Large scale isolation of maternally inherited lincomycin resistance mutations, in diploid Nicotiana plumbaginifolia protoplast cultures

1984 ◽  
Vol 196 (3) ◽  
pp. 407-412 ◽  
Author(s):  
Ágnes Cséplő ◽  
Pál Maliga
Keyword(s):  
Large Scale ◽  
Nicotiana Plumbaginifolia ◽  
Resistance Mutations ◽  
Lincomycin Resistance

scholarly journals MiDRMpol: A High-Throughput Multiplexed Amplicon Sequencing Workflow to Quantify HIV-1 Drug Resistance Mutations against Protease, Reverse Transcriptase, and Integrase Inhibitors

Viruses ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 806
Author(s):  
Shambhu G. Aralaguppe ◽  
Anoop T. Ambikan ◽  
Manickam Ashokkumar ◽  
Milner M. Kumar ◽  
Luke Elizabeth Hanna ◽  
...  
Keyword(s):  
Drug Resistance ◽  
High Throughput ◽  
Large Scale ◽  
High Throughput Sequencing ◽  
Polymorphism Analysis ◽  
Resistance Mutations ◽  
Subtype C ◽  
Bioinformatics Pipeline ◽  
Drug Resistance Mutations ◽  
Hiv 1

The detection of drug resistance mutations (DRMs) in minor viral populations is of potential clinical importance. However, sophisticated computational infrastructure and competence for analysis of high-throughput sequencing (HTS) data lack at most diagnostic laboratories. Thus, we have proposed a new pipeline, MiDRMpol, to quantify DRM from the HIV-1 pol region. The gag-vpu region of 87 plasma samples from HIV-infected individuals from three cohorts was amplified and sequenced by Illumina HiSeq2500. The sequence reads were adapter-trimmed, followed by analysis using in-house scripts. Samples from Swedish and Ethiopian cohorts were also sequenced by Sanger sequencing. The pipeline was validated against the online tool PASeq (Polymorphism Analysis by Sequencing). Based on an error rate of <1%, a value of >1% was set as reliable to consider a minor variant. Both pipelines detected the mutations in the dominant viral populations, while discrepancies were observed in minor viral populations. In five HIV-1 subtype C samples, minor mutations were detected at the <5% level by MiDRMpol but not by PASeq. MiDRMpol is a computationally as well as labor efficient bioinformatics pipeline for the detection of DRM from HTS data. It identifies minor viral populations (<20%) of DRMs. Our method can be incorporated into large-scale surveillance of HIV-1 DRM.

scholarly journals Evolution of the Insecticide Target Rdl in African Anopheles Is Driven by Interspecific and Interkaryotypic Introgression

2020 ◽  
Vol 37 (10) ◽  
pp. 2900-2917 ◽  
Author(s):  
Xavier Grau-Bové ◽  
Sean Tomlinson ◽  
Andrias O O’Reilly ◽  
Nicholas J Harding ◽  
Alistair Miles ◽  
...  
Keyword(s):  
Large Scale ◽  
Sequence Data ◽  
Management Strategies ◽  
Natural Populations ◽  
Resistance Mechanisms ◽  
Health Concern ◽  
Malaria Vectors ◽  
Resistance Mutations ◽  
Development Of Resistance ◽  
Evolution Of Resistance

Abstract The evolution of insecticide resistance mechanisms in natural populations of Anopheles malaria vectors is a major public health concern across Africa. Using genome sequence data, we study the evolution of resistance mutations in the resistance to dieldrin locus (Rdl), a GABA receptor targeted by several insecticides, but most notably by the long-discontinued cyclodiene, dieldrin. The two Rdl resistance mutations (296G and 296S) spread across West and Central African Anopheles via two independent hard selective sweeps that included likely compensatory nearby mutations, and were followed by a rare combination of introgression across species (from A. gambiae and A. arabiensis to A. coluzzii) and across nonconcordant karyotypes of the 2La chromosomal inversion. Rdl resistance evolved in the 1950s as the first known adaptation to a large-scale insecticide-based intervention, but the evolutionary lessons from this system highlight contemporary and future dangers for management strategies designed to combat development of resistance in malaria vectors.

scholarly journals Evolution of the insecticide target Rdl in African Anopheles is driven by interspecific and interkaryotypic introgression

2019 ◽  
Author(s):  
Xavier Grau-Bové ◽  
Sean Tomlinson ◽  
Andrias O. O’Reilly ◽  
Nicholas J. Harding ◽  
Alistair Miles ◽  
...  
Keyword(s):  
Large Scale ◽  
Sequence Data ◽  
Management Strategies ◽  
Natural Populations ◽  
Resistance Mechanisms ◽  
Health Concern ◽  
Malaria Vectors ◽  
Resistance Mutations ◽  
Development Of Resistance ◽  
Evolution Of Resistance

AbstractThe evolution of insecticide resistance mechanisms in natural populations of Anopheles malaria vectors is a major public health concern across Africa. Using genome sequence data, we study the evolution of resistance mutations in the resistance to dieldrin locus (Rdl), a GABA receptor targeted by several insecticides, but most notably by the long-discontinued cyclodiene, dieldrin. The two Rdl resistance mutations (296G and 296S) spread across West and Central African Anopheles via two independent hard selective sweeps that included likely compensatory nearby mutations, and were followed by a rare combination of introgression across species (from A. gambiae and A. arabiensis to A. coluzzii) and across non-concordant karyotypes of the 2La chromosomal inversion. Rdl resistance evolved in the 1950s as the first known adaptation to a large-scale insecticide-based intervention, but the evolutionary lessons from this system highlight contemporary and future dangers for management strategies designed to combat development of resistance in malaria vectors.

scholarly journals Landscape of drug-resistance mutations in kinase regulatory hotspots

2020 ◽  
Author(s):  
Pora Kim ◽  
Hanyang Li ◽  
Junmei Wang ◽  
Zhongming Zhao
Keyword(s):  
Drug Resistance ◽  
Large Scale ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Systematic Investigation ◽  
Drug Binding ◽  
Data Sets ◽  
Resistance Mutations ◽  
Cancer Data

Abstract More than 48 kinase inhibitors (KIs) have been approved by Food and Drug Administration. However, drug-resistance (DR) eventually occurs, and secondary mutations have been found in the previously targeted primary-mutated cancer cells. Cancer and drug research communities recognize the importance of the kinase domain (KD) mutations for kinasopathies. So far, a systematic investigation of kinase mutations on DR hotspots has not been done yet. In this study, we systematically investigated four types of representative mutation hotspots (gatekeeper, G-loop, αC-helix and A-loop) associated with DR in 538 human protein kinases using large-scale cancer data sets (TCGA, ICGC, COSMIC and GDSC). Our results revealed 358 kinases harboring 3318 mutations that covered 702 drug resistance hotspot residues. Among them, 197 kinases had multiple genetic variants on each residue. We further computationally assessed and validated the epidermal growth factor receptor mutations on protein structure and drug-binding efficacy. This is the first study to provide a landscape view of DR-associated mutation hotspots in kinase’s secondary structures, and its knowledge will help the development of effective next-generation KIs for better precision medicine.

scholarly journals Population Genetics Study of Isoniazid Resistance Mutations and Evolution of Multidrug-Resistant Mycobacterium tuberculosis

2006 ◽  
Vol 50 (8) ◽  
pp. 2640-2649 ◽  
Author(s):  
Manzour Hernando Hazbón ◽  
Michael Brimacombe ◽  
Miriam Bobadilla del Valle ◽  
Magali Cavatore ◽  
Marta Inírida Guerrero ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Large Scale ◽  
Sample Selection ◽  
Multidrug Resistant ◽  
Small Sample ◽  
Inverse Association ◽  
Resistance Mutations ◽  
Isoniazid Resistance ◽  
Large Scale Analysis ◽  
Small Sample Sizes

ABSTRACT The molecular basis for isoniazid resistance in Mycobacterium tuberculosis is complex. Putative isoniazid resistance mutations have been identified in katG, ahpC, inhA, kasA, and ndh. However, small sample sizes and related potential biases in sample selection have precluded the development of statistically valid and significant population genetic analyses of clinical isoniazid resistance. We present the first large-scale analysis of 240 alleles previously associated with isoniazid resistance in a diverse set of 608 isoniazid-susceptible and 403 isoniazid-resistant clinical M. tuberculosis isolates. We detected 12 mutant alleles in isoniazid-susceptible isolates, suggesting that these alleles are not involved in isoniazid resistance. However, mutations in katG, ahpC, and inhA were strongly associated with isoniazid resistance, while kasA mutations were associated with isoniazid susceptibility. Remarkably, the distribution of isoniazid resistance-associated mutations was different in isoniazid-monoresistant isolates from that in multidrug-resistant isolates, with significantly fewer isoniazid resistance mutations in the isoniazid-monoresistant group. Mutations in katG315 were significantly more common in the multidrug-resistant isolates. Conversely, mutations in the inhA promoter were significantly more common in isoniazid-monoresistant isolates. We tested for interactions among mutations and resistance to different drugs. Mutations in katG, ahpC, and inhA were associated with rifampin resistance, but only katG315 mutations were associated with ethambutol resistance. There was also a significant inverse association between katG315 mutations and mutations in ahpC or inhA and between mutations in kasA and mutations in ahpC. Our results suggest that isoniazid resistance and the evolution of multidrug-resistant strains are complex dynamic processes that may be influenced by interactions between genes and drug-resistant phenotypes.

scholarly journals PremPLI: a machine learning model for predicting the effects of missense mutations on protein-ligand interactions

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Tingting Sun ◽  
Yuting Chen ◽  
Yuhao Wen ◽  
Zefeng Zhu ◽  
Minghui Li
Keyword(s):  
Machine Learning ◽  
Ligand Binding ◽  
Binding Affinity ◽  
Large Scale ◽  
Predictive Accuracy ◽  
Predictive Performance ◽  
Driver Mutations ◽  
Missense Mutations ◽  
Resistance Mutations ◽  
Benchmark Datasets

AbstractResistance to small-molecule drugs is the main cause of the failure of therapeutic drugs in clinical practice. Missense mutations altering the binding of ligands to proteins are one of the critical mechanisms that result in genetic disease and drug resistance. Computational methods have made a lot of progress for predicting binding affinity changes and identifying resistance mutations, but their prediction accuracy and speed are still not satisfied and need to be further improved. To address these issues, we introduce a structure-based machine learning method for quantitatively estimating the effects of single mutations on ligand binding affinity changes (named as PremPLI). A comprehensive comparison of the predictive performance of PremPLI with other available methods on two benchmark datasets confirms that our approach performs robustly and presents similar or even higher predictive accuracy than the approaches relying on first-principle statistical mechanics and mixed physics- and knowledge-based potentials while requires much less computational resources. PremPLI can be used for guiding the design of ligand-binding proteins, identifying and understanding disease driver mutations, and finding potential resistance mutations for different drugs. PremPLI is freely available at https://lilab.jysw.suda.edu.cn/research/PremPLI/ and allows to do large-scale mutational scanning.

scholarly journals ABSENCE OF DETECTABLE MITOCHONDRIAL RECOMBINATION IN PARAMECIUM

Genetics ◽  
1979 ◽  
Vol 93 (4) ◽  
pp. 797-831
Author(s):  
André Adoutte ◽  
Jonathan K Knowles ◽  
Annie Sainsard-Chanet
Keyword(s):  
Antibiotic Resistance ◽  
Large Scale ◽  
Nuclear Gene ◽  
Paramecium Tetraurelia ◽  
Wild Type ◽  
Resistance Mutations ◽  
Mitochondrial Recombination ◽  
Mitochondrial Ribosomes ◽  
Molecular Alterations ◽  
Resistance Markers

ABSTRACT An extensive search for recombination between mitochondrial markers was carried out in Paramecium tetraurelia. Thirty-two combinations, altogether involving 24 different markers, were studied. The markers belonged to the three main categories of mitochondrial mutations presently available in this organism. (a) Spontaneous or UV-induced antibiotic resistance mutations, most probably affecting mitochondrial ribosomes, (b) nitrowguanidine-induced antibiotic resistance markers displaying thermosensitivity or slow growth, enabling easy selection of possible wild-type recombinants, and (c) mitochondrial partial suppressors of a nuclear gene, probably corresponding to molecular alterations distinct from the preceding two categories. In addition, different genetic configurations were analyzed (i e., mutant x mutant, double-mutant x wild-type, etc.).——None of the combinations yielded any evidence for the occurrence of recombined genomes despite the fact that: (1) all of them were studied on a large scale involving the screening of at least several thousand mitochondrial genomes (often several millions), (2) in many of them the detection level was sufficiently high to enable the isolation of spontaneous mutants in control cells, and (3) in several of them, reconstitution experiments carried out in parallel show that the conditions were fully adequate to detect recombinant genotypes. The results are in marked contrast with those obtained on the few other organisms in which mitochondrial recombination has been studied, particularly Saccharomyces cerevisiae, in which mitochondrial recombination is intense.——The most likely basis for the various manifestations of mitochondrial genetic autonomy in Paramecium, described in this as well as in previous publications, is that the chondriome of this organism is made up of thousands of structurally discrete, noninteracting units.

scholarly journals Lincomycin Resistance Mutations in Two Regions Immediately Downstream of the −10 Region of lmr Promoter Cause Overexpression of a Putative Multidrug Efflux Pump in Bacillus subtilis Mutants

2003 ◽  
Vol 47 (1) ◽  
pp. 432-435 ◽  
Author(s):  
Miyuki Kumano ◽  
Masaya Fujita ◽  
Kouji Nakamura ◽  
Makiko Murata ◽  
Reiko Ohki ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Efflux Pump ◽  
Resistance Mutations ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Lincomycin Resistance

ABSTRACT We isolated 19 lincomycin-resistant Bacillus subtilis mutants by expressing lmrB encoding a putative multidrug efflux protein. Eighteen of the mutants altered at two regions (−3 to −1 and +15) immediately downstream of the −10 region of the lmr promoter increased lmr transcription in vivo and in vitro.

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