Population analysis, mutant prevention concentrations and characterization of resistance mutations to novel beta-lactams in wild-type, mutator, and high-risk clones of Pseudomonas aeruginosa
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ABSTRACT:
PROVIDER: PRJEB78485 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR13431700_1.fastq.gz | Fastqsanger.gz | |||
| ERR13431700_2.fastq.gz | Fastqsanger.gz | |||
| ERR13432200_1.fastq.gz | Fastqsanger.gz | |||
| ERR13432200_2.fastq.gz | Fastqsanger.gz | |||
| ERR13432400_1.fastq.gz | Fastqsanger.gz |
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Project description:Serogroup A Neisseria meningitidis has repeatedly caused widespread epidemics of meningitis and septicemia throughout the 20th century. Recently, in a limited collection of strains, epidemic serogroup A isolates were found to have elevated mutation rates that was caused by defects in mismatch repair pathways. To ascertain the role of these mutators in the epidemic spread of this serogroup, the prevalence of hypermutability in a collection of 95 serogroup A N. meningitidis invasive isolates was determined. Overall mutability in Neisseriae can be described by measuring both missense mutation rates as well as phase variation frequencies of "contingency loci." Fifty-seven percent of serogroup A isolates possessed elevated mutability, which could be divided into two classes: intermediate and high level. Eleven of 20 high-level mutators, with phase variation rates >100-fold higher than wild-type isolates, were defective in mismatch repair. Ten of the 34 intermediate mutators possessing >10-fold increases in phase variation rates could be partially complemented by a wild-type mutL allele. A high prevalence of mutators in epidemic isolates indicates that hypermutability may play a major role in the transmission of this pathogen. The added diversity derived from increased phase variation rates may allow fixation of mutator alleles more frequently during epidemic spread.
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Project description:BACKGROUND: Tumorigenesis requires multiple genetic changes. Mutator mutations are mutations that increase genomic instability, and according to the mutator hypothesis, accelerate tumorigenesis by facilitating oncogenic mutations. Alternatively, repeated lineage selection and expansion without increased mutation frequency may explain observed cancer incidence. Mutator lineages also risk increased deleterious mutations, leading to extinction, thus providing another counterargument to the mutator hypothesis. Both selection and extinction involve changes in lineage fitness, which may be represented as "trajectories" through a "fitness landscape" defined by genetics and environment. METHODOLOGY/PRINCIPAL FINDINGS: Here I systematically analyze the relative efficiency of tumorigenesis with and without mutator mutations by evaluating archetypal fitness trajectories using deterministic and stochastic mathematical models. I hypothesize that tumorigenic mechanisms occur clinically in proportion to their relative efficiency. This work quantifies the relative importance of mutator pathways as a function of experimentally measurable parameters, demonstrating that mutator pathways generally enhance efficiency of tumorigenesis. An optimal mutation rate for tumor evolution is derived, and shown to differ from that for species evolution. CONCLUSIONS/SIGNIFICANCE: The models address the major counterarguments to the mutator hypothesis, confirming that mutator mechanisms are generally more efficient routes to tumorigenesis than non-mutator mechanisms. Mutator mutations are more likely to occur early, and to occur when more oncogenic mutations are required to create a tumor. Mutator mutations likely occur in a minority of premalignant lesions, but these mutator premalignant lesions are disproportionately likely to develop into malignant tumors. Tumor heterogeneity due to mutator mutations may contribute to therapeutic resistance, and the degree of heterogeneity of tumors may need to be considered when therapeutic strategies are devised. The model explains and predicts important biological observations in bacterial and mouse systems, as well as clinical observations.
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Project description:Comparison of one-step and two-step PCR for 16S Illumina MiSeq
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Project description:Comparison of one-step and two-step PCR for 16S Illumina MiSeq
| PRJEB48796 | ENA
Project description:BackgroundHuman genetic disorders and transgenic mouse models have shown that mitochondrial DNA (mtDNA) mutations and telomere dysfunction instigate the aging process. Epidemiologically, exercise is associated with greater life expectancy and reduced risk of chronic diseases. While the beneficial effects of exercise are well established, the molecular mechanisms instigating these observations remain unclear.ResultsEndurance exercise reduces mtDNA mutation burden, alleviates multisystem pathology, and increases lifespan of the mutator mice, with proofreading deficient mitochondrial polymerase gamma (POLG1). We report evidence for a POLG1-independent mtDNA repair pathway mediated by exercise, a surprising notion as POLG1 is canonically considered to be the sole mtDNA repair enzyme. Here, we show that the tumor suppressor protein p53 translocates to mitochondria and facilitates mtDNA mutation repair and mitochondrial biogenesis in response to endurance exercise. Indeed, in mutator mice with muscle-specific deletion of p53, exercise failed to prevent mtDNA mutations, induce mitochondrial biogenesis, preserve mitochondrial morphology, reverse sarcopenia, or mitigate premature mortality.ConclusionsOur data establish a new role for p53 in exercise-mediated maintenance of the mtDNA genome and present mitochondrially targeted p53 as a novel therapeutic modality for diseases of mitochondrial etiology.
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Project description:The barley chloroplast mutator (cpm) is an allele of a nuclear gene that when homozygous induces several types of cytoplasmically inherited chlorophyll deficiencies. In this work, a plastome Targeting Induced Local Lesions in Genomes (TILLING) strategy based on mismatch digestion was used on families that carried the cpm genotype through many generations. Extensive scanning of 33 plastome genes and a few intergenic regions was conducted. Numerous polymorphisms were detected on both genic and intergenic regions. The detected polymorphisms can be accounted for by at least 61 independent mutational events. The vast majority of the polymorphisms originated in substitutions and small indels (insertions/deletions) in microsatellites. The rpl23 and the rps16 genes were the most polymorphic. Interestingly, the variation observed in the rpl23 gene consisted of several combinations of 5 different one nucleotide polymorphisms. Besides, 4 large indels that have direct repeats at both ends were also observed, which appear to be originated from recombinational events. The cpm mutation spectrum suggests that the CPM gene product is probably involved in plastome mismatch repair. The numerous subtle molecular changes that were localized in a wide range of plastome sites show the cpm as a valuable source of plastome variability for plant research and/or plant breeding. Moreover, the cpm mutant appears to be an interesting experimental material for investigating the mechanisms responsible for maintaining the stability of plant organelle DNA.
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Project description:BackgroundRecent developments in high-throughput genomic technologies make it possible to have a comprehensive view of genomic alterations in tumors on a whole genome scale. Only a small number of somatic alterations detected in tumor genomes are driver alterations which drive tumorigenesis. Most of the somatic alterations are passengers that are neutral to tumor cell selection. Although most research efforts are focused on analyzing driver alterations, the passenger alterations also provide valuable information about the history of tumor development.ResultsIn this paper, we develop a method for estimating the age of the tumor lineage and the timing of the driver alterations based on the number of passenger alterations. This method also identifies mutator genes which increase genomic instability when they are altered and provides estimates of the increased rate of alterations caused by each mutator gene. We applied this method to copy number data and DNA sequencing data for ovarian and lung tumors. We identified well known mutators such as TP53, PRKDC, BRCA1/2 as well as new mutator candidates PPP2R2A and the chromosomal region 22q13.33. We found that most mutator genes alter early during tumorigenesis and were able to estimate the age of individual tumor lineage in cell generations.ConclusionsThis is the first computational method to identify mutator genes and to take into account the increase of the alteration rate by mutator genes, providing more accurate estimates of the tumor age and the timing of driver alterations.
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