Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “deCode Genetics”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 397 records · Page 22Linked to original sources
PubMed2004

Quasi-linkage: a confounding factor in linkage analysis of complex diseases?

Human linkage analysis is based on the assumption that unlinked genomic loci, particularly loci located on non-homologous chromosomes, segregate independently during meiosis. An exception to this rule is the phenomenon of quasi-linkage (QL) that describes the non-random segregation of non-homologous chromosomes, which can undermine the basic concept of linkage. Molecular mechanisms of QL are not clear; however, observations in mice and plants suggest a possible affinity between non-homologous chromosomal regions containing repetitive or like sequences. QL has not been investigated in humans. As QL may generate false linkages in genome scans of complex diseases, we sought to determine whether genomic loci detected in such genome scans exhibit QL. A number of individual markers showing linkage to schizophrenia, asthma, multiple sclerosis, inflammatory bowel disease and type-1 diabetes were tested for QL in a pairwise linkage analysis against all other markers exhibiting evidence for linkage in each specific study. The Marshfield genotype dataset of eight CEPH families was used for this purpose. The best QL lod scores generated from the analysis were within the range of the "lukewarm" lod scores reported in the majority of linkage studies for complex disorders. In addition, we performed a genome-wide QL analysis on the Marshfield family database which detected eight QL lod scores >6. The replication of the best Marshfield QL scores was performed using the deCODE families and although none of the eight pairs demonstrated independent evidence for QL, three pairs generated maximal lod scores of 0.11, 0.3, and 1.51. In conclusion, although complex disease relevant markers did not produce high QL lod scores, the general phenomenon of QL in humans cannot be excluded and potentially can be a confounding factor in genetic studies of complex traits.

Asthma↗
PubMed2003

Triple decoding of hepatitis C virus RNA by programmed translational frameshifting.

Ribosomes can be programmed to shift from one reading frame to another during translation. Hepatitis C virus (HCV) uses such a mechanism to produce F protein from the -2/+1 reading frame. We now report that the HCV frameshift signal can mediate the synthesis of the core protein of the zero frame, the F protein of the -2/+1 frame, and a 1.5-kDa protein of the -1/+2 frame. This triple decoding function does not require sequences flanking the frameshift signal and is apparently independent of membranes and the synthesis of the HCV polyprotein. Two consensus -1 frameshift sequences in the HCV type 1 frameshift signal facilitate ribosomal frameshifts into both overlapping reading frames. A sequence which is located immediately downstream of the frameshift signal and has the potential to form a double stem-loop structure can significantly enhance translational frameshifting in the presence of the peptidyl-transferase inhibitor puromycin. Based on these results, a model is proposed to explain the triple decoding activities of the HCV ribosomal frameshift signal.

Amino Acid Sequence↗
PubMed2026

Rab9 depletion enhances human adenovirus type 26 transduction efficiency through increased internalization and reduced late endosomal/lysosomal retention.

Understanding intracellular trafficking is central to decoding viral pathogenesis and engineering optimized viral vectors. How a virus or vector is routed through the endocytic pathway directly dictates its genome release, immune sensing, and overall transduction efficiency. Human adenovirus type 26 (HAdV-D26) presents a promising platform for vector design due to its low preexisting immunity, potent immune stimulation, scalable production, and versatile genetic engineering capacity. Although increasingly significant, the fundamental mechanisms governing HAdV-D26 intracellular trafficking are still not fully understood. Our study demonstrates that compared to well-described human adenovirus type 5 (HAdV-C5), HAdV-D26 undergoes prolonged intracellular trafficking, transiently localizing to early endosomes before residing in late endosomes/lysosomes for up to four hours post-infection. Inhibition of lysosomal acidification modestly enhances HAdV-D26 transduction efficiency, whereas blocking transport from early to late endosomes/lysosomes does not. Strikingly, Rab9 knockdown reduces HAdV-D26 late endosomal/lysosomal localization while increasing both virus internalization and genome delivery to the host cell nucleus. These findings indicate that late endosomal sorting pathways actively influence HAdV-D26 infection outcomes. By identifying a previously unappreciated role for Rab9 in adenovirus transduction, our results provide new mechanistic insight into HAdV-D26 intracellular trafficking, highlight serotype-specific differences in adenovirus entry pathways, and identify endosomal trafficking steps that may be targeted to improve adenoviral vector performance.

Humans↗
PubMed1998

Post-transcriptional gene regulatory mechanisms in eukaryotes: an overview.

Expression of a gene can be controlled at many levels, including transcription, mRNA splicing, mRNA stability, translation and post-translational events such as protein stability and modification. The majority of studies to date have focused on transcriptional control mechanisms, but the importance of post-transcriptional mechanisms in regulating gene expression in eukaryotes is becoming increasingly clear. In this short review, selected examples of post-transcriptional gene regulatory mechanisms operating in both lower and higher eukaryotes will be used to highlight the plethora of such mechanisms already identified. The underlying theme is that post-transcriptional gene regulation relies on specific RNA-protein interactions that either result in the targeted degradation of the mRNA or prevent access of the ribosome to the translation start codon. Such interactions can occur in the 5' or 3' untranslated regions of an mRNA or within the decoded portion of the molecule. The importance of these regulatory mechanisms in a range of biological systems is also illustrated.

Animals↗
PubMed2001

Forty years of decoding the silence in X-chromosome inactivation.

In 1961, Mary Lyon first put forth the hypothesis that one X chromosome is inactivated in each cell of the female mammal. As we enter the new millennium and complete 40 years of study, the field of X-inactivation is rich with ideas and many contrasting viewpoints. This review will focus on the random form of X-inactivation and present the latest views on its mechanism. Much attention has been focused on the genetic parsing of X-chromosome counting, choice, silencing and maintenance. It is now known that counting is functionally distinct from choice and that initiation and establishment of silencing are distinct from maintenance. Since Xist's seminal discovery 10 years ago, significant progress has been made towards understanding its function. Required only for initiation and establishment, Xist must act within a narrow developmental window, but its precise mode of action remains elusive. The ongoing search for Xist RNA-binding factors and effector proteins for silencing has led to members of the macroH2A family of histone variants. Finally, the recent discovery of Tsix implicates regulation of Xist expression by an antisense mechanism. Required for choice but not counting, Tsix blocks Xist RNA accumulation and hence blocks initiation of silencing on the future active X.

Animals↗
PubMed1999

The Candida albicans CUG-decoding ser-tRNA has an atypical anticodon stem-loop structure.

In many Candida species, the leucine CUG codon is decoded by a tRNA with two unusual properties: it is a ser-tRNA and, uniquely, has guanosine at position 33 (G33). Using a combination of enzymatic (V1 RNase, RnI nuclease) and chemical (Pb(2+), imidazole) probing of the native Candida albicans ser-tRNACAG, we demonstrate that the overall tertiary structure of this tRNA resembles that of a ser-tRNA rather than a leu-tRNA, except within the anticodon arm where there is considerable disruption of the anticodon stem. Using non-modified in vitro transcripts of the C. albicans ser-tRNACAG carrying G, C, U or A at position 33, we demonstrate that it is specifically a G residue at this position that induces the atypical anticodon stem structure. Further quantitative evidence for an unusual structure in the anticodon arm of the G33-tRNA is provided by the observed change in kinetics of methylation of the G at position 37, by purified Escherichia coli m(1)G37 methyltransferase. We conclude that the anticodon arm distortion, induced by a guanosine base at position 33 in the anticodon loop of this novel tRNA, results in reduced decoding ability which has facilitated the evolution of this tRNA without extinction of the species encoding it.

Anticodon↗
PubMed1996

Characterization of a B. subtilis minor isoleucine tRNA deduced from tDNA having a methionine anticodon CAT.

Bacillus subtilis, which belongs to Gram-positive eubacteria, has been predicted to have a minor isoleucine tRNA transcribed from the gene possessing the CAT anticodon, which corresponds to methionine. We isolated this tRNA and determined its sequence including modified nucleotides. Modified nucleotide analyses using TLC, UV, and FAB mass spectroscopy revealed that the first letter of the anticodon is modified to lysidine [4-amino-2-(N6-lysino)-1-beta-d-ribofuranosyl pyrimidine]. As a result, this tRNA agrees with the minor one predicted from the DNA sequence and is thought to decode the isoleucine codon AUA.

Acylation↗
PubMed1984

The sup8 tRNALeu gene of Schizosaccharomyces pombe has an unusual intervening sequence and reduced pairing in the anticodon stem.

We have cloned and sequenced the wild-type and suppressor alleles of the S. pombe sup8 tRNA gene. The wild-type allele has a leucine UAA anticodon and the suppressor (sup8-e) carries the opal suppressor anticodon UCA. The gene has a 16 base pair intervening sequence that, in the RNA, is predicted to form a secondary structure which involves base pairing to the 5', rather than the usual 3' side of the 5' splice site. When incubated in Saccharomyces cerevisiae cell-free extracts both alleles are efficiently transcribed, the 5' leader and 3' trailer sequences are removed and CCA is added to the 3' processed end; however, the intervening sequence is not excised. This finding implies that the structural requirements of the splicing endonucleases in the two yeasts have diverged. No other tRNA genes with related sequences were detected in S. pombe DNA by hybridization, suggesting that other UUA isoacceptors may be structurally dissimilar to sup8 or that the UUA codon may be decoded by a UUG leucine isoacceptor.

Alleles↗
PubMed2005

Deacylated tRNA is released from the E site upon A site occupation but before GTP is hydrolyzed by EF-Tu.

The presence or absence of deacylated tRNA at the E site sharply influences the activation energy required for binding of a ternary complex to the ribosomal A site indicating the different conformations that the E-tRNA imparts on the ribosome. Here we address two questions: (i) whether or not peptidyltransferase--the essential catalytic activity of the large ribosomal subunit--also depends on the occupancy state of the E site and (ii) at what stage the E-tRNA is released during an elongation cycle. Kinetics of the puromycin reaction on various functional states of the ribosome indicate that the A-site substrate of the peptidyltransferase center, puromycin, requires the same activation energy for peptide-bond formation under all conditions tested. We further demonstrate that deacylated tRNA is released from the E site by binding a ternary complex aminoacyl-tRNA*EF-Tu*GDPNP to the A site. This observation indicates that the E-tRNA is released after the decoding step but before both GTP hydrolysis by EF-Tu and accommodation of the A-tRNA. Collectively these results reveal that the reciprocal linkage between the E and A sites affects the decoding center on the 30S subunit, but does not influence the rate of peptide-bond formation at the active center of the 50S subunit.

Guanosine Triphosphate↗
PubMed2006

Genome-wide prediction of transcriptional regulatory elements of human promoters using gene expression and promoter analysis data.

BACKGROUND: A complete understanding of the regulatory mechanisms of gene expression is the next important issue of genomics. Many bioinformaticians have developed methods and algorithms for predicting transcriptional regulatory mechanisms from sequence, gene expression, and binding data. However, most of these studies involved the use of yeast which has much simpler regulatory networks than human and has many genome wide binding data and gene expression data under diverse conditions. Studies of genome wide transcriptional networks of human genomes currently lag behind those of yeast. RESULTS: We report herein a new method that combines gene expression data analysis with promoter analysis to infer transcriptional regulatory elements of human genes. The Z scores from the application of gene set analysis with gene sets of transcription factor binding sites (TFBSs) were successfully used to represent the activity of TFBSs in a given microarray data set. A significant correlation between the Z scores of gene sets of TFBSs and individual genes across multiple conditions permitted successful identification of many known human transcriptional regulatory elements of genes as well as the prediction of numerous putative TFBSs of many genes which will constitute a good starting point for further experiments. Using Z scores of gene sets of TFBSs produced better predictions than the use of mRNA levels of a transcription factor itself, suggesting that the Z scores of gene sets of TFBSs better represent diverse mechanisms for changing the activity of transcription factors in the cell. In addition, cis-regulatory modules, combinations of co-acting TFBSs, were readily identified by our analysis. CONCLUSION: By a strategic combination of gene set level analysis of gene expression data sets and promoter analysis, we were able to identify and predict many transcriptional regulatory elements of human genes. We conclude that this approach will aid in decoding some of the important transcriptional regulatory elements of human genes.

Algorithms↗
PubMedDate not supplied

[Genomic polymorphism in the resolution of the fundamental and applied problems of microbiology and epidemiology].

As shown in this work, the methods of genomic fingerprinting make it possible to study genotypic links between strains, closely related phenotypically and genotypically, but having different epidemiological significance, to decode the mechanisms of the appearance and formation of epidemic strains, as well as to determine areas of their spread. The application principles of the methods of the study of genomic polymorphism for solving a number of fundamental problems of microbiology and epidemiology, as well as for carrying out effective retrospective and operative epidemiological analysis, are presented. Schemes for the genetic typing of a number of causative agents of bacterial infections are given. As an example, the optimum scheme of the identification and typing of Mycobacterium tuberculosis strains on the basis of polymerase chain reaction is presented and its advantages in comparison with the routine methods of laboratory diagnostics and typing are shown.

Animals↗
PubMed2004

HIV infection of naturally occurring and genetically reprogrammed human regulatory T-cells.

A T-cell subset, defined as CD4(+)CD25(hi) (regulatory T-cells [Treg cells]), was recently shown to suppress T-cell activation. We demonstrate that human Treg cells isolated from healthy donors express the HIV-coreceptor CCR5 and are highly susceptible to HIV infection and replication. Because Treg cells are present in very few numbers and are difficult to expand in vitro, we genetically modified conventional human T-cells to generate Treg cells in vitro by ectopic expression of FoxP3, a transcription factor associated with reprogramming T-cells into a Treg subset. Overexpression of FoxP3 in naïve human CD4(+) T-cells recapitulated the hyporesponsiveness and suppressive function of naturally occurring Treg cells. However, FoxP3 was less efficient in reprogramming memory T-cell subset into regulatory cells. In addition, FoxP3-transduced T-cells also became more susceptible to HIV infection. Remarkably, a portion of HIV-positive individuals with a low percentage of CD4(+) and higher levels of activated T-cells have greatly reduced levels of FoxP3(+)CD4(+)CD25(hi) T-cells, suggesting disruption of the Treg cells during HIV infection. Targeting and disruption of the T-cell regulatory system by HIV may contribute to hyperactivation of conventional T-cells, a characteristic of HIV disease progression. Moreover, the ability to reprogram human T-cells into Treg cells in vitro will greatly aid in decoding their mechanism of suppression, their enhanced susceptibility to HIV infection, and the unique markers expressed by this subset.

CD4-Positive T-Lymphocytes↗
PubMed2000

Pseudouridine in RNA: what, where, how, and why.

Pseudouridine (5-ribosyluracil) is a ubiquitous yet enigmatic constituent of structural RNAs (transfer, ribosomal, small nuclear, and small nucleolar). Although pseudouridine (psi) was the first modified nucleoside to be discovered in RNA, and is the most abundant, its biosynthesis and biological roles have remained poorly understood since its identification as a "fifth nucleoside" in RNA. Recently, a combination of biochemical, biophysical, and genetic approaches has helped to illuminate the structural consequences of psi in polyribonucleotides, the biochemical mechanism of U-->psi isomerization in RNA, and the role of modification enzymes (psi synthases) and box H/ACA snoRNAs, a class of eukaryotic small nucleolar RNAs, in the site-specific biosynthesis of psi. Through its unique ability to coordinate a structural water molecule via its free N1-H, psi exerts a subtle but significant "rigidifying" influence on the nearby sugar-phosphate backbone and also enhances base stacking. These effects may underlie the biological role of most (but perhaps not all) of the psi residues in RNA. Certain genetic mutants lacking specific psi residues in tRNA or rRNA exhibit difficulties in translation, display slow growth rates, and fail to compete effectively with wild-type strains in mixed culture. In particular, normal growth is severely compromised in an Escherichia coli mutant deficient in a pseudouridine synthase responsible for the formation of three closely spaced psi residues in the mRNA decoding region of the 23S rRNA. Such studies demonstrate that pseudouridylation of RNA confers an important selective advantage in a natural biological context.

Animals↗
PubMed2005

A reduced level of charged tRNAArgmnm5UCU triggers the wild-type peptidyl-tRNA to frameshift.

Frameshift mutations can be suppressed by a variety of differently acting external suppressors. The +1 frameshift mutation hisC3072, which has an extra G in a run of Gs, is corrected by the external suppressor mutation sufF44. We have shown that sufF44 and five additional allelic suppressor mutations are located in the gene argU coding for the minor tRNAArgmnm5UCU and alter the secondary and/or tertiary structure of this tRNA. The C61U, G53A, and C32U mutations influence the stability, whereas the C56U, C61U, G53A, and G39A mutations decrease the arginylation of tRNAArgmnm5UCU. The T-10C mutant has a base substitution in the -10 consensus sequence of the argU promoter that reduces threefold the synthesis of tRNAArgmnm5UCU . The lower amount of tRNAArgmnm5UCU or impaired arginylation, either independently or in conjunction, results in inefficient reading of the cognate AGA codon that, in turn, induces frameshifts. According to the sequence of the peptide produced from the suppressed -GGG-GAA-AGA- frameshift site, the frameshifting tRNA in the argU mutants is tRNAGlumnm5s2UUC, which decodes the GAA codon located upstream of the AGA arginine codon, and not the mutated tRNAArgmnm5UCU. We propose that an inefficient decoding of the AGA codon by a defective tRNAArgmnm5UCU stalls the ribosome at the A-site codon allowing the wild-type form of peptidyl-tRNAGlumnm5s2UUC to slip forward 1 nucleotide and thereby re-establish the ribosome in the 0-frame. Similar frame-shifting events could be the main cause of various phenotypes associated with environmental or genetically induced changes in the levels of aminoacylated tRNA.

Alleles↗
PubMed1998

A pseudouridine synthase required for the formation of two universally conserved pseudouridines in ribosomal RNA is essential for normal growth of Escherichia coli.

Escherichia coli rRNA contains 10 pseudouridines of unknown function. They are made by synthases, each of which is specific for one or more pseudouridines. Here we show that the sfhB (yfil) ORF of E. coli is a pseudouridine synthase gene by cloning, protein overexpression, and reaction in vitro with rRNA transcripts. Gene disruption by miniTn10(cam) insertion revealed that this synthase gene, here renamed rluD, codes for a synthase which is solely responsible in vivo for synthesis of the three pseudouridines clustered in a stem-loop at positions 1911, 1915, and 1917 of 23S RNA. The absence of RluD results in severe growth inhibition. Both the absence of pseudouridine and the growth defect could be reversed by insertion of a plasmid carrying the rluD gene into the mutant cell, clearly linking both effects to the absence of RIuD. This is the first report of a major physiological defect due to the deletion of any pseudouridine synthase. Growth inhibition may be due to the lack of one or more of the 23S RNA pseudouridines made by this synthase since pseudouridines 1915 and 1917 are universally conserved and are located in proximity to the decoding center of the ribosome where they could be involved in modulating codon recognition.

Amino Acid Sequence↗
PubMed1993

Competition between frameshifting, termination and suppression at the frameshift site in the Escherichia coli release factor-2 mRNA.

Competition between frameshifting, termination, and suppression at the frameshifting site in the release factor-2 (RF-2) mRNA was determined in vitro using a coupled transcription-translation system by adding a UGA suppressor tRNA. The expression system was programmed with a plasmid containing a trpE-prfB fusion gene so that each of the products of the competing events could be measured. With increasing concentrations of suppressor tRNA the readthrough product increased at the expense of both the termination and the frameshifting product indicating all three processes are in direct competition. The readthrough at the internal UGA termination codon was greater than that at the natural UGA termination codon at the end of the coding sequence. The results suggest that this enhanced suppression may reflect slower decoding of the internal stop codon by the release factor giving suppression a competitive advantage. The internal UGAC stop signal at the frameshift site has been proposed to be a relatively poor signal, but in addition the release factor may be less able to recognise the signal with the mRNA in such a constrained state. Consequently, the frameshifting event itself will be more competitive with termination in vivo because of this longer pause as the release factor is decoding the stop signal.

Base Sequence↗
PubMed2005

Increased prevalence of Mediterranean and Muslim populations in mutation-related research literature.

This paper assesses the prevalence of 569 population groups in mutation-related research literature by means of prevalence scores, calculated on the basis of a systematic search of the PubMed database. The main finding is that Mediterranean and Muslim populations are mentioned more often than other groups. The observed overrepresentation is attributed to the pervasiveness of hemoglobin disorders in these populations, the early decoding of hemoglobin and the relative commonness of consanguineous marriage in some of these populations. The paper points at potential benefits as well as predicaments that the intensive targeting of these populations for mutation research may entail.

Genetic Research↗
PubMed2001

Animal lectins: from initial description to elaborated structural and functional classification.

The genetic code connects the two biochemical dimensions of nucleic acids and proteins. Theoretical calculations on coding capacity reveal that oligosaccharides as hardware surpass peptides by more than seven orders of magnitude based on hexamer synthesis. Thus, the sugar code establishes the third dimension of biological information transfer. Using carbohydrate-binding proteins (lectins, enzymes and antibodies) the information content of such epitopes is decoded. Currently, five families of animal lectins are defined in structural terms. i.e. the C-type, I-type and P-type groups, the galectins and the pentraxins. They are involved in intra- and intercellular glycan routing using oligosaccharides as postal-code equivalents and acting as defense molecules homing in on foreign or aberrant glycosignatures, as crosslinking agent in biosignaling and as coordinator of transient or firm cell-cell/cell-matrix contacts. By delineating the driving forces toward complex formation, knowledge about the causes for specificity can be turned into design of custom-made high-affinity ligands for clinical application, e.g. in anti-adhesion therapy, drug targeting or diagnostic histopathology.

Animals↗