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At least 325 records · Page 18Linked to original sources
PubMed2006

Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes.

Recently, the transcription factor 7-like 2 (TCF7L2) gene has been associated with type 2 diabetes in subjects of European origin in the DeCode study. We genotyped the two most associated variants (rs7903146 and rs12255372) in 2,367 French type 2 diabetic subjects and in 2,499 control subjects. Both the T-allele of rs7903146 and the T-allele of rs12255372 significantly increase type 2 diabetes risk with an allelic odds ratio (OR) of 1.69 (95% CI 1.55-1.83) (P = 6.0 x 10(-35)) and 1.60 (1.47-1.74) (P = 7.6 x 10(-28)), respectively. In nonobese type 2 diabetic subjects (BMI <30 kg/m2, n = 1,346), the ORs increased to 1.89 (1.72-2.09) (P = 2.1 x 10(-38)) and 1.79 (1.62-1.97) (P = 5.7 x 10(-31)), respectively. The rs7903146 T at-risk allele associates with decreased BMI and earlier age at diagnosis in the type 2 diabetic subjects (P = 8.0 x 10(-3) and P = 3.8 x 10(-4), respectively), which is supported by quantitative family-based association tests. TCF7L2 is expressed in most human tissues, including mature pancreatic beta-cells, with the exception of the skeletal muscle. In the subcutaneous and omental fat from obese type 2 diabetic subjects, TCF7L2 expression significantly decreased compared with obese normoglycemic individuals. During rat fetal beta-cell differentiation, TCF7L2 expression pattern mimics the key marker NGN3 (neurogenin 3), suggesting a role in islet development. These data provide evidence that TCF7L2 is a major determinant of type 2 diabetes risk in European populations and suggests that this transcription factor plays a key role in glucose homeostasis.

Adipose Tissue↗
PubMed1994

Unique structure of new serine tRNAs responsible for decoding leucine codon CUG in various Candida species and their putative ancestral tRNA genes.

In an asporogenic yeast, Candida cylindracea, codon CUG is not translated as leucine but as serine. On the basis of our recent work on the determination of the genetic code using in vitro translation systems coupled with isolation of the corresponding tRNA molecules, it appears that this non-universal genetic code is unitized not only in C cylindracea but also in various Hemiascomycetes. Here we show that in addition to the species already reported, three pathogenic yeasts, C guilliermondii, C lusitaniae and C tropicalis, have tRNA(Ser)CAG, indicating that this non-universal genetic code (CUG=Ser) also exists in these species. Determination of their primary structures revealed that the uridine conserved at position 33 in usual tRNAs, is replaced by guanosine or cytidine. This suggests that the three-dimensional structures of the anticodon loop of these tRNAs differ from the conventional structure comprising the U turn in this position. Moreover, we succeeded in isolating putative ancestral serine tRNA genes whose sequences are highly homologous to tRNA(Ser)CAG in each case. These tRNA genes all have the anticodon sequence CGA corresponding to the codon UCG, indicating that tRNA(Ser)CAG might have emerged from tRNA(Ser)CGA during evolutionary change of the assignment of codon CUG.

Base Sequence↗
PubMed2004

ITC in the post-genomic era...? Priceless.

The information available after decoding the genome of the human species and many others is opening the possibility of new approaches to target thousands of protein interactions critical for a continuously increasing list of genetic and infectious diseases and pathologies, and to understand complex regulatory pathways and interaction networks describing cell function and interrelation. There is a need for a reliable technique offering the capability of measuring accurately macromolecular interactions (e.g. protein/ligand, protein/protein, protein/nucleic acid) in the laboratory. Compared to other analytical techniques, isothermal titration calorimetry (ITC) exhibits some important advantages for characterizing intermolecular interactions and binding equilibria. ITC is suitable for characterizing both low affinity interactions (e.g. protein network regulation and natural ligands) and high affinity interactions (e.g. rational drug design). Considering the advanced technological level reached as well as the outstanding quality of the information accessible through this technique, ITC is expected to play a very prominent role in the next years in the areas of rational drug design and protein network regulation.

Calorimetry↗
PubMedDate not supplied

An engineer's view on genetic information and biological evolution.

We develop ideas on genome replication introduced in Battail [Europhys. Lett. 40 (1997) 343]. Starting with the hypothesis that the genome replication process uses error-correcting means, and the auxiliary one that nested codes are used to this end, we first review the concepts of redundancy and error-correcting codes. Then we show that these hypotheses imply that: distinct species exist with a hierarchical taxonomy, there is a trend of evolution towards complexity, and evolution proceeds by discrete jumps. At least the first two features above may be considered as biological facts so, in the absence of direct evidence, they provide an indirect proof in favour of the hypothesized error-correction system. The very high redundancy of genomes makes it possible. In order to explain how it is implemented, we suggest that soft codes and replication decoding, to be briefly described, are plausible candidates. Experimentally proven properties of long-range correlation of the DNA message substantiate this claim.

Biological Evolution↗
PubMed2000

One protein from two open reading frames: mechanism of a 50 nt translational bypass.

Translating ribosomes bypass a 50 nt coding gap in order to fuse the information found in the two open reading frames (ORFs) of bacteriophage T4 gene 60. This study investigates the underlying mechanism by focusing on the competition between initiation of bypassing and termination at the end of the first ORF. While nearly all ribosomes initiate bypassing, no more than 50% resume translation in the second ORF. Two previously described cis-acting stimulatory signals are critical for favoring initiation of bypassing over termination. Genetic analysis of these signals supports a working model in which the first (a stem-loop structure at the junction between the first ORF and the coding gap) interferes with decoding in the A-site, and the second (a stretch of amino acids in the nascent peptide encoded by the first ORF) destabilizes peptidyl-tRNA-mRNA pairing.

Amino Acid Sequence↗
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↗
PubMed2002

Genetics, genomics and gene discovery in the auditory system.

The sounds of silence have forever been broken as genetics and genomics approaches in human and model organisms have provided a powerful and rapid entry into gene discovery in the auditory system. An understanding of the complexities and beauty of the biological process of hearing itself is unfolding as genes underlying hereditary hearing impairment are identified. Genes involved in modifying hearing are also being found, and will be critical to a full comprehension of genotype-phenotype relationships. Investigations in the auditory system will provide important insight into how the nervous system decodes molecular information. Deafness represents a common sensory disorder that can interfere dramatically in the acquisition of speech and language in children, and in the quality of life for a growing aged population. As newborn screening for hearing impairment is being implemented in many birth hospitals, the prospects for precise clinical diagnosis, appropriate genetic counseling and proper medical management for auditory disorders has never been at a more exciting crossroad.

Animals↗
PubMed2006

[Integrating obtained knowledge from transcriptome data by a new framework for data analysis].

Microarray analyses facilitate the investigation of quantitative information coded in the genome by measuring transcriptome, which records the decoded information from the genome. The state of a cell and differences from other states can be studied through genome information, by comparing one set of transcriptome data to other sets. Clearly, those data should be shared and compared with researchers, and the knowledge should be integrated. Unfortunately, at present data comparisons in microarray analyses are quite difficult; the accuracy as well as the reproducibility is low. The difficulties are originated from data analyses methods. Data comparison requires an intelligent framework, such as that discussed by philosopher Sir Karl R Popper. Frameworks for microarray analyses have been developed by many efforts of bioinformatitians. The frameworks currently used are being inspected and critically discussed. By checking the mathematical models that form the practical frameworks, arbitrariness such as the lack of falsifiability has been pointed out. The paradigm in this field of analyses is also criticized by disagreement with the scientific standard, and it is shown as the origin of errors in analyses. The excessive numbers of frameworks produced in an ad hoc manner has also been criticized, since the existence of so many allows researchers to select different frameworks, discussions beyond frameworks are always difficult. A new framework that uses a parametric model is introduced with an explanation of the bases of the framework and the process of testing. Additionally, differences of obtained results by these frameworks are presented using GeneChip data, in stability of log-ratio measurements and reproducibility of analyses. The possibility of artificial decoding of genome information by an extended framework is also discussed.

Gene Expression Profiling↗
PubMed2026

Disentangling adiposity-related and non-adiposity-related genetic pathways for type 2 diabetes.

OBJECTIVE: To identify circulating proteins associated with type 2 diabetes (T2D) risk through pathways not fully explained by body mass index (BMI), and to assess therapeutic actionability. RESEARCH DESIGN AND METHODS: We applied GWAS-by-subtraction within a genomic structural equation model to European ancestry summary statistics for T2D (74,124 cases, 824,006 controls) and BMI (n = 681,275), partitioning T2D liability into BMI-related and BMI-subtracted components. We then performed proteome-wide Mendelian randomization (MR) using cis-protein quantitative trait loci from four plasma proteomics cohorts: ARIC, deCODE, Fenland, and the UK Biobank Pharma Proteomics Project. Prioritized proteins passed sensitivity analyses with alternative MR methods and were supported by colocalization evidence. Tissue-resolution regulatory support was assessed using cis-eQTL colocalization across GTEx and pancreatic islet, subcutaneous adipose, and whole-blood resources. Actionability was evaluated using the druggable genome and Open Targets. RESULTS: GWAS-by-subtraction attenuated the genetic correlation between BMI and BMI-subtracted T2D from 0.54 (SE 0.02) to 0.35 (SE 0.02). Proteome-wide MR prioritized 29 proteins for BMI-subtracted T2D. Thirteen showed eQTL colocalization in at least one tissue, implicating liver and intermediary metabolism (GCDH, NOTCH2), pancreatic islet biology (CTRB2, MANBA), adipose and Wnt signaling (RSPO3, GALNT3), and whole blood regulatory signals (PAM, SNUPN). Sixteen proteins were classified within druggable-genome Tiers 1-3, and five had existing Open Targets compounds. CONCLUSIONS: Integrating GWAS-by-subtraction, proteome-wide MR, and colocalization nominated 29 proteins associated with T2D liability not fully explained by BMI. These findings highlight genetically supported targets for follow-up studies of T2D therapies that complement weight-centered approaches.

Journal Article↗
PubMed2003

Amusia and musicogenic epilepsy.

Amusia and musicogenic epilepsy are clinical disorders that provide a window into the localization of music in the brain. Classic clinical studies of patients with these disorders, coupled with more recent studies employing modern neuroimaging and sophisticated neuropsychologic paradigms, have converged in helping to elucidate the complex neural systems that are utilized in decoding music. The notion of cerebral dominance for music has been replaced by a concept of modular but interconnected networks that have wide bilateral localization in the brain and that are molded both by genetics and experience. These disorders also provide insight into the important interface between music and emotion.

Auditory Perception↗
PubMed2004

Linkage analyses of four regions previously implicated in dyslexia: confirmation of a locus on chromosome 15q.

Dyslexia is a common, complex disorder, which is thought to have a genetic component. There have been numerous reports of linkage to several regions of the genome for dyslexia and continuous dyslexia-related phenotypes. We attempted to confirm linkage of continuous measures of (1) accuracy and efficiency of phonological decoding; and (2) accuracy of single word reading (WID) to regions on chromosomes 2p, 6p, 15q, and 18p, using 111 families with a total of 898 members. We used both single-marker and multipoint variance components linkage analysis and Markov Chain Monte Carlo (MCMC) joint segregation and linkage analysis for initial inspection of these regions. Positive results were followed with traditional parametric lod score analysis using a model estimated by MCMC segregation analysis. No positive linkage signals were found on chromosomes 2p, 6p, or 18p. Evidence of linkage of WID to chromosome 15q was found with both methods of analysis. The maximum single-marker parametric lod score of 2.34 was obtained at a distance of 3 cM from D15S143. Multipoint analyses localized the putative susceptibility gene to the interval between markers GATA50C03 and D15S143, which falls between a region implicated in a recent genome screen for attention-deficit/hyperactivity disorder, and DYX1C1, a candidate gene for dyslexia. This apparent multiplicity of linkage signals in the region for developmental disorders may be the result of errors in map and/or model specification obscuring the pleiotropic effect of a single gene on different phenotypes, or it may reflect the presence of multiple genes.

Chromosomes, Human, Pair 15↗
PubMed1995

From stand-by to decoding site. Adjustment of the mRNA on the 30S ribosomal subunit under the influence of the initiation factors.

The hypothesis of an adjustment of the mRNA in its ribosomal channel under the influence of the initiation factors has been tested by site-directed crosslinking experiments. Complexes containing 30S subunits with bound mRNA having 4-thio-uracil at specific positions were prepared in the presence or absence of initiation factors and/or fMet-tRNA and subjected to UV irradiation to obtain specific crosslinks of the radioactively labeled mRNA with bases of the 16S rRNA and with ribosomal proteins. The subsequent identification of the specific sites of both mRNA and rRNA and individual ribosomal proteins involved in the crosslinking, obtained under different conditions of complex formation, provide direct evidence for the occurrence of a partial relocation of the mRNA on the 30S ribosomal subunits under the influence of the factors. The nature of this mRNA relocation is compatible with our previous proposal of a shift of the template from an initial ribosomal "stand-by site" to a second site closer to that occupied when the initiation triplet of the mRNA is decoded in the P-site.

Base Sequence↗