Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “genetic code expansion”

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 235 records · Page 13Linked to original sources
PubMed1998

Genetic structure of five susceptibility gene regions for coronary artery disease: disequilibria within and among regions.

We analyzed two-locus disequilibria for 16 polymorphic loci of seven susceptibility genes for coronary artery disease located in five chromosomal regions distributed across four chromosomes. Included were the genes coding for apolipoprotein B (ApoB, chromosome 2, four marker loci), lipoprotein lipase (LPL, chromosome 8, three marker loci), apolipoproteins AI, CIII AIV (ApoAI-CIII-AIV, chromosome 11, three marker loci), apolipoprotein E (ApoE, chromosome 19, two marker loci), and the low density lipoprotein receptor (LDLR, chromosome 19, four marker loci). Our sample included 540 unrelated individuals from the Rochester, Minn. population. There were no statistically significant deviations of single-locus genotypes from Hardy-Weinberg equilibrium. The strongest associations within genes were for composite diallelic disequilibria; 17/19 were significant (13 at Pr <0.001, 1 at Pr <0.01, 3 at Pr <0.05). These observations suggest marker alleles within genes have a shared evolutionary history reflected by disequilibria that have not been dissipated by recombination. Disequilibrium was not generally concordant with the physical orderings of markers. Only two significant higher-order disequilibria were observed although 12 triallelic disequilibria were at maximum possible values. We observed 19 statistically significant disequilibria (Pr <0.05; 4 composite diallelic, 13 triallelic, and 2 quadriallelic) between 101 pairs of marker loci, where each locus in a pair was from a different unlinked region. These unexpected results are most likely explained by recent historical factors, including worldwide population expansion and amalgamation with continuous admixture, that influence the genetic structure (organization of alleles and non-alleles into genotypes) of a population. We conclude that disequilibria between loci from unlinked regions may be more extensive than is commonly assumed. Our findings also suggest that it is, on average, at least 15 times more likely to not detect significant disequilibrium among unlinked loci when it is really present than to make a false positive inference. Disequilibria between functional loci within or between regions will impact estimates of genetic variance associated with particular functional mutations within a susceptibility gene region.

Apolipoproteins↗
PubMed1999

[Growing genes cause neurological diseases].

A growing number of hereditary neurodegenerative disorders have been found to be caused by expansion of trinucleotide repeats. A smaller number of diseases such as fragile X syndrome, myotonic dystrophy, and Friedreich's ataxia, have been found to be due to expansions in non-coding DNA. In a large group of diseases, the expansion consists of CAG repeats in the coding region of the gene, producing an expanded polyglutamine sequence in the protein. Nine diseases have so far been identified as belonging to this group: Huntington's disease, spinobulbar muscular atrophy (SBMA), dentatorubral pallidoluysian atrophy (DRPLA), autosomal dominant "pure" spastic paraplegia (ADPSP), and five forms of spinocerebellar ataxia (SCA 1,2,3,6 and 7). Except for SBMA, all of the CAG repeat disorders are characterised by autosomal dominant heredity and anticipation (i.e., earlier onset age and increasing severity in successive generations). The mutated protein causes disease via an as yet unidentified gain-of-function mechanism in specific subsets of neurones. Today, DNA analysis permits the diagnosis of a trinucleotide disease in individual cases.

Anticipation, Genetic↗
PubMed1984

Evolution of anticodons.

Anticodons are trinucleotides in transfer RNA (tRNA) molecules. The latter carry amino acids for insertion into the polypeptide sequences of proteins during the translation of messenger RNA (mRNA) molecules. Messenger RNA molecules are transcribed from genes. Evolution of tRNA molecules has resulted in a set of anticodons for the 20 amino acids that are used in protein synthesis. This set of anticodons is slightly different in mitochondrial codes from the set that used in the nuclear "universal" code. Theories for the evolution of the code include frozen accident, doublet expansion, repeating triplets and coevolutionary distribution. The number of codons has always been fixed at 64 by mathematical rules, but because an anticodon may pair with more than one codon, the number of anticodons is only 54 in the universal code, is smaller in mitochondrial codes, and was probably even smaller in archetypal primitive codes. Evidence of anticodon evolution can be seen by comparing mitochondrial codes with the universal code. Codes used by very primitive organisms that are now extinct might have specified fewer amino acids than are now used.

Amino Acids↗
PubMed2000

Nickel(II) induces microsatellite mutations in human lung cancer cell lines.

Nickel(II) is a human carcinogen causing respiratory cancers. The purpose of this study was to determine whether Ni(II) may induce microsatellite mutations in human cells. We transfected the three human lung tumor cell lines A427, HCC15 and NCI-H2009 with a mammalian expression vector containing a (CA)(13) repeat in the coding sequences of the reporter hygromycin gene (hyg). A total of 33 clones carrying the integrated vector derived from the three cell lines was investigated for spontaneous and Ni(II)-induced hygromycin-resistant (hyg(r)) reversion mutants. Significantly higher frequencies of hyg(r) reversion mutations were observed in Ni(II)-treated cells (NCI-H2009 and HCC-15) than control cells. In the majority of the colonies hyg(r) phenotype was due to mutations within the integrated (CA) repeat sequence. The type of mutations consisted of both contraction and expansion of the (CA) repeat unit. The finding that Ni(II) promotes microsatellite mutations raises the possibility that genetic instability may be a mechanism involved in nickel carcinogenesis.

Cell Survival↗
PubMed2004

HIV-1 subtype distribution and the problem of drug resistance.

Genetic diversity is a hallmark of HIV-1 infection with regard to the expansion of distinct viral subtypes (clades A, B, C, D, E, F, G, K, and O) in different geographical regions. Here, we discuss the issues of HIV-1 sensitivity to antiretroviral drugs and drug resistance in the context of HIV-1 subtype diversity. Virtually all available evidence suggests that all subtypes of HIV display similar sensitivity to antiviral drugs, but viruses from some subtypes or geographical regions may occasionally have a greater propensity to develop resistance against certain drugs than other viral variants. In some situations, the types of mutations associated with resistance may vary, as a result of subtle differences among subtypes with regard to the genetic code. This consideration notwithstanding, drug resistance is unlikely to become a more serious issue in developing than developed countries, and there is an urgency to make anti-HIV drugs available to all who are in need.

Drug Resistance, Viral↗
PubMed2005

Expansion of triplex recognition codes by the use of novel bicyclic nucleoside derivatives (WNA).

Recently, we have developed new base analogs (WNA) and demonstrated that WNA-[see text];T with thymine and WNA-[see text];C with cytosine stabilize n on-natural antiparallel triplexes with a TA or CG interrupting site, respectively. However, limitations in recognizable sequences with the WNA-containing TFO were also found. The objective of this study is to search better WNA analogs for expansion of triplex recognition codes to general duplex sequences. In this study, we designed new WNA analogs by systematic modification of the aromatic part and the recognition part. The new WNA analogs with the benzene ring substituted with bromide or cyanide have determined for selective stabilization of triplexes at a TA interrupting site, and general formation of triplexes having a TA interrupting site has been achieved.

Base Composition↗
PubMed1999

The identification of polymorphisms in the coding region of the apolipoprotein (a) gene--association with earlier identified polymorphic sites and influence on the lipoprotein (a) concentration.

Lipoprotein (a) [Lp(a)] is a quantitative genetic trait in human plasma and elevated levels represent a major inherited risk factor for the development of atherosclerotic disease. In our search for sequence polymorphisms in the coding region of the apolipoprotein(a) [apo(a)] gene that may affect the Lp(a) concentration, four new polymorphic sites were identified. These include two coinciding polymorphisms with an allele frequency of 38% located at amino acid positions 87 and 101 (Leu87,101-->Val) in the interkringle region of kringle IV (K.IV) type 7 and two polymorphisms located in K.IV type 7 (Arg60-->Ser) and in K.IV type 10 (Tyr2-->Phe) both with estimated allele frequencies of about 1%. The linkage between the newly identified K.IV type 7 Leu87,101 -->Val polymorphism and earlier described polymorphic sites in the non-coding and coding regions of the apo(a) gene, its distribution over the apo(a) isoform sizes and its possible influence on the Lp(a) concentration was analysed in 201 healthy unrelated Caucasians. The earlier described polymorphic sites included in this study were the variable number of a TTTTA pentanucleotide repeat (7-11 PNR) starting at -1231 bp, the -772 bp G/A polymorphism, the +93 bp C/T polymorphism and the +121 bp G/A polymorphism in the non-coding region, and the K.IV type 8 Thr12/Pro polymorphism and the K.IV type 10 Thr66/Met polymorphism in the coding region of the apo(a) gene. Linkage disequilibria were observed between the polymorphic sites in the 5' non-coding region and the sites in K.IV type 7 and 8 in the coding region of the apo(a) gene, confirming that the expansion of the variable number of K.IV type 2 repeats results from intrachromosomal recombinational events. The distribution over the apo(a) isoform sizes of the K.IV type 7 Val87,101 subtype was not significantly different from that of the K.IV type 7 Leu87,101 wild-type, suggesting a relative ancient mutational event. No influence of the K.IV type 7 Leu87,101-->Val polymorphism on the Lp(a) level was observed. In fact, of all the polymorphic sites studied, only the +121 A subtype could be associated with an increased, and the K.IV type 8 Pro12 and the 10 PNR subtypes with a reduced, Lp(a) concentration corrected for apo(a) isoform size (p <0.05).

Alleles↗
PubMed2004

[Hereditary chorea--update].

Understanding molecular genetical background of hereditary chorea has recently been progressed so far. Triplet repeat expansion diseases including, Huntington disease, in which CAG expansion has been identified in the IT-15 or Huntingtin gene, and Huntington disease like-2, in which CTG expansion in junctophilin-3 (JPH3) gene occurs, causes selective degeneration of striatum in the brain. Octapeptide repeat expansion in the prion gene in Huntington disease like-1 has been also identified. Neuroacanthocytosis syndromes including McLeod syndrome and chorea-acanthocytosis cause acanthocytosis in the red blood cells and chorea due to the degeneration of caudate nucleus in the brain. The XK gene on the X chromosome is mutated to lose its function in McLeod syndrome. CHAC gene coding chorein is mutated to lead loss of function in chorea-acanthocytosis. Selective degeneration in the striatum, especially in the caudate nucleus might be associated with the molecular cascade of expanded polyglutamine or polyleucine or octapeptide and the loss of function of the XK protein and of chorein protein.

Chorea↗
PubMed1991

Repetitive sequence-mediated rearrangements in Chlorella ellipsoidea chloroplast DNA: completion of nucleotide sequence of the large inverted repeat.

A 3454 base pair (bp) sequence of the large inverted repeat (IR) of chloroplast DNA (cpDNA) from the unicellular green alga Chlorella ellipsoidea has been determined. The sequence includes: (1) the boundaries between the IR and the large single copy (LSC) and the small single copy (SSC) regions, (2) the gene for psbA and (3) an approximately 1.0 kbp region between psbA and the rRNA genes which contains a variety of short dispersed repeats. The total size of the Chlorella IR was determined to be 15243 bp. The junction between the IR and the small single copy region is located close to the putative promoter of the rRNA operon (906 bp upstream of the -35 sequence on each IR). The junction between the IR and the large single copy region is also just upstream of the putative psbA promoter, 218 bp upstream from the ATG initiation codon. A few sets of unique sequences were found repeatedly around both junctions. Some of the sequences flanking the IR-LSC junction suggest a unidirectional and serial expansion of the IR within the genome. The psbA gene is located close to the LSC-side junction and codes for a protein of 352 amino acid residues. A highly conserved C-terminal Gly is absent Unlike the psbA of Chlamydomonas species, which contains 2-4 large introns, the gene of Chlorella has no introns.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2006

Characterizing the composition and evolution of homoeologous genomes in hexaploid wheat through BAC-end sequencing on chromosome 3B.

Bread wheat (Triticum aestivum) is one of the most important crops worldwide. However, because of its large, hexaploid, highly repetitive genome it is a challenge to develop efficient means for molecular analysis and genetic improvement in wheat. To better understand the composition and molecular evolution of the hexaploid wheat homoeologous genomes and to evaluate the potential of BAC-end sequences (BES) for marker development, we have followed a chromosome-specific strategy and generated 11 Mb of random BES from chromosome 3B, the largest chromosome of bread wheat. The sequence consisted of about 86% of repetitive elements, 1.2% of coding regions, and 13% remained unknown. With 1.2% of the sequence length corresponding to coding sequences, 6000 genes were estimated for chromosome 3B. New repetitive sequences were identified, including a Triticineae-specific tandem repeat (Fat) that represents 0.6% of the B-genome and has been differentially amplified in the homoeologous genomes before polyploidization. About 10% of the BES contained junctions between nested transposable elements that were used to develop chromosome-specific markers for physical and genetic mapping. Finally, sequence comparison with 2.9 Mb of random sequences from the D-genome of Aegilops tauschii suggested that the larger size of the B-genome is due to a higher content in repetitive elements. It also indicated which families of transposable elements are mostly responsible for differential expansion of the homoeologous wheat genomes during evolution. Our data demonstrate that BAC-end sequencing from flow-sorted chromosomes is a powerful tool for analysing the structure and evolution of polyploid and highly repetitive genomes.

Base Sequence↗
PubMed2026

Genetic Deletion of Cis-Regulatory Elements to Dissect the Function of the Non-coding Genome in human Preimplantation Models.

Cis-regulatory elements coordinate gene expression in a spatially and temporally controlled manner and contribute to the establishment of distinct cellular states during development. A substantial proportion of transcriptionally active cis-regulatory elements in primate embryos originated from ancient retroviral integrations into the germline. These endogenous retroviruses, also known as long terminal repeat retrotransposons, retain intrinsic regulatory activity and are often species-specific, making them strong candidates for regulating species-divergent aspects of embryonic development. Ethical and legal restrictions on human embryo research have historically limited direct investigation of gene regulation during human embryogenesis. Human naive pluripotent stem cells and three-dimensional stem cell-based blastocyst models provide alternative systems for studying early developmental processes. This protocol describes the CRISPR-Cas9-mediated deletion of endogenous retrovirus-derived cis-regulatory elements in human naive pluripotent stem cells. Preassembled Cas9 and single-guide RNA ribonucleoprotein complexes are delivered by nucleofection, followed by single-cell cloning, PCR-based genotyping, Sanger sequencing, expansion, cryopreservation, and genomic stability assessment of the edited lines. The resulting wild-type, heterozygous, and homozygous or hemizygous deletion clones provide a platform for investigating the contribution of individual endogenous retrovirus-derived elements to gene regulation in human preimplantation models. This method enables direct functional interrogation of species-specific non-coding regulatory sequences and supports the study of transcriptional mechanisms involved in early human development.

Humans↗
PubMed2001

[Interactions of fibroblasts, adipocytes and immunocompeent cells in the pathogenesis of endocrine ophthalmopathy].

Graves' ophthalmopathy is thought to result from a complex interplay of genetic and environmental factors. Various genes including those coding for HLA may determine a patient's susceptibility to the disease and its severity, but in addition numerous and often unknown environmental factors may determine its course. The orbital immune process is thought to be initiated, on the background of a permissive immunogenetic milieu, by circulating T cells directed against certain antigens on thyroid follicular cells that also recognize antigenic epitopes which are shared by tissues contained in the orbital space. Analysis of variable region genes of T cell antigen receptors in orbital T cells of patients with active Graves' ophthalmopathy has revealed limited variability of TcR V gene usage, suggesting that antigen-driven selection and/or expansion of specific T cells may occur during the early stages of Graves' ophthalmopathy. T cell recruitment into the orbital tissues is facilitated by certain chemokines and cytokines, which attract T cells by stimulating the expression of several adhesion molecules (e.g. ICAM-1, VCAM-1, CD44) in vascular endothelium and connective tissue cells. Adhesion molecules are known to be important for a variety of interactions between immunocompetent cells, preadipocyte fibroblasts and adipocytes. In addition, these molecules play a central role in lymphocyte activation and localization, facilitating antigen recognition, T cell costimulation, and various effector-target cell functions at the inflammatory sites, which result in amplification of the cellular immune process in active Graves' ophthalmopathy. T cells and macrophages populate the orbital space and release a number of cytokines (most likely a Th-1-type spectrum) into the surrounding tissues. Cytokines, oxygen free radicals and fibrogenic growth factors, released both from infiltrating inflammatory and residential cells, act upon orbital preadipocytes in a paracrine and autocrine manner to stimulate adipogenesis, fibroblast proliferation, glycosaminoglycan synthesis, and the expression of immunomodulatory molecules. Smoking, a well-known aggravating factor in Graves' ophthalmopathy, may aggravate tissue hypoxia and exert important immunomodulatory and pro-oxidant effects. Differentiation of orbital preadipocyte fibroblasts into mature adipocytes expressing increased levels of TSHR may also be driven by stimulation with circulating or locally produced cytokines or effectors. TSHR-directed autoantibodies or T cells may thus play a direct role promoting adipogenesis, glycosaminoglycan synthesis and expression of immunomodulatory proteins within the orbits. Once the net effect of these changes has come to increase the volume of the fatty connective tissues within the orbit, then proptosis, extraocular muscle dysfunction, and periorbital congestion will ensue.

Adipocytes↗
PubMedDate not supplied

[Clinical and genetic study of juvenile form of Huntington's disease].

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by high instability and extension of CAG sequences within the coding region of IT15 gene. It affects both sexes and age at onset of the disease may be different but usually occurs in midlife. The term Juvenile Huntington's disease is generally applied to 10% of the cases with onset before 20. We present clinical features and results of DNA analysis in 16 patients from 14 families aged 9 to 36. The age of onset was between 5 to 20 years; duration of the disease was from 2 to 16 years. In 10 cases the mutated gene was transmitted by the affected father; only in two cases by the mother. In all cases anticipation manifested by earlier onset of the disease in subsequent generations and expansion of CAG repeats was documented. The number of CAG repeats was between 50 and 92 (mean 67.3). Progressive mental deterioration, declining school performance, hyperactivity and emotional disturbances were the first symptoms of juvenile HD. Neuropsychological assessment showed mean IQ in Wechsler test 59.6 and Mini-Mental State Examination scores 22.8. Rigidity and bradykinesia were predominant features in the cases with juvenile onset, the remaining ones developed choreatic movements. Three persons had epileptic seizures; two (both females) revealed behaviour and psychiatric disturbances. Amplitudes of somatosensory evoked potentials, visual evoked potentials and brainstem auditory evoked potentials were markedly reduced. MRI of the brain showed atrophy of heads of the caudate nuclei, putamen and globus pallidus.

Adenine↗
PubMed2025

PhyClone: accurate Bayesian reconstruction of cancer phylogenies from bulk sequencing.

MOTIVATION: Cancer is driven by somatic mutations that result in the expansion of genomically distinct sub-populations of cells called clones. Identifying the clonal composition of tumours and understanding the evolutionary relationships between clones is a crucial task in cancer genomics. Bulk DNA sequencing is commonly used for studying the clonal composition of tumours, but it is challenging to infer the genetic relationship between different clones due to the mixture of different cell populations. RESULTS: In this work, we introduce a new probabilistic model called PhyClone that can infer clonal phylogenies from bulk-sequencing data. We demonstrate the performance of PhyClone on simulated and real-world datasets and show that it outperforms previous methods in terms of accuracy and sample scalability. AVAILABILITY AND IMPLEMENTATION: Source code is available on Github at: https://github.com/Roth-Lab/PhyClone under the GPL v3.0 license.

Neoplasms↗
PubMed1999

Triplet repeat disorders: discussion of molecular mechanisms.

Comparison of the growing number of disorders known to be associated with triplet repeat expansions reveals both common features and a diversity of molecular pathways. Despite significant progress towards the characterization of proteins coded by the mutant genes, the complex nature of these disorders requires identification of all molecular components of the triplet repeat pathways. In this brief review we will discuss recent progress in determining the molecular mechanisms of disorders with unstable trinucleotide mutations.

Animals↗
PubMed2003

Eukaryotic domain evolution inferred from genome comparisons.

Comparative analyses of eukaryotic genomes are providing insights into the mode and tempo of domain family evolution. Gene duplication, the source of family expansion, far exceeds the rate of emergence of domains from non-coding sequence, and the rate of recruitment of domains into novel architectures. Domain families that appear to be restricted to certain lineages are likely to be the result of gene duplication, coupled with rapid sequence diversification. If such families are evidence of past adaptation, then their functions must relate to the underlying mechanism of selection: competition among organisms.

Animals↗
PubMed2002

Tumor regression of human and murine melanoma after intratumoral injection of IL-12-encoding plasmid DNA in mice.

DNA coding for murine interleukin 12 (IL-12) prevents the formation of B16-melanoma metastasis when administered intramuscularly. Here, the antitumor effect of IL-12-encoding DNA on established mouse B16 melanoma and human melanoma tumors was investigated in vivo using two animal models: B16 melanoma in C57B/6 mice and human melanoma in nude mice. In B16 melanoma, intratumoral injections of IL-12-encoding DNA resulted in highly significant growth retardation when compared with mice injected with control vector. In the case of the human melanoma model, treatment with DNA coding for IL-12 induced regression of tumors in all cases, with complete disappearance of the tumor in two out of five animals. DNA treatment did not induce systemic side-effects. In the animals injected with control vector the human melanoma tumors grew expansively. The therapeutic effect of the DNA injection was mediated in part by natural killer (NK) cells as shown by NK-depletion experiments. An antivascular effect of IL-12 treatment was evident in histological examination with endothelial thickening and abrupt changes in vessel diameters. These results suggest that intratumoral plasmid DNA coding for IL-12 holds some promise as a new therapeutic tool for accessible melanoma lesions and should be tested in clinical trial.

Animals↗
PubMed2002

Skewed T-cell receptor repertoire, decreased thymic output, and predominance of terminally differentiated T cells in ataxia telangiectasia.

Ataxia telangiectasia (A-T), a genetic disorder caused by the homozygous mutation of the ATM gene, frequently associates with variable degrees of cellular and humoral immunodeficiency. However, the immune defects occurring in patients with A-T are still poorly characterized. Here we show that the T-cell receptor (TCR) variable beta (BV)-chain repertoire of 9 A-T patients was restricted by diffuse expansions of some variable genes prevalently occurring within the CD4 subset and clustering to certain TCRBV genes (eg, 5.1, 11, 14, and 23). In addition, the study of the third complementarity-determining region (CDR3) showed, in all patients, significantly altered profiles in most BV genes examined suggesting diffuse oligoclonal expansions. The sequencing of TCR CDR3 regions revealed completely normal V(D)J coding joints and confirmed a reduced diversity of the antigen-receptor repertoire. The B-cell repertoire was similarly restricted and skewed by diffuse oligoclonal expansions with normal V(D)J joints. Thymic output, evaluated by measuring TCR rearrangement excision circles, was extremely low. The majority of peripheral T cells had the phenotype and the function of effector memory cells, indicating that in vivo they are able to respond normally by terminal differentiation to antigenic stimulation. These results indicate that ATM mutation limits the generation of a wide repertoire of normally functioning T and B cells.

Adolescent↗