ and MATH was due to genetic factors that also influence VIQ and PHON. When data from 132 MZ and 91 same-sex DZ control twin pairs in which neither twin had a history of reading problems were subjected to the same analyses, the covariation between READ and MATH was found to be due to both genetic and shared environmental influences. Thus genetic factors that influence VIQ and PHON also contribute to the observed covariation between READ and MATH in both a reading-disabled and a control twin sample.

Achievement↗
PubMed2026

Molecular Determinants and Therapeutic Targeting of Stop Codon Readthrough in Eukaryotic Translation.

Accurate translation termination is essential for proteome integrity and in eukaryotes is primarily governed by the release factors eRF1 and eRF3, which ensure precise recognition of stop codons and efficient release of nascent polypeptides. However, proteome integrity is challenged by mutations that generate premature termination codons (PTCs), leading to truncated, nonfunctional proteins and degradation of the aberrant transcript via nonsense-mediated mRNA decay (NMD). Collectively, these events account for ∼1800 human genetic diseases. Translational readthrough, the process by which near-cognate tRNAs decode stop codons and allow ribosomes to continue elongation beyond the stop codon, represents a possibility to suppress PTCs and restore full-length protein synthesis. Initially discovered in viruses as a mechanism to expand coding capacity, readthrough is now recognized as a regulated feature of eukaryotic gene expression influenced by both cis-acting sequence elements and trans-acting factors. Recent evidence highlights the remarkable context dependence of readthrough, revealing variation across transcripts, tissues, and developmental stages. In this review, we examine the molecular determinants that define stop codon recognition and readthrough efficiency, with particular emphasis on nucleotide context. We further discuss the mechanisms and binding sites of small molecules that promote PTC readthrough, and summarize the clinical development landscape of readthrough-inducing compounds for the treatment of diseases caused by nonsense mutations.

Humans↗
PubMed2002

A map of the common chimpanzee genome.

The completion of the chimpanzee genome will greatly help us determine which genetic changes are unique to humanity. Chimpanzees are our closest living relative, and a recent study has made considerable progress towards decoding the genome of our sister taxon.1 Over 75,000 common chimpanzee (Pan troglodytes) bacterial artificial chromosome end sequences were aligned and mapped to the human genome. This study shows the remarkable genetic similarity (98.77%) between humans and chimpanzees, while highlighting intriguing areas of potential difference. If we wish to understand the genetic basis of humankind, the completion of the chimpanzee genome deserves high priority.

Animals↗
PubMed2026

Hidden Diversity in the Sands: Genomic Footprints of Pleistocene Refugia and Fragile Futures of the Turkestan Ground-Jay (Podoces panderi) in Central Asia.

The Turkestan ground-jay (Podoces panderi), a corvid endemic to Central Asia's deserts and steppes, exemplifies how extreme environments drive speciation. Our study provides the first comprehensive high-resolution genomic analysis of this species, using complete mitochondrial genomes (49 individuals) to decode its population structure and demographic past. Our analyses revealed three highly divergent genetic clusters with strong geographic structure. The P. p. iliensis population (Cluster_3) showed particularly pronounced genetic distinctiveness, with significant differentiation from P. p. panderi (Cluster_2 and Cluster_1) populations. This clear genetic separation supports the taxonomic validity of P. p. iliensis as a distinct evolutionary lineage. Demographic reconstruction indicated that Cluster_2 likely represents the ancestral group, with subsequent southward expansion into the Karakum region. The isolated P. p. iliensis population exhibited signatures of long-term isolation, including reduced genetic diversity and absence of recent gene flow with other clusters. These results provide strong evidence that P. p. iliensis represents a distinct evolutionary unit. The genetic structuring into three clusters reflects historical isolation in desert refugia during Pleistocene climatic fluctuations. Notably, we detected asymmetric gene flow among three clusters. These findings redefine P. panderi as a model for desert adaptation, where climatic extremes forged genetic fragmentation amid limited dispersal. Beyond taxonomy, our work highlights how aridification sculpted biodiversity in Asia's interior, urging conservation attention for these evolutionarily distinct lineages.

Animals↗
PubMed2003

The rate of peptidyl-tRNA dissociation from the ribosome during minigene expression depends on the nature of the last decoding interaction.

The expression of some very short open reading frames (ORFs) in Escherichia coli results in peptidyl-tRNA accumulation that is lethal to cells defective in peptidyl-tRNA hydrolase activity. In an attempt to understand the factors that affect this phenotype, we have surveyed the toxicity of a complete set of two-codon ORFs cloned as minigenes in inducible expression vectors. The minigenes were tested in hydrolase-defective hosts and classified according to their degree of toxicity. In general, minigenes harboring codons belonging to the same box in the standard table of the genetic code mediated similar degrees of toxicity. Moreover, the levels of peptidyl-tRNA accumulation for synonymous minigenes decoded by the same tRNA were comparable. However, two exceptions were observed: (i) expression of minigenes harboring the Arg codons CGA, CGU, and CGC, resulted in the accumulation of different levels of the unique peptidyl-tRNAArg-2 and (ii) the toxicity of minigenes containing CUG and UCU codons, each recognized by two different tRNAs, depended on peptidyl-tRNA accumulation of only one of them. Non-toxic, or partly toxic, minigenes prompted higher accumulation levels of peptidyl-tRNA upon deprivation of active RF1, implying that translation termination occurred efficiently. Our data indicate that the nature of the last decoding tRNA is crucial in the rate of peptidyl-tRNA release from the ribosome.

Blotting, Northern↗
PubMedDate not supplied

[Coding in molecular biology and radiation].

In work, on the basis of known base biological laws, the new natural three-dimensional designs are under construction: codonogram and aminogram. Codonogram and aminogram have revealed the new laws of coding and constructions in molecular biology. The secondary coding codonogram, at the expense of redundancy, has enabled for DNA, RNA, and mRNA to construct the hidden coding layers (HLC). HLC are constructed on a base of pirimidine and purine. In interaction with ferments HLC, should guarantee: addressation, synchronization, correction and other functional transformations of a gene. Radiation can damage a layer mRNA of synthesis protein, hidden layers of coding and structure of the ferments of the cell. In work are given: kodonogram, aminogram UGC, basis of construction HLC, the references to the literature with an example of decoding.

Base Sequence↗
PubMed2003

Genebanks: a comparison of eight proposed international genetic databases.

OBJECTIVE: To identify and compare population-based genetic databases, or "genebanks", that have been proposed in eight international locations between 1998 and 2002. A genebank can be defined as a stored collection of genetic samples in the form of blood or tissue, that can be linked with medical and genealogical or lifestyle information from a specific population, gathered using a process of generalized consent. METHODS: Genebanks were identified by searching Medline and internet search engines with key words such as "genetic database" and "biobank" and by reviewing literature on previously identified databases such as the deCode project. Collection of genebank characteristics was by an electronic and literature search, augmented by correspondence with informed individuals. The proposed genebanks are located in Iceland, the United Kingdom, Estonia, Latvia, Sweden, Singapore, the Kingdom of Tonga, and Quebec, Canada. Comparisons of the genebanks were based on the following criteria: genebank location and description of purpose, role of government, commercial involvement, consent and confidentiality procedures, opposition to the genebank, and current progress. RESULTS: All of the groups proposing the genebanks plan to search for susceptibility genes for complex diseases while attempting to improve public health and medical care in the region and, in some cases, stimulating the local economy through expansion of the biotechnology sector. While all of the identified plans share these purposes, they differ in many aspects, including funding, subject participation, and organization. The balance of government and commercial involvement in the development of each project varies. Genetic samples and health information will be collected from participants and coded in all of the genebanks, but consent procedures range from presumed consent of the entire eligible population to recruitment of volunteers with informed consent. Issues regarding confidentiality and consent have resulted in opposition to some of the more publicized projects. None of the proposed databases are currently operational and at least one project was terminated due to opposition. CONCLUSIONS: Ambitious genebank projects have been proposed in numerous countries and provinces. The characteristics of the projects vary, but all intend to map genes for common diseases and hope to improve the health of the populations involved. The impact of these projects on understanding genetic susceptibility to disease will be increasingly apparent if the projects become operational. The ethical, legal, and social implications of the projects should be carefully considered during their development.

Canada↗
PubMed1993

[Current situation of dominant autosomal renal polycystosis].

Adult onset polycystic kidney disease causes 11% of all end-stage renal disease in Spain. Recent advantages in the molecular genetics of autosomal dominant polycystic kidney disease (ADPKD) point the way towards the cloning and decoding. One of the gene loci, namely PKD1, was located to the short arm of chromosome 16. Recombinants between 16p polimorphic loci and the PKD1 locus are described. The clinical consecuents of ADPKD are analyzed. Hypertension arterial are found more frequent in the those patients. Caution is therefore recommend in using ACE inhibitors who are at high risk because of compromised renal function. Our study clarifies several clinical extrarenal manifestations of ADPKD. All modalities of renal replacement therapy are appropriate therapeutics choices.

Humans↗
PubMed2026

The Tor pathway, ribosome concentration, and wobble decoding mediate inhibitory effects of the Leu-Pro CUC-CCG codon pair in Saccharomyces cerevisiae.

Translation elongation and efficiency are modulated by the genetic code, with reduced translation efficiency and slow translation caused by 17 inhibitory codon pairs in the yeast Saccharomyces cerevisiae Nine of these inhibitory pairs are functionally important as they are disproportionately strongly conserved within orthologous genes in Saccharomyces sensu stricto For three pairs, including CGA-CGA, inhibition is triggered by ribosome collisions followed by known quality control responses, but the mechanisms by which nine other pairs cause inhibition are unknown. Here, our examination of the molecular basis of inhibition by one such pair, the highly conserved Leu-Pro CUC-CCG codon pair, yielded four findings. First, inhibition is mediated by tRNALeu(UAG), which decodes CUC by a U•C wobble interaction and effectively competes with the nonessential Watson-Crick base-pairing tRNALeu(GAG) Second, despite nearly universal conservation of U33 in tRNAs, the C33 alteration in tRNALeu(GAG) does not significantly impair its function. Third, inhibition likely is mediated by ribosome collisions, as many suppressors bear mutations known or predicted to reduce ribosome concentration, and as local reduction in ribosome concentration suppresses inhibition. Thus, differences between CUC-CCG and CGA-CGA inhibition likely occur downstream from ribosome collisions. Fourth, we find a link between the metabolic state and CUC-CCG inhibition, as we find six suppressor mutations in SCH9, a downstream effector of TORC1 that mediates ribosome production. As Sch9 is inactive during starvation, causing reduced ribosome concentration, one biological function of inhibitory pairs may be to mediate a change in relative expression during starvation conditions.

Ribosomes↗