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PubMed1992

Encoded combinatorial chemistry.

The diversity of chemical synthesis and the power of genetics are linked to provide a powerful, versatile method for drug screening. A process of alternating parallel combinatorial synthesis is used to encode individual members of a large library of chemicals with unique nucleotide sequences. After the chemical entity is bound to a target, the genetic tag can be amplified by replication and utilized for enrichment of the bound molecules by serial hybridization to a subset of the library. The nature of the chemical structure bound to the receptor is decoded by sequencing the nucleotide tag.

Amino Acid Sequence↗
PubMed1999

The zebrafish genome contains two distinct selenocysteine tRNA[Ser]sec genes.

The zebrafish is widely used as a model system for studying mammalian developmental genetics and more recently, as a model system for carcinogenesis. Since there is mounting evidence that selenium can prevent cancer in mammals, including humans, we characterized the selenocysteine tRNA[Ser]sec gene and its product in zebrafish. Two genes for this tRNA were isolated and sequenced and were found to map at different loci within the zebrafish genome. The encoding sequences of both are identical and their flanking sequences are highly homologous for several hundred bases in both directions. The two genes likely arose from gene duplication which is a common phenomenon among many genes in this species. In addition, zebrafish tRNA[Ser]sec was isolated from the total tRNA population and shown to decode UGA in a ribosomal binding assay.

Animals↗
PubMed2006

Between genotype and phenotype.

Genome-wide profiling of cytosine methylation for three human chromosomes in a variety of normal tissues provides a reference resource to begin to decode the epigenetic regulation of gene expression in normal development and to understand gene silencing in cancer.

Chromosomes, Human↗
PubMedDate not supplied

How mitochondria redefine the code.

Annotated, complete DNA sequences are available for 213 mitochondrial genomes from 132 species. These provide an extensive sample of evolutionary adjustment of codon usage and meaning spanning the history of this organelle. Because most known coding changes are mitochondrial, such data bear on the general mechanism of codon reassignment. Coding changes have been attributed variously to loss of codons due to changes in directional mutation affecting the genome GC content (Osawa and Jukes 1988), to pressure to reduce the number of mitochondrial tRNAs to minimize the genome size (Anderson and Kurland 1991), and to the existence of transitional coding mechanisms in which translation is ambiguous (Schultz and Yarus 1994a). We find that a succession of such steps explains existing reassignments well. In particular, (1) Genomic variation in the prevalence of a codon's third-position nucleotide predicts relative mitochondrial codon usage well, though GC content does not. This is because A and T, and G and C, are uncorrelated in mitochondrial genomes. (2) Codons predicted to reach zero usage (disappear) do so more often than expected by chance, and codons that do disappear are disproportionately likely to be reassigned. However, codons predicted to disappear are not significantly more likely to be reassigned. Therefore, low codon frequencies can be related to codon reassignment, but appear to be neither necessary nor sufficient for reassignment. (3) Changes in the genetic code are not more likely to accompany smaller numbers of tRNA genes and are not more frequent in smaller genomes. Thus, mitochondrial codons are not reassigned during demonstrable selection for decreased genome size. Instead, the data suggest that both codon disappearance and codon reassignment depend on at least one other event. This mitochondrial event (leading to reassignment) occurs more frequently when a codon has disappeared, and produces only a small subset of possible reassignments. We suggest that coding ambiguity, the extension of a tRNA's decoding capacity beyond its original set of codons, is the second event. Ambiguity can act alone but often acts in concert with codon disappearance, which promotes codon reassignment.

Base Composition↗
PubMed2026

Decoding glioblastoma evolution and heterogeneity through mechanistic modeling: implications for clinical translation.

Glioblastoma (GBM) is one of the most aggressive and lethal primary brain tumors in adults, characterized by dynamic clonal evolution and extensive genomic, cellular, spatial, and microenvironmental heterogeneity. Multi-omics studies have revealed that GBM follows complex evolutionary trajectories involving genetic, epigenetic, transcriptional, and immune-microenvironmental remodeling as tumors grow, adapt to the brain microenvironment, and acquire therapeutic resistance. Increasing evidence suggests that GBM may originate from aberrant neural stem or progenitor cells, including those residing in the subventricular zone, and that glioblastoma stem cells (GSCs) contribute to tumor propagation, heterogeneity, and recurrence. A key conceptual challenge is to reconcile hierarchical cancer stem cell models, in which GSCs are viewed as relatively stable tumor-propagating subpopulations, with dynamic state plasticity models, in which stem-like properties can be reversibly acquired or lost during transitions among proneural-like, mesenchymal-like, invasive, and therapy-tolerant states. Recent advances in single-cell profiling, spatial transcriptomics, lineage tracing, organoid culture, 3D bioprinting, genetically engineered models, and artificial intelligence (AI)-assisted computational modeling have substantially improved the ability to study these processes. However, no currently available model fully recapitulates human GBM heterogeneity, recurrence, treatment history, and tumor-microenvironment interactions. Therefore, model selection should be guided by clearly defined mechanistic questions rather than by reliance on any single platform. This review summarizes current advances in in vitro, ex vivo, in vivo, and computational models for studying GBM evolution and heterogeneity, and discusses how integrated model pipelines may improve preclinical drug testing, treatment-response prediction, and precision neuro-oncology.

Humans↗
PubMed2004

Decoding the genome: a modified view.

Transfer RNA's role in decoding the genome is critical to the accuracy and efficiency of protein synthesis. Though modified nucleosides were identified in RNA 50 years ago, only recently has their importance to tRNA's ability to decode cognate and wobble codons become apparent. RNA modifications are ubiquitous. To date, some 100 different posttranslational modifications have been identified. Modifications of tRNA are the most extensively investigated; however, many other RNAs have modified nucleosides. The modifications that occur at the first, or wobble position, of tRNA's anticodon and those 3'-adjacent to the anticodon are of particular interest. The tRNAs most affected by individual and combinations of modifications respond to codons in mixed codon boxes where distinction of the third codon base is important for discriminating between the correct cognate or wobble codons and the incorrect near-cognate codons (e.g. AAA/G for lysine versus AAU/C asparagine). In contrast, other modifications expand wobble codon recognition, such as U*U base pairing, for tRNAs that respond to multiple codons of a 4-fold degenerate codon box (e.g. GUU/A/C/G for valine). Whether restricting codon recognition, expanding wobble, enabling translocation, or maintaining the messenger RNA, reading frame modifications appear to reduce anticodon loop dynamics to that accepted by the ribosome. Therefore, we suggest that anticodon stem and loop domain nucleoside modifications allow a limited number of tRNAs to accurately and efficiently decode the 61 amino acid codons by selectively restricting some anticodon-codon interactions and expanding others.

Animals↗
PubMed1995

The involvement of two distinct regions of 23 S ribosomal RNA in tRNA selection.

The role of ribosomal RNA in maintaining the accuracy of translation has been investigated genetically by selecting for rRNA mutations that promoted frameshifting at a specific site in a reporter gene in Escherichia coli. Mutations were recovered in two different regions of 23 S rRNA and each promoted readthrough of stop codons as well as increasing the levels of frameshifting. The first group of mutations was in a small stem loop (the 1916 loop) in domain IV of 23 S rRNA. This stem-loop has been mapped to the subunit interface of the ribosome, close to the decoding center on the 30 S subunit. The second group of mutations was in helix 89, one of the helices emerging from the central loop of domain V. Helix 89 has been implicated in subunit-subunit interactions and peptidyltransferase activity, and it is proposed that mutations in helix 89 influence the accuracy of decoding by affecting the interaction of the CCA end of the tRNA with the peptidyltransferase center.

Base Sequence↗
PubMed2005

Statistical evidence for conserved, local secondary structure in the coding regions of eukaryotic mRNAs and pre-mRNAs.

Owing to the degeneracy of the genetic code, protein-coding regions of mRNA sequences can harbour more than only amino acid information. We search the mRNA sequences of 11 human protein-coding genes for evolutionarily conserved secondary structure elements using RNA-Decoder, a comparative secondary structure prediction program that is capable of explicitly taking the known protein-coding context of the mRNA sequences into account. We detect well-defined, conserved RNA secondary structure elements in the coding regions of the mRNA sequences and show that base-paired codons strongly correlate with sparse codons. We also investigate the role of repetitive elements in the formation of secondary structure and explain the use of alternate start codons in the caveolin-1 gene by a conserved secondary structure element overlapping the nominal start codon. We discuss the functional roles of our novel findings in regulating the gene expression on mRNA level. We also investigate the role of secondary structure on the correct splicing of the human CFTR gene. We study the wild-type version of the pre-mRNA as well as 29 variants with synonymous mutations in exon 12. By comparing our predicted secondary structures to the experimentally determined splicing efficiencies, we find with weak statistical significance that pre-mRNAs with high-splicing efficiencies have different predicted secondary structures than pre-mRNAs with low-splicing efficiencies.

Animals↗
PubMed2005

Structural insights into translational fidelity.

The underlying basis for the accuracy of protein synthesis has been the subject of over four decades of investigation. Recent biochemical and structural data make it possible to understand at least in outline the structural basis for tRNA selection, in which codon recognition by cognate tRNA results in the hydrolysis of GTP by EF-Tu over 75 A away. The ribosome recognizes the geometry of codon-anticodon base pairing at the first two positions but monitors the third, or wobble position, less stringently. Part of the additional binding energy of cognate tRNA is used to induce conformational changes in the ribosome that stabilize a transition state for GTP hydrolysis by EF-Tu and subsequently result in accelerated accommodation of tRNA into the peptidyl transferase center. The transition state for GTP hydrolysis is characterized, among other things, by a distorted tRNA. This picture explains a large body of data on the effect of antibiotics and mutations on translational fidelity. However, many fundamental questions remain, such as the mechanism of activation of GTP hydrolysis by EF-Tu, and the relationship between decoding and frameshifting.

Anti-Bacterial Agents↗
PubMed1997

Multiple von Neumann computers: an evolutionary approach to functional emergence.

A novel system composed of multiple von Neumann computers and an appropriate problem environment is proposed and simulated. Each computer has a memory to store the machine instruction program, and when a program is executed, a series of machine codes in the memory is sequentially decoded, leading to register operations in the central processing unit (CPU). By means of these operations, the computer not only can handle its generally used registers but also can read and write the environmental database. Simulation is driven by genetic algorithms (GAs) performed on the population of program memories. Mutation and crossover create program diversity in the memory, and selection facilitates the reproduction of appropriate programs. Through these evolutionary operations, advantageous combinations of machine codes are created and fixed in the population one by one, and the higher function, which enables the computer to calculate an appropriate number from the environment, finally emerges in the program memory. In the latter half of the article, the performance of GAs on this system is studied. Under different sets of parameters, the evolutionary speed, which is determined by the time until the domination of the final program, is examined and the conditions for faster evolution are clarified. At an intermediate mutation rate and at an intermediate population size, crossover helps create novel advantageous sets of machine codes and evidently accelerates optimization by GAs.

Algorithms↗
PubMed1982

Origin of life: a hypothesis for the origin of adaptor-mediated ordered synthesis of proteins and an explanation for the choice of terminating codons in the genetic code.

Life can be defined as a system of self-sustained chemical processes springing from the ordered synthesis of proteins directed by nucleic acids. To the notoriously difficult problem of the origin of this basic process of nucleic acid-directed protein synthesis, we give a solution of molecular interactions between pentanucleotides and amino acids. A particular conformation of a pentanucleotide forms a double sided template, with its 'inside' capable of nestling an amino acid while the 'outside' acts as an adaptor to a 'codon' triplet on long-chain nucleic acids. This serves as a primitive decoding system. An important aspect of our postulate is that a dynamic interaction is triggered, by this decoding system, through which amino acids are brought to juxtaposition facilitating peptide bond formation. Almost all the important and unique features of contemporary protein-synthesizing machinery are seen to be a direct and natural consequence of our postulate. The emergence of the termination codons also fits in, as a natural consequence of this molecular mechanism.

Animals↗
PubMed2026

Integrative proteogenomic and observational analysis identifies potential biomarkers for latent autoimmune diabetes in adults.

BACKGROUND: Latent autoimmune diabetes in adults (LADA) shares core genetic and immunological features with type 1 diabetes (T1D) but is frequently misdiagnosed as type 2 diabetes (T2D). With few biomarkers for its timely diagnosis and management, this study integrated proteome-wide Mendelian randomisation (MR) and observational clinical analysis to identify potential LADA biomarkers. METHODS: We performed proteome-wide MR using cis-protein quantitative trait loci (cis-pQTLs) for 1,389 plasma proteins from the deCODE study (n = 35,559) and genome-wide association study (GWAS) data for LADA (2,634 cases and 5,947 controls, European ancestry). Robustness was enhanced via multiple sensitivity analyses. Pathway enrichment analysis, druggability evaluation, phenome-wide MR, and interaction analyses were performed to investigate the clinical relevance and biological context of candidate proteins. Candidate proteins were further evaluated using enzyme-linked immunosorbent assays in a matched Chinese clinical study (n = 241) to assess their discriminative ability for LADA. RESULTS: Proteome-wide MR and colocalisation analyses indicated associations between genetically predicted plasma levels of C-X-C motif chemokine ligand 10 (CXCL10; OR [95% CI] per 1-SD increase in protein levels: 5.49 [1.74,17.32]), serum amyloid A1 (SAA1; 1.28 [1.14,1.45]), and SAA2 (1.22 [1.11,1.34]) with LADA risk. Replication, multi-tissue eQTL, and multivariable MR supported CXCL10's association. Druggability evaluation suggested CXCL10 as a drug target under investigation, and phenome-wide MR of 1,006 diseases and traits indicated no major safety concerns for CXCL10 as a potential biomarker. In the observational clinical study, CXCL10 differentiated LADA from healthy controls (area under the receiver operating characteristic curve [ROC-AUC]: 0.889; precision-recall area under the curve [PR-AUC]: 0.919) and T2D (ROC-AUC: 0.838; PR-AUC: 0.921), with both models showing adequate calibration. CONCLUSIONS: This study suggests that CXCL10 is a putative biomarker associated with LADA, demonstrating discriminative ability to distinguish LADA from T2D in an observational clinical cohort. These findings contribute to understanding the autoimmune molecular aetiology of LADA and support its diagnostic potential in resolving the clinical ambiguity between LADA and T2D.

Humans↗
PubMed2026

Characterizing the impact of plasma protein levels on human brain structure and disorders leveraging integrative multi-omics analysis.

With recent advances in high-throughput proteomic technologies, population-scale plasma proteomics datasets, often linked to extensive genetic and phenotypic information, have become increasingly accessible. Yet the relationships between circulating protein levels, brain imaging phenotypes, and risk for neurological and psychiatric disorders remain largely unexplored. Proteome-wide association studies offer a promising approach for elucidating biological mechanisms that connect genetic variation to complex brain-related traits and diseases. In this study, we integrated protein quantitative trait loci (pQTLs) from the two largest plasma proteomic resources (the UK Biobank Pharma Proteomics Project [UKB-PPP] and Ferkingstad et al. [deCODE]) with genome-wide association studies of brain imaging-derived phenotypes in UK Biobank using Mendelian randomization and colocalization analyses. We identified 120 cis and 20 trans associations between plasma proteins and imaging phenotypes and validated these findings using brain tissue-derived proteomic and transcriptomic datasets. Multivariable Mendelian randomization revealed eleven plasma proteins (coding genes APOE, ARL3, MICB, NSF, RHOC, RSPO3, ENPP2, BTN2A1, EIF2AK3, MRVI1, and OPLAH) with significant direct effects on the risk of Alzheimer's disease, Parkinson's disease, multiple sclerosis, bipolar disorder, and schizophrenia. Single-cell expression and pathway enrichment analyses further revealed cell-type-specific effects and distinct biological processes underlying these protein-disease associations. Together, these findings demonstrate robust links between plasma protein variation and brain structure, delineate protein-disease pathways, and highlight the cellular and molecular mechanisms that contribute to neurobiological diversity and pathology.

Journal Article↗
PubMed1998

Toward a new natural medicine.

Treatments summarized under the term "natural medicine," i.e., those offered as an alternative or in addition to conventional medicine, have enjoyed a surge in popularity in recent years. The "natural" descriptor employed in connection with these healing methods is frequently misunderstood, leading to underestimation of the risks arising from incorrect use. However, the essential principle underlying traditional natural medicine, mobilization of the body's own forces against disease, is increasingly being employed in a new, rational form of medicine: molecular medicine. A range of natural endogenous substances for medical use are already available. Human proteins such as erythropoietin can now be produced as medicines in highly pure form with the aid of genetic engineering techniques. Our increasing understanding of the function of our genes and the resulting descriptions of molecular mechanisms underlying disease are also helping us to utilize the body's own construction set. New techniques such as gene therapy will in future enable us to reproduce the natural conditions in the healthy body with increasing specificity in our attempts to cure illnesses. One such application will be the activation of the immune system to combat cancer. The complete decoding of the human genome will not only allow illnesses to be described, and possibly prevented, at an earlier stage. Illnesses will also be able to described more precisely and individually at the molecular level, opening up the possibility of targeted, patient-specific cures.

Amino Acid Sequence↗
PubMed2004

Pleiotropic effects of a chromosome 3 locus on speech-sound disorder and reading.

Speech-sound disorder (SSD) is a complex behavioral disorder characterized by speech-sound production errors associated with deficits in articulation, phonological processes, and cognitive linguistic processes. SSD is prevalent in childhood and is comorbid with disorders of language, spelling, and reading disability, or dyslexia. Previous research suggests that developmental problems in domains associated with speech and language acquisition place a child at risk for dyslexia. Recent genetic studies have identified several candidate regions for dyslexia, including one on chromosome 3 segregating in a large Finnish pedigree. To explore common genetic influences on SSD and reading, we examined linkage for several quantitative traits to markers in the pericentrometric region of chromosome 3 in 77 families ascertained through a child with SSD. The quantitative scores measured several processes underlying speech-sound production, including phonological memory, phonological representation, articulation, receptive and expressive vocabulary, and reading decoding and comprehension skills. Model-free linkage analysis was followed by identification of sib pairs with linkage and construction of core shared haplotypes. In our multipoint analyses, measures of phonological memory demonstrated the strongest linkage (marker D3S2465, P=5.6 x 10(-5), and marker D3S3716, P=6.8 x 10(-4)). Tests for single-word decoding also demonstrated linkage (real word reading: marker D3S2465, P=.004; nonsense word reading: marker D3S1595, P=.005). The minimum shared haplotype in sib pairs with similar trait values spans 4.9 cM and is bounded by markers D3S3049 and D3S3045. Our results suggest that domains common to SSD and dyslexia are pleiotropically influenced by a putative quantitative trait locus on chromosome 3.

Articulation Disorders↗
PubMedDate not supplied

"Decoding" informed consent. Insights from women regarding breast cancer susceptibility testing.

Cancer susceptibility testing is likely to become routine in medical practice, despite many limitations and unanswered questions. These uncertainties greatly complicate the process of informed consent, creating an excellent opportunity to reconsider exactly how it should be conducted. Research with women's reactions to the availability of genetic susceptibility testing for breast cancer dramatically underscores that informed consent ought to be highly individualized, taking care to discern what patients believe about the disease and its causes and what role they want their physician to play.

Attitude to Health↗