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Results for “genetic code expansion”

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At least 325 records · Page 18Linked to original sources
PubMed2003

Analysis of the mouse transcriptome for genes involved in the function of the nervous system.

We analyzed the mouse Representative Transcript and Protein Set for molecules involved in brain function. We found full-length cDNAs of many known brain genes and discovered new members of known brain gene families, including Family 3 G-protein coupled receptors, voltage-gated channels, and connexins. We also identified previously unknown candidates for secreted neuroactive molecules. The existence of a large number of unique brain ESTs suggests an additional molecular complexity that remains to be explored.A list of genes containing CAG stretches in the coding region represents a first step in the potential identification of candidates for hereditary neurological disorders.

Adenine↗
PubMed2004

Molecular origins of rapid and continuous morphological evolution.

Mutations in cis-regulatory sequences have been implicated as being the predominant source of variation in morphological evolution. We offer a hypothesis that gene-associated tandem repeat expansions and contractions are a major source of phenotypic variation in evolution. Here, we describe a comparative genomic study of repetitive elements in developmental genes of 92 breeds of dogs. We find evidence for selection for divergence at coding repeat loci in the form of both elevated purity and extensive length polymorphism among different breeds. Variations in the number of repeats in the coding regions of the Alx-4 (aristaless-like 4) and Runx-2 (runt-related transcription factor 2) genes were quantitatively associated with significant differences in limb and skull morphology. We identified similar repeat length variation in the coding repeats of Runx-2, Twist, and Dlx-2 in several other species. The high frequency and incremental effects of repeat length mutations provide molecular explanations for swift, yet topologically conservative morphological evolution.

Alleles↗
PubMed1997

Animal model for fragile X syndrome.

The fragile X syndrome, one of the most common forms of inherited mental retardation, is caused by an expansion of a polymorphic CGG repeat upstream of the coding region in the FMR1 gene. The expansion blocks expression of the FMR1 gene due to methylation of the FMR1 promoter. Functional studies on the FMR1 protein have shown that the protein can bind RNA and might be involved in transport of RNAs from the nucleus to the cytoplasm. A role of FMR1 protein on translation of certain mRNAs has been suggested. An animal model for fragile X syndrome exists and these mice show some behavioural difficulties mimicking the human fragile X syndrome phenotype. This review presents what is known about the protein and what is learned from the animal model for fragile X syndrome.

Animals↗
PubMed2005

Satellog: a database for the identification and prioritization of satellite repeats in disease association studies.

BACKGROUND: To date, 35 human diseases, some of which also exhibit anticipation, have been associated with unstable repeats. Anticipation has been reported in a number of diseases in which repeat expansion may have a role in etiology. Despite the growing importance of unstable repeats in disease, currently no resource exists for the prioritization of repeats. Here we present Satellog, a database that catalogs all pure 1-16 repeat unit satellite repeats in the human genome along with supplementary data. Satellog analyzes each pure repeat in UniGene clusters for evidence of repeat polymorphism. RESULTS: A total of 5,546 such repeats were identified, providing the first indication of many novel polymorphic sites in the genome. Overall, polymorphic repeats were over-represented within 3'-UTR sequence relative to 5'-UTR and coding sequence. Interestingly, we observed that repeat polymorphism within coding sequence is restricted to trinucleotide repeats whereas UTR sequence tolerated a wider range of repeat period polymorphisms. For each pure repeat we also calculate its repeat length percentile rank, its location either within or adjacent to EnsEMBL genes, and its expression profile in normal tissues according to the GeneNote database. CONCLUSION: Satellog provides the ability to dynamically prioritize repeats based on any of their characteristics (i.e. repeat unit, class, period, length, repeat length percentile rank, genomic co-ordinates), polymorphism profile within UniGene, proximity to or presence within gene regions (i.e. cds, UTR, 15 kb upstream etc.), metadata of the genes they are detected within and gene expression profiles within normal human tissues. Unstable repeats associated with 31 diseases were analyzed in Satellog to evaluate their common repeat properties. The utility of Satellog was highlighted by prioritizing repeats for Huntington's disease and schizophrenia. Satellog is available online at http://satellog.bcgsc.ca.

3' Untranslated Regions↗
PubMed2005

Gene conversion and the evolution of three leucine-rich repeat gene families in Arabidopsis thaliana.

The high number of duplicated genes in plant genomes provides a potential template for gene conversion and unequal crossing-over. Within a gene family these two processes can render all members homogeneous or generate diversity by reassorting variants among paralogs. The latter is especially feasible in families where gene diversity confers a selective advantage and thus conversion events are likely to be retained. Consequently, the most complete record of gene conversion is expected to be most evident in gene families commonly subjected to positive selection. Here, we describe the extent and characteristics of gene conversion and unequal crossing-over in the coding and noncoding regions of nucleotide-binding site leucine-rich repeat (NBS-LRR), receptor-like kinases (RLK), and receptor-like proteins (RLP) in the plant Arabidopsis thaliana. Members of these three gene families are associated with disease resistance and their pathogen-recognition domain is a documented target of positive selection. Our bioinformatic approach to study the major family features that may influence gene conversion revealed that in these families there is a significant association between the occurrence of gene conversion and high levels of sequence similarity, close physical clustering, gene orientation, and recombination rate. We discuss these results in the context of the overlap between gene conversion and positive selection during the evolutionary expansion of the NBS-LRR, RLK, and RLP gene families.

Arabidopsis↗
PubMed2006

MBNL1 and CUGBP1 modify expanded CUG-induced toxicity in a Drosophila model of myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a CTG expansion in the 3' UTR of the dystrophia myotonica protein kinase (DMPK) gene. It has been hypothesized that the pathogenesis in DM1 is triggered by a toxic gain of function of the expanded DMPK RNA. This expanded RNA is retained in nuclear foci where it sequesters and induces alterations in the levels of RNA-binding proteins (RNA-BP). To model DM1 and study the implication of RNA-BP in CUG-induced toxicity, we have generated a Drosophila DM1 model expressing a non-coding mRNA containing 480 interrupted CUG repeats; i.e. [(CUG)20CUCGA]24. This (iCUG)480 transcript accumulates in nuclear foci and its expression leads to muscle wasting and degeneration in Drosophila. We also report that altering the levels of two RNA-BP known to be involved in DM1 pathogenesis, MBNL1 and CUGBP1, modify the (iCUG)480 degenerative phenotypes. Expanded CUG-induced toxicity in Drosophila is suppressed when MBNL1 expression levels are increased, and enhanced when MBNL1 levels are reduced. In addition, (iCUG)480 also causes a decrease in the levels of soluble MBNL1 that is sequestered in the CUG-containing nuclear foci. In contrast, increasing the levels of CUGBP1 worsens (iCUG)480-induced degeneration even though CUGBP1 distribution is not altered by the expression of the expanded triplet repeat. Our data supports a mechanism for DM1 pathogenesis in which decreased levels of MBNL and increased levels of CUGBP mediate the RNA-induced toxicity observed in DM1. Perhaps more importantly, they also provide proof of the principle that CUG-induced muscle toxicity can be suppressed.

Animals↗
PubMed1999

Intimate association of microsatellite repeats with retrotransposons and other dispersed repetitive elements in barley.

Simple sequence repeat (SSR)-based genetic markers are being actively developed for the majority of crop plant species. In barley, characterization of 290 dinucleotide repeat-containing clones from SSR-enriched libraries has revealed that a high percentage are associated with cereal retrotransposon-like and other dispersed repetitive elements. Associations found were with BARE-1, WIS2-1A, PREM1 and the dispersed repetitive element R173. Additional similarities between different SSR clones, which have no matches in DNA sequence databases, indicate that this phenomenon is probably widespread in the barley genome. Sequence homologies to the non-coding regions of several cereal genes were also explained by homology to mobile genetic elements. The SSRs found can therefore be classified into two types: (1) those with unique sequences on either flank, and (2) those which are intimately associated with retro-transposons and other dispersed repetitive elements. As the cereal genome is thought to consist largely of this type of DNA, some random association would be expected. However, the conserved positions of the SSRs, relative to repetitive elements, indicate that they have arisen non-randomly. Furthermore, this class of SSRs can be classified into three subtypes: (1) those which are positioned 3' of a transposable element with unique sequence on the other flank, (2) those positioned 5' of a transposable element, and (3) those which have arisen from an internal sequence and so have transposable element sequence on both flanks. The first appear to be analogous to the class of SSRs in mammalian systems which are associated with Alu elements and SINEs (short interspersed elements) and which have been postulated to arise following integration of an extended and polyadenylated retro-transcript into the host genome, followed by mutation of the poly(A) tract and expansion into an SSR. For the second, we postulate that a proto-SSR (A-rich sequence) has acted as a 'landing pad' for transposable element insertion (rather than being the result of insertion), while the third includes those which have evolved as a component of an active transposable element which has spread throughout the genome during bursts of transposition activity. The implications of these associations for genome and SSR evolution in barley are discussed.

Base Sequence↗
PubMed2007

CAG and CTG repeat polymorphism in exons of human genes shows distinct features at the expandable loci.

Although the trinucleotide repeats are present in the exons of numerous human genes, the allele distribution is not well known, and the factors responsible for their intergenic and intragenic variability are not well understood. We have analyzed the length and sequence variation within the most commonly occurring CAG and CTG repeats in a large number of human genes selected to contain the longest reported repeat tracts. Our study revealed that in genes other than those implicated in the Triplet Repeat Expansion Diseases (TREDs), the very long and highly polymorphic repeats are rather infrequent. The length of pure repeat tract in the most frequent allele was found to correlate well with the rate of the repeat length polymorphism, and CAA triplets were shown to be the most frequent CAG repeat interruptions. As both the CAG and CAA triplets code for glutamine, our results may suggest that the selective pressure disfavors the long uninterrupted CAG repeats in genes and transcripts but not the long normal polyglutamine tracts in proteins. This may indicate that hairpin structures formed in ssDNA and RNA by long pure CAG repeats would be selected against as they may impede normal cellular processes.

3' Untranslated Regions↗
PubMed1995

A conformationally homogeneous combinatorial peptide library.

In search for a rational way to convert the information encoded in peptide structures into peptidomimetics, major progress could be made by coupling the power of selection methods, now enormously increased in number as a result of the development of combinatorial peptide libraries, with the rational design of structure-inducing templates for the selectable sequences. The availability of libraries of peptides with predetermined structure would enable selection-driven peptidomimetic design, whereby a conformational model for the peptide pharmacophore would be directly derived from the screening, allowing the design of a suitable non-peptidic scaffold to replace the peptide backbone. We describe here the first example of a conformationally homogeneous combinatorial peptide library, which yields ligands with the expected structure upon selection. The library was built by randomising five positions in the alpha-helical portion of a 26 amino acid Cys2His2 consensus "zinc-finger" motif. Since in zinc-fingers metal coordination and folding are coupled, in our library metal-dependent binding represents a built-in control against the selection of structurally undefined sequences. The alpha-helical library was produced as both fusion with the pVIII protein of filamentous phage and soluble peptides by chemical synthesis, the latter enabling the expansion of the selectable repertoire by the inclusion of non-coded amino acids. The two libraries were independently screened with the same receptor (a monoclonal IgA reactive against the lipopolysaccharide of the human pathogen Shigella flexneri), yielding a very similar consensus. In particular, the peptides defined by both methods showed very strong, zinc-dependent binding to the IgA. The geometrical arrangement of the side-chains of the selected peptide pharmacophore was shown by circular dichroism, Co(II)-complex absorption and high-resolution NMR to be structurally invariant with respect to the parent zinc-finger.

Amino Acid Sequence↗
PubMed1999

Inventory, assembly and analysis of Bacillus subtilis ABC transport systems.

We have undertaken the inventory and assembly of the ATP binding cassette (ABC) transporter systems in the complete genome of Bacillus subtilis. We combined the identification of the three protein partners that compose an ABC transporter (nucleotide-binding domain, NBD; membrane spanning domain, MSD; and solute-binding protein, SBP) with constraints on the genetic organization. This strategy allowed the identification of 86 NBDs in 78 proteins, 103 MSD proteins and 37 SBPs. The analysis of transcriptional units allows the reconstruction of 59 ABC transporters, which include at least one NBD and one MSD. A particular class of five dimeric ATPases was not associated to MSD partners and is assumed to be involved either in macrolide resistance or regulation of translation elongation. In addition, we have detected five genes encoding ATPases without any gene coding for MSD protein in their neighborhood and 11 operons that encode only the membrane and solute-binding proteins. On the bases of similarities, three ATP-binding proteins are proposed to energize ten incomplete systems, suggesting that one ATPase may be recruited by more than one transporter. Finally, we estimate that the B. subtilis genome encodes for at least 78 ABC transporters that have been split in 38 importers and 40 extruders. The ABC systems have been further classified into 11 sub-families according to the tree obtained from the NBDs and the clustering of the MSDs and the SBPs. Comparisons with Escherichia coli show that the extruders are over-represented in B. subtilis, corresponding to an expansion of the sub-families of antibiotic and drug resistance systems.

ATP-Binding Cassette Transporters↗
PubMed1994

An in-frame trinucleotide repeat in the coding region of the human cellular glutathione peroxidase (GPX1) gene: in vivo polymorphism and in vitro instability.

We report the variation in vivo and instability in vitro of an in-frame GCG trinucleotide repeat in the human cellular glutathione peroxidase (GPX1) gene. In a population study of 110 alleles from 55 unrelated individuals, the allele frequencies for 4, 5, and 6 GCG repeats were 0.40, 0.35, and 0.25, respectively. No allele was associated with diminished enzyme activity. Current stocks of HL-60 cells, a human myeloid leukemia cell line, are homozygous for the 6-repeat allele. Early passage HL-60 cells frozen in 1976 show a 4/6 genotype and "intermediate" passage cells frozen in 1985 contain both 4/6 and 5/6 genotypes. Thus, the expansion of the repeat appears to have developed in the course of multiple passages of the rapidly proliferating cell line.

Alleles↗
PubMed2004

NR2A and NR2B receptor gene variations modify age at onset in Huntington disease.

N -Methyl-d-aspartate (NMDA) receptor-mediated excitotoxicity has been proposed to play a role in the pathogenesis of Huntington disease (HD), an autosomal dominantly inherited disorder associated with defined expansions in a stretch of perfect CAG repeats in the 5' part of the IT15 gene. The number of CAG repeat units is highly predictive for the age at onset (AO) in HD. However, AO is only modestly correlated with repeat length when the HD expansion range is in the high 30s or low 40s. Therefore, we investigated whether the genes for the different subunits composing the multimeric complexes of NMDA receptors (GRIN glutamate receptor, ionotropic, N-methyl-d-aspartate) represent candidates for modulating the AO of HD. In the studied cohort of 167 HD patients, the repeat range from 41 to 45 CAG units accounted for 30.8% of the variance in AO; 12.3% additional variance could be attributed to GRIN2B genotype variation and 4.5% to GRIN2A genotype variation. We conclude that these two genes, coding for NR2B and NR2A subtypes mainly expressed in the striatum, may influence the variability in AO of HD. Neuroprotective strategies for HD patients and persons at risk should be reconsidered in the light of these findings.

Adult↗
PubMed2006

A comprehensive catalog of human KRAB-associated zinc finger genes: insights into the evolutionary history of a large family of transcriptional repressors.

Krüppel-type zinc finger (ZNF) motifs are prevalent components of transcription factor proteins in all eukaryotes. KRAB-ZNF proteins, in which a potent repressor domain is attached to a tandem array of DNA-binding zinc-finger motifs, are specific to tetrapod vertebrates and represent the largest class of ZNF proteins in mammals. To define the full repertoire of human KRAB-ZNF proteins, we searched the genome sequence for key motifs and then constructed and manually curated gene models incorporating those sequences. The resulting gene catalog contains 423 KRAB-ZNF protein-coding loci, yielding alternative transcripts that altogether predict at least 742 structurally distinct proteins. Active rounds of segmental duplication, involving single genes or larger regions and including both tandem and distributed duplication events, have driven the expansion of this mammalian gene family. Comparisons between the human genes and ZNF loci mined from the draft mouse, dog, and chimpanzee genomes not only identified 103 KRAB-ZNF genes that are conserved in mammals but also highlighted a substantial level of lineage-specific change; at least 136 KRAB-ZNF coding genes are primate specific, including many recent duplicates. KRAB-ZNF genes are widely expressed and clustered genes are typically not coregulated, indicating that paralogs have evolved to fill roles in many different biological processes. To facilitate further study, we have developed a Web-based public resource with access to gene models, sequences, and other data, including visualization tools to provide genomic context and interaction with other public data sets.

Computational Biology↗
PubMed1989

Transfer RNA structure and coding specificity. II. A D-arm tertiary interaction that restricts coding range.

We investigated the structural basis of the kinetic effect on coding specificity by the D-arm mutant (G24 to A) of Escherichia coli tRNATrp. A set of tRNA genes with structural alterations in the D-arm was constructed by site-directed mutagenesis in vitro, and we determined the in vivo translational activities of these tRNAs. Our results suggest that a hydrogen-bond donor in the major groove of the D-helix at position 24 is required for the expansion of tRNA wobble coding specificity. From inspection of tRNA crystal structure, we identified a potential new tertiary pairing of base 24 with the base at position 9 (this base links the acceptor and D-stems). We constructed tRNAs with mutations at position 9 and showed that the phenotypes of position 11-24 D-arm mutants are indeed dependent on the identity of base 9. Our analysis of the effects of these mutations on the interactions of tRNA with the ribosome and with aminoacyl-tRNA synthetase suggests that the conformation or conformational dynamics of the middle of the tRNA molecule alters the kinetics of the interaction with the ribosomal coding site. The 9-23 and putative 9-24 tertiaries, and perhaps other normal tertiary interactions in this region, modulate these kinetics to increase or decrease coding specificity.

Amino Acyl-tRNA Synthetases↗
PubMed1981

Evidence for a new HLA-region determinant detected by human T-lymphocyte clones (TLCs).

Human peripheral blood T-lymphocytes were stimulated by allogeneic cells in primary MLC and subsequently cloned by limiting dilution in the presence of lymphocyte conditioned medium (LyCM). Following expansion, clones were tested for specific proliferation against a panel of 32 stimulator cells including cells from the family of the original stimulator (FLAM). Two clones, TLC 14-14 and TLC 14-86, responded to FLAM and to a cell homozygous for Dw5 (JPSU), but not to other unrelated panel members; reactivity segregated with the haplotype containing Dw1 in FLAM's family. In separate experiments, TLC 14-14 was restimulated by an antigen encoded by the maternal "c" haplotype in JPSU's family. This antigen may be a new determinant on the same molecule as Dw1 and 5 or, more likely, encoded by a new gene associated with these specificities.

Clone Cells↗
PubMed1994

Anchored polymerase chain reaction based analysis of the V beta repertoire in the non-obese diabetic (NOD) mouse.

We have performed extensive analyses of T cell receptor V beta usage in the thymus, the spleen and the infiltrated islets of preclinical non-obese diabetic (NOD) mice. A semiquantitative anchored polymerase chain reaction (An-PCR) protocol has been developed for this purpose. The validity of the method has been first assessed by antibody staining with a panel of anti-V beta monoclonal antibodies (mAb). The results obtained by An-PCR are accurate, reproducible, and in good agreement with cell surface protein staining. A strict comparison between thymus and spleen repertoires reveals no major V beta-specific deletion except the already reported V beta 3 deletion due to Mtv-3. Certain V beta such as V beta 15, 18, 20 are found with a low frequency in the spleen, but the fact that they are also scarce in the thymus probably reflects a poor availability of these genetic elements during beta chain rearrangement rather than negative selection. Other V beta, such as V beta 2, V beta 12 and V beta 14 are significantly more abundant in the spleen than in the thymus. This finding was confirmed by mAb staining for V beta 2 and V beta 14. The expansion asymmetrically affects the CD4+ subset and can be traced back to the mature, single-positive thymocyte subset, suggesting an intrathymic positive selection event. V beta repertoires in infiltrated islets of 13- and 18-week-old, non-diabetic mice are polymorphic. Practically all the V beta found in the peripheral lymphoid tissues are present in the islets, in similar proportions. The major exception is V beta 12, one of the V beta which is subject to expansion during intrathymic differentiation and which is further augmented in the islets, both at 13 and 18 weeks. This increase probably reflects further peripheral amplification of the V beta 12-bearing subset due to encounter with the same ligand as in the thymus or with a cross-reactive motif. Finally, the nucleotide sequencing of all the V beta segments in usage in the NOD strain confirms the absence of allelic polymorphism of V beta-coding regions.

Animals↗
PubMed2001

Identification of a mononucleotide repeat as a major target for mitochondrial DNA alterations in human tumors.

Mitochondrial DNA (mtDNA) mutations scattered through coding and noncoding regions have been reported in cancer. The mechanisms that generate such mutations and the importance of mtDNA mutations in tumor development are still not clear. Here we present the identification of a specific and highly polymorphic homopolymeric C stretch (D310), located within the displacement (D) loop, as a mutational hotspot in primary tumors. Twenty-two % of the 247 primary tumors analyzed harbored somatic deletions/insertions at this mononucleotide repeat. Moreover, these alterations were also present in head and neck preneoplastic lesions. We further characterized the D310 variants that appeared in the lung and head and neck tumors. Most of the somatic alterations found in tumors showed deletion/insertions of 1- or 2-bp generating D310 variants identical to constitutive polymorphisms described previously. Sequencing analysis of individual clones from lymphocytes revealed that patients with D310 mutations in the tumors had statistically significant higher levels of D310 heteroplasmy (more than one length variant) in the lymphocyte mtDNA as compared with the patients without D310 mutations in the tumor mtDNA. On the basis of our observations, we propose a model in which D310 alterations are already present in normal cells and achieve homoplasmy in the tumor through a restriction/amplification event attributable to random genetic drift and clonal expansion.

Carcinoma, Squamous Cell↗
PubMed1998

Hormone response units: one plus one equals more than two.

The transcription rate of many genes, and particularly those which code for metabolically important proteins, is regulated by various hormones. Detailed analysis of the promoters of these genes has shown that, while functional 'Hormone response elements' exist, the hormonal responsiveness of many promoters is often synergistically mediated by several cis-elements, collectively referred to as a hormone response unit. The utilization of a hormone response unit to mediate a response offers several regulatory advantages, including an expansion of the range of transcriptional responses and modulation of the response by tissue- and developmental-specific cues. Furthermore, the presence of Hormone Response Units may provide a mechanism for the coordination of information from two or more signaling pathways into a single, integrated and exquisitely controlled transcriptional response. The protein-protein interactions that likely mediate many of the synergistic functional characteristics of Hormone Response Units may provide unique targets for therapeutic intervention.

Animals↗