Search results for "MUTATION"
showing 10 items of 2830 documents
Highly heterogeneous mutation rates in the hepatitis C virus genome.
2016
Spontaneous mutations are the ultimate source of genetic variation and have a prominent role in evolution. RNA viruses such as hepatitis C virus (HCV) have extremely high mutation rates, but these rates have been inferred from a minute fraction of genome sites, limiting our view of how RNA viruses create diversity. Here, by applying high-fidelity ultradeep sequencing to a modified replicon system, we scored >15,000 spontaneous mutations, encompassing more than 90% of the HCV genome. This revealed >1,000-fold differences in mutability across genome sites, with extreme variations even between adjacent nucleotides. We identify base composition, the presence of high- and low-mutation clusters a…
Enhanced emergence of antibiotic-resistant pathogenic bacteria after in vitro induction with cancer chemotherapy drugs.
2019
International audience; BACKGROUND:Infections with antibiotic-resistant pathogens in cancer patients are a leading cause of mortality. Cancer patients are treated with compounds that can damage bacterial DNA, potentially triggering the SOS response, which in turn enhances the bacterial mutation rate. Antibiotic resistance readily occurs after mutation of bacterial core genes. Thus, we tested whether cancer chemotherapy drugs enhance the emergence of resistant mutants in commensal bacteria.METHODS:Induction of the SOS response was tested after the incubation of Escherichia coli biosensors with 39 chemotherapeutic drugs at therapeutic concentrations. The mutation frequency was assessed after …
Analysis of DNA Polymerases Reveals Specific Genes Expansion in Leishmania and Trypanosoma spp.
2020
Leishmaniasis and trypanosomiasis are largely neglected diseases prevailing in tropical and subtropical conditions. These are an arthropod-borne zoonosis that affects humans and some animals and is caused by infection with protozoan of the genera Leishmania and Trypanosoma, respectively. These parasites present high genomic plasticity and are able to adapt themselves to adverse conditions like the attack of host cells or toxicity induced by drug exposure. Different mechanisms allow these adapting responses induced by stress, such as mutation, chromosomal rearrangements, establishment of mosaic ploidies, and gene expansion. Here we describe how a subset of genes encoding for DNA polymerases …
C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation
2021
BACKGROUND. Deciphering the function of the many genes previously classified as uncharacterized open reading frame (ORF) would complete our understanding of a cell’s function and its pathophysiology. METHODS. Whole-exome sequencing, yeast 2-hybrid and transcriptome analyses, and molecular characterization were performed in this study to uncover the function of the C2orf69 gene. RESULTS. We identified loss-of-function mutations in the uncharacterized C2orf69 gene in 8 individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction, and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial…
Whole Exome Sequencing Is the Preferred Strategy to Identify the Genetic Defect in Patients With a Probable or Possible Mitochondrial Cause
2018
Mitochondrial disorders, characterized by clinical symptoms and/or OXPHOS deficiencies, are caused by pathogenic variants in mitochondrial genes. However, pathogenic variants in some of these genes can lead to clinical manifestations which overlap with other neuromuscular diseases, which can be caused by pathogenic variants in non-mitochondrial genes as well. Mitochondrial pathogenic variants can be found in the mitochondrial DNA (mtDNA) or in any of the 1,500 nuclear genes with a mitochondrial function. We have performed a two-step next-generation sequencing approach in a cohort of 117 patients, mostly children, in whom a mitochondrial disease-cause could likely or possibly explain the phe…
Revisiting the pH-gated conformational switch on the activities of HisKA-family histidine kinases
2020
13 páginas, 6 figuras, 3 tablas
Rescuing the CFTR protein function: Introducing 1,3,4-oxadiazoles as translational readthrough inducing drugs.
2018
Nonsense mutations in the CFTR gene prematurely terminate translation of the CFTR mRNA leading to the production of a truncated protein that lacks normal function causing a more severe form of the cystic fibrosis (CF) disease. About 10% of patients affected by CF show a nonsense mutation. A potential treatment of this alteration is to promote translational readthrough of premature termination codons (PTCs) by Translational Readthrough Inducing Drugs (TRIDs) such as PTC124. In this context we aimed to compare the activity of PTC124 with analogues differing in the heteroatoms position in the central heterocyclic core. By a validated protocol consisting of computational screening, synthesis an…
High-Pressure-Driven Reversible Dissociation of α-Synuclein Fibrils Reveals Structural Hierarchy
2017
The analysis of the α-synuclein (aS) aggregation process, which is involved in Parkinson's disease etiopathogenesis, and of the structural feature of the resulting amyloid fibrils may shed light on the relationship between the structure of aS aggregates and their toxicity. This may be considered a paradigm of the ground work needed to tackle the molecular basis of all the protein-aggregation-related diseases. With this aim, we used chemical and physical dissociation methods to explore the structural organization of wild-type aS fibrils. High pressure (in the kbar range) and alkaline pH were used to disassemble fibrils to collect information on the hierarchic pathway by which distinct β-sh…
Structure of AP205 Coat Protein Reveals Circular Permutation in ssRNA Bacteriophages.
2016
We are thankful to the MAX-lab staff for their support during our visit at the synchrotron.; International audience; AP205 is a single-stranded RNA bacteriophage that has a coat protein sequence not similar to any other known single-stranded RNA phage. Here, we report an atomic-resolution model of the AP205 virus-like particle based on a crystal structure of an unassembled coat protein dimer and a cryo-electron microscopy reconstruction of the assembled particle, together with secondary structure information from site-specific solid-state NMR data. The AP205 coat protein dimer adopts the conserved Leviviridae coat protein fold except for the N-terminal region, which forms a beta-hairpin in …
Ursolic acid enhances stress resistance, reduces ROS accumulation and prolongs life span in C. elegans serotonin-deficient mutants.
2021
Introduction: Depression and anxiety disorders contribute to the global disease burden. Ursolic acid (UA), a natural compound present in many vegetables, fruits and medicinal plants, was tested in vivo for its effect on (1) enhancing resistance to stress and (2) its effect on life span. Methods: The compound was tested for its antioxidant activity in C. elegans. Stress resistance was tested in the heat and osmotic stress assay. Additionally, the influence on normal life span was examined. RT-PCR was used to assess possible serotonin targets. Results: UA prolonged the life span of C. elegans. Additionally, UA significantly lowered reactive oxygen species (ROS). Molecular docking studies, PCR…