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PubMed2026

Advancing precision tacrolimus therapy: a systems genetics dissection in BXD platform.

BACKGROUND: Tacrolimus is a core immunosuppressant in organ transplantation, but its narrow therapeutic window and significant pharmacokinetic variability hinder precision dosing. Although CYP3A5-guided strategies have established clinical relevance for tacrolimus initial dose adjustment, they do not fully account for the marked interindividual variability in tacrolimus exposure, highlighting the need for complementary models to decode more complex genetic regulation. This study aimed to identify candidate genetic modulators of tacrolimus metabolism and develop an integrated predictive framework for individualized therapy. METHODS: Using 46 BXD recombinant inbred mouse strains, we characterized transcriptomics and machine learning, and validated key genes. We then constructed a clinical model using data from 168 renal transplant recipients. RESULTS: We identified 19 genomic loci associated with tacrolimus pharmacokinetic traits and supported DBP/CYP2A6 as candidate modulators associated with tacrolimus disposition. The clinical prediction model, incorporating these genes and clinical variables, achieved robust AUROC. CONCLUSIONS: These findings support a polygenic contribution to tacrolimus metabolism and provide an experimental and computational framework for identifying candidate modulators relevant to individualized dosing. The BXD mouse platform offers a systems-genetics approach for mechanistic discovery that may inform future translational studies on tacrolimus precision dosing.

Animals↗
PubMed2003

Decoding property of C5 uridine modification at the wobble position of tRNA anticodon.

Post-transcriptional modification at the first (wobble) position of the tRNA anticodon participates in precise decoding of the genetic code. We recently identified a novel taurine-containing modified uridine (tau m5U; 5-taurinomethyluridine) at the wobble position of mammalian mitochondrial tRNAs and found lack of this modification in mutant mitochondrial tRNAs from human pathogenic cells of the mitochondrial encephalomyopathies, investigate molecular pathogenesis of the diseases, decoding activity of wobble uridines with or without C5 modification was measured using E. coli cell-free translation system. It has been revealed that C5 modification has a functional role for stabilizing U:G wobble base pair.

Amino Acid Sequence↗
PubMed1993

cDNA analyses in the human genome project.

The ultimate goal of the human genome project is to decode all the genetic information carried in the genome. Towards this goal, the physical structure of the genome, as well as the functional aspects of the genome, must be understood. We initiated a cDNA project to collect the 'expression profiles' of all human genes, a database with which to describe which genes are expressed, and to what extent, in any given human cell at a particular time. Single-cycle sequencing of randomly selected members from a 3'-directed cDNA library is most appropriate for this purpose: the sequence data serve as a 'gene signature' to identify the expressing gene, and the frequency of appearance of the gene signature reflects the activity of the gene. The compiled data, which usually cover some 1000 sequencing results per sample, are referred to as an 'expression profile.' We applied this analysis to HepG2 (a cell line derived from a hepatocellular carcinoma), liver cells and lung cells. The expression profiles shed some light upon the unique features of gene expression in the cell or tissue tested. A comparison of the expression profiles among different cells has allowed active genes to be classified as housekeepers or those with cell-specific functions. A significant fraction of the abundantly expressed genes include those that are unique to the cell. In addition, the resulting collection of thousands of gene signatures is a useful source of probes for mapping and for isolating full-size cDNAs.

Animals↗
PubMed1993

Identification of new genes by systematic analysis of cDNAs and database construction.

The large-scale collection of partial cDNA sequences is becoming a powerful tool in biology. Similarity or motif searches in DNA databases using these partial cDNA sequences have facilitated the discovery of new genes of interest. By collecting and registering large numbers of partial sequences with a well designed non-biased cDNA library, an expression profile of active genes in a particular tissue can be obtained. Tissue-specific or stage-specific genes can be discovered by comparing the profiles from different tissues or from a tissue at different stages of development, respectively. The compilation of such expression profiles enables genes to be mapped to the tissue(s) where they are actively transcribed. The large-scale collation of gene sequences actively expressed in the body into databases complements efforts directed towards the structural analysis of the genome, with the ultimate aim of decoding all the genetic information carried in the human genome. This cDNA strategy is also being widely applied to organisms other than man.

Animals↗
PubMed2006

Gene expression profiling as novel tool in experimental asthma research.

With the advances achieved in decoding of the genetic structures of species and the novel possibilities of simultaneous measurements of the regulation of all genes of a given tissue, the last 10 years have seen a massive increase of our knowledge about genetic regulation of diseases. Additionally, the possibilities to control transcriptional processes within the cells will speed up the process of disentangling the various pathways leading to disease.

Animals↗
PubMed1983

Inhibition of adenovirus early region IV transcription in vitro by a purified viral DNA binding protein.

Adenoviruses depend on cellular mechanisms for the decoding of their genetic information, and so provide a useful and simple model system for the investigation of mammalian gene expression. The five regions transcribed early in adenovirus infection are termed EIa, EIb, EII, EIII and EIV. We report here that the primary product of the EII region, a 72,000 molecular weight DNA-binding protein (DBP), specifically represses transcription from the EIV promoter in an in vitro transcription system. Single-stranded DNA binds to the DBP with high affinity, and as a result inhibits its repressor activity. Our data extend previous genetic evidence that the DBP represses EIV transcription in vivo, and suggest that it acts directly by suppressing transcription from the EIV promoter.

Adenoviridae↗
PubMed2002

Age, body mass index and glucose tolerance in 11 European population-based surveys.

AIMS: To describe the variation in the estimated prevalence of diabetes and impaired glucose regulation (IGR) within Europe in relation to age and body mass index (BMI). METHODS: Cross-sectional data from European population-based studies with both fasting and 2-h glucose after a standard 75-g oral glucose tolerance test were included (9449 men, 7752 women). RESULTS: There was a large variation in the estimated prevalence of diabetes and impaired glucose regulation among 11 European centres, ranging from 2% to 24% for diabetes and 5% to 43% for IGR. In cross-sectional analysis the estimated prevalence of diabetes and IGR increased with age and BMI. The impact of age did not differ between centres with similar age range, and the impact of BMI was similar in most centres. CONCLUSIONS: Differences in age and BMI within Europe partly explained the variation in estimates of the IGR and diabetes prevalence. The impact of age and BMI did not differ between centres. Variations in prevalence must therefore be due to other factors that we could not adjust for, such as methodology, differences in diet, physical activity and genetic predisposition.

Adult↗
PubMed2025

Integrative proteomic analysis provides novel therapeutic insights for etiological subtypes of diabetes.

AIMS: Type 2 diabetes (T2D) is a highly heterogeneous disease characterised by subtypes with variations in aetiology, disease progression, and risk of complications. However, potential drug targets for these subtypes have not been explored. This study aims to investigate potential drug targets by integrating proteomics. MATERIALS AND METHODS: Summary-level data of circulating proteins were extracted from the UK Biobank and the deCODE Health Study. Genetic associations with five diabetes subtypes were obtained from Swedish All New Diabetics in Scania and Malmö Diet and Cancer cohort, including severe autoimmune diabetes (SAID), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD). The associations between circulating proteins and diabetes subtypes were assessed through Mendelian randomisation, followed by multiple sensitivity and colocalization analyses. Additionally, tissue-specific, pathway and functional enrichment analysis, assessment of protein druggability, and the protein-protein interaction (PPI) networks were used to further explore biological mechanisms and therapeutic potential. RESULTS: Genetically predicted levels of 2, 2, 9, 3, and 5 circulating proteins were associated with SIRD, SIDD, MARD, MOD, and SAID, respectively. Colocalization analyses further revealed links between GRN with MARD/SIRD, LILRB5 with SIDD/MARD, CR1 with MARD, TNFSF12 with MOD, and DAPK2 with SAID. Enrichment analysis suggested that these proteins were mainly enriched in blood and adipose tissues and involved in immune and inflammatory related pathways. PPI analysis revealed GRN, TNFSF12, and DAPK2 are associated with known T2D targets. CONCLUSIONS: Our study identified several potential drug targets for different subtypes of diabetes using an integrated genetic approach, yielding new insights for precision medicine of diabetes.

Humans↗
PubMed1996

The human genome efforts and the cDNA project.

Molecular biology has been moving swiftly toward clarifying the entire genome of organisms, including human. The human genome efforts that promote this transaction are characterized by the large-scale, high throughput production of data about the structure of the genome of the molecular level and its computer-assisted management. In addition, functional analyses of the genome have become important for decoding the entire genetic information carried in the human genome. In the functional analyses of the genome, the large-scale collection of partial cDNA sequences, the cDNA project, is becoming important, because it allows researchers to register genes active in any given tissue, on one hand, and, on the other hand, it allows for quantitative description of gene activities in tissues. Tissue-specific or stage-specific genes can be discovered by comparing expression profiles from different tissues or from a tissue at different stages of development, respectively.

DNA, Complementary↗
PubMed2006

Recognition of schematic facial displays of emotion in parents of children with autism.

Performance on an emotional labeling task in response to schematic facial patterns representing five basic emotions without the concurrent presentation of a verbal category was investigated in 40 parents of children with autism and 40 matched controls. 'Autism fathers' performed worse than 'autism mothers', who performed worse than controls in decoding displays representing sadness or disgust. This indicates the need to include facial expression decoding tasks in genetic research of autism. In addition, emotional expression interactions between parents and their children with autism, particularly through play, where affect and prosody are 'physiologically' exaggerated, may stimulate development of social competence. Future studies could benefit from a combination of stimuli including photographs and schematic drawings, with and without associated verbal categories. This may allow the subdivision of patients and relatives on the basis of the amount of information needed to understand and process social-emotionally relevant information.

Adult↗
PubMedDate not supplied

[First class transcription termination factors--functional analogs of aminoacyl tRNA].

Reviewed and discussed are the recent data demonstrating profound functional similarity between class-1 translation termination factors (RF1 and RF2 in prokaryotes, aRF1 and eRF1 in Archaea and eukaryotes, respectively) and aminoacyl-tRNA as regards their roles in the course of translation on the ribosome. Functional analogy of these two components of the cell protein-synthesizing machinery was suggested long ago; however, numerous experimental proofs have been obtained only recently. This similarity implies that decoding of the genetic information by the ribosomal machine is performed similarly at all stages of translation, though tRNA plays the main role at initiation and elongation, while the protein is most important for termination. Earlier it was found that nucleic acids (ribozymes) can operate like the protein enzymes, and now we have got evidence for the reverse: a protein (translation termination factor) can act like a nucleic acid (tRNA). Thus one can speak of "exchange" of molecular functions between proteins and nucleic acids. Therefore, the profound chemical difference between proteins and nucleic acids is not an insuperable barrier to their mutual functional replacement in certain situations.

Animals↗
PubMed1994

[Body mapping of human genes].

The ultimate goal of the human genome project to decode all the genetic information carried in the genome. Towards this goal, the physical structure of the genome, as well as the functional aspects of the genome, must be understood. We initiated a cDNA project to collect the "expression profiles" of all human genes, a database with which to describe which genes are expressed, and to what extent, in any given human cell at a particular time. Single-cycle sequencing of randomly selected members from a 3'-directed cDNA library is most appropriate for this purpose: the sequence data serve as a "gene signature" to identify the expressing gene, and the frequency of appearance of the gene signature reflects the activity of the gene. The compiled data, which usually covers some 1000 sequencing results per sample, is referred to as an "expression profile". We applied this analysis to HepG2 (a cell line derived from a hepatocellular carcinoma), liver cells and lung cells. The expression profiles shed some light upon the unique features of gene expression in the cell or tissue tested. A comparison of the expression profiles among different cells has allowed active genes to be classified as housekeepers or those with cell-specific functions. A significant fraction of the abundantly expressed genes include those that are unique to the cell. In addition, the resulting collection of thousands of gene signatures is a useful source of probes for mapping and for isolating full size cDNAs.

Cells, Cultured↗
PubMed2001

Genetic interaction between yeast Saccharomyces cerevisiae release factors and the decoding region of 18 S rRNA.

Functional and structural similarities between tRNA and eukaryotic class 1 release factors (eRF1) described previously, provide evidence for the molecular mimicry concept. This concept is supported here by the demonstration of a genetic interaction between eRF1 and the decoding region of the ribosomal RNA, the site of tRNA-mRNA interaction. We show that the conditional lethality caused by a mutation in domain 1 of yeast eRF1 (P86A), that mimics the tRNA anticodon stem-loop, is rescued by compensatory mutations A1491G (rdn15) and U1495C (hyg1) in helix 44 of the decoding region and by U912C (rdn4) and G886A (rdn8) mutations in helix 27 of the 18 S rRNA. The rdn15 mutation creates a C1409-G1491 base-pair in yeast rRNA that is analogous to that in prokaryotic rRNA known to be important for high-affinity paromomycin binding to the ribosome. Indeed, rdn15 makes yeast cells extremely sensitive to paromomycin, indicating that the natural high resistance of the yeast ribosome to paromomycin is, in large part, due to the absence of the 1409-1491 base-pair. The rdn15 and hyg1 mutations also partially compensate for inactivation of the eukaryotic release factor 3 (eRF3) resulting from the formation of the [PSI+] prion, a self-reproducible termination-deficient conformation of eRF3. However, rdn15, but not hyg1, rescues the conditional cell lethality caused by a GTPase domain mutation (R419G) in eRF3. Other antisuppressor rRNA mutations, rdn2(G517A), rdn1T(C1054T) and rdn12A(C526A), strongly inhibit [PSI+]-mediated stop codon read-through but do not cure cells of the [PSI+] prion. Interestingly, cells bearing hyg1 seem to enable [PSI+] strains to accumulate larger Sup35p aggregates upon Sup35p overproduction, suggesting a lower toxicity of overproduced Sup35p when the termination defect, caused by [PSI+], is partly relieved.

Anti-Bacterial Agents↗
PubMed2001

Analysis of codon:anticodon interactions within the ribosome provides new insights into codon reading and the genetic code structure.

Although the decoding rules have been largely elucidated, the physical-chemical reasons for the "correctness" of codon:anticodon duplexes have never been clear. In this work, on the basis of the available data, we propose that the correct codon:anticodon duplexes are those whose formation and interaction with the ribosomal decoding center are not accompanied by uncompensated losses of hydrogen and ionic bonds. Other factors such as proofreading, base-base stacking and aminoacyl-tRNA concentration contribute to the efficiency and accuracy of aminoacyl-tRNA selection, and certainly these factors are important; but we suggest that analyses of hydrogen and ionic bonding alone provides a robust first-order approximation of decoding accuracy. Thus our model can simplify predictions about decoding accuracy and error. The model can be refined with data, but is already powerful enough to explain all of the available data on decoding accuracy. Here we predict which duplexes should be considered correct, which duplexes are responsible for virtually all misreading, and we suggest an evolutionary scheme that gave rise to the mixed boxes of the genetic code.

Anticodon↗
PubMed2006

Evolution of the genetic code in yeasts.

During the last 30 years, a number of genetic code alterations have been uncovered in bacteria and in the mitochondria and cytoplasm of various eukaryotes, invalidating the hypothesis that the genetic code is universal and frozen. In the mitochondria of most yeasts, the UGA stop codon is decoded as tryptophan and the four leucine codons of the CUN family (N = any nucleotide) are decoded as threonine. Recently, a unique genetic code change involving the decoding of the leucine CUG codon as serine was discovered in the cytoplasm of Candida and Debaryomyces species, indicating that the genetic code of yeasts may be under specific evolutionary pressures whose molecular nature is not yet fully understood. This genetic code alteration is mediated by a novel serine-tRNA that acquired a leucine 5'-CAG-3' anticodon (ser-tRNACAG) through insertion of an adenosine in the intron of its gene. This event, which occurred 272 +/- 25 million years ago, reprogrammed the identity of approximately 30 000 CUG codons existent in the ancestor of these yeasts and had a profound impact on the evolution of the genus Candida and of other species. Here, we review the most recent results and concepts arising from the study of this genetic code change and highlight how its study is changing our views of the evolution of the genetic code.

Base Sequence↗
PubMed1993

[Perspectives of molecular genetics of hearing disorders].

In the last few years research efforts have succeeded in detectury the genetic background of several hereditary hearing disorders by molecular biological methods. The genetic code was been decoded for Neurofibromatosis types 1 and 2, as well as for such X-linked diseases as Alport's syndrome or Norrie's disease. Besides the classic genetic tools as chromosomal analysis, molecular biological techniques and methods have become important clinically for the ENT-specialist. In the present review we show the principles and applications of DNA-and RNA-analysis with hybridization techniques in Southern- and Northern-blot techniques, as well as in-situ hybridization and polymerase chain reaction (PCR). These molecular biological techniques will help improve the detection and analysis of hereditary inner ear disorders, but also be able to study in greater detail tumor carcinogenesis and mutagenesis. The various techniques are explained and the applications are demonstrated.

Chromosome Aberrations↗
PubMed2002

Familial aggregation of dyslexia phenotypes. II: paired correlated measures.

Dyslexia is a common and complex behavioral disorder characterized by unexpected difficulty in learning to read. Psychometric measures used to assess dyslexia often evaluate overlapping processes or abilities. To identify subphenotypes amenable to model-based linkage analyses, we have used careful language phenotyping, familial aggregation analyses of single phenotype measures, and segregation analyses. In the current study, to identify covariates to use in future segregation analyses we examined six pairs of related measures selected from among the most promising candidates in the initial aggregation analyses whose aggregation patterns were most consistent with a genetic basis. For these reciprocal aggregation analyses each measure is evaluated with the paired measure as the covariate to obtain information about the interdependence of the paired measures on shared genetic factors. Six pairs of measures were evaluated: 1) accuracy and efficiency of phonological decoding; 2) phonological nonword memory and written spelling; 3) phonological decoding accuracy and written spelling; 4) inattention ratings and rapid automatized naming for switching letters and numerals (RAS); 5) inattention ratings and oral reading rate; and 6) RAS and oral reading rate. Results of these analyses provide evidence that there may be a genetic contribution to efficiency of phonological decoding in addition to the genetic contribution it shares with accuracy of phonological decoding, a genetic contribution to phonological nonword memory in addition to the genetic contribution it shares with written spelling, a genetic contribution to written spelling in addition to the genetic contribution it shares with accuracy of phonological decoding, and a genetic contribution to inattention ratings in addition to the genetic contribution it shares with either RAS or oral reading rate.

Child↗