scholarly journals From Global to Local—New Insights into Features of Pyrethroid Detoxification in Vector Mosquitoes

Insects ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 276
Author(s):  
William C. Black ◽  
Trey K. Snell ◽  
Karla Saavedra-Rodriguez ◽  
Rebekah C. Kading ◽  
Corey L. Campbell
Keyword(s):  
Pyrethroid Resistance ◽  
Regulation Of Gene Expression ◽  
Gene Copy Number ◽  
Resistance Mechanisms ◽  
Gene Copy ◽  
Tropical Regions ◽  
New Genes ◽  
Oxidation Reduction ◽  
Cellular Pathways ◽  
Post Transcriptional Regulation

The threat of mosquito-borne diseases continues to be a problem for public health in subtropical and tropical regions of the world; in response, there has been increased use of adulticidal insecticides, such as pyrethroids, in human habitation areas over the last thirty years. As a result, the prevalence of pyrethroid-resistant genetic markers in natural mosquito populations has increased at an alarming rate. This review details recent advances in the understanding of specific mechanisms associated with pyrethroid resistance, with emphasis on features of insecticide detoxification and the interdependence of multiple cellular pathways. Together, these advances add important context to the understanding of the processes that are selected in resistant mosquitoes. Specifically, before pyrethroids bind to their targets on motoneurons, they must first permeate the outer cuticle and diffuse to inner tissues. Resistant mosquitoes have evolved detoxification mechanisms that rely on cytochrome P450s (CYP), esterases, carboxyesterases, and other oxidation/reduction (redox) components to effectively detoxify pyrethroids to nontoxic breakdown products that are then excreted. Enhanced resistance mechanisms have evolved to include alteration of gene copy number, transcriptional and post-transcriptional regulation of gene expression, as well as changes to cellular signaling mechanisms. Here, we outline the variety of ways in which detoxification has been selected in various mosquito populations, as well as key gene categories involved. Pathways associated with potential new genes of interest are proposed. Consideration of multiple cellular pathways could provide opportunities for development of new insecticides.

Evolutionary Trajectories toward Ceftazidime-Avibactam Resistance in Klebsiella pneumoniae Clinical Isolates

2021 ◽  
Author(s):  
Alessandra Carattoli ◽  
Gabriele Arcari ◽  
Giulia Bibbolino ◽  
Federica Sacco ◽  
Dario Tomolillo ◽  
...  
Keyword(s):  
High Risk ◽  
Klebsiella Pneumoniae ◽  
Copy Number ◽  
Residual Activity ◽  
Gene Copy Number ◽  
Resistance Mechanisms ◽  
University Hospital ◽  
Gene Copy ◽  
Carbapenemase Gene ◽  
Evolutionary Trajectories

From January 2019 to April 2020, 32 KPC-producing, ceftazidime-avibactam (CZA) resistant Klebsiella pneumoniae strains were isolated in a university hospital in Rome, Italy. These strains belonged to the ST512, ST101 and ST307 high-risk clones. Nine different CZA-resistant KPC-3 protein variants were identified, five of them never previously reported (KPC-66 to KPC-70). Among them, KPC-31, KPC-39, KPC-49, KPC-66, KP-68, KPC-69 and KPC-70 showed amino acid substitutions, insertions and deletions in the Ω loop of the protein. KPC-29 has the duplication, while the novel KPC-67 has the triplication of the KDD triplet in the 270-loop of the protein. Genomics performed on contemporary resistant and susceptible clones underlined that those novel mutations emerged in bla KPC-3 genes located on conserved plasmids: in ST512, all bla KPC-3 mutant genes were located in pKpQIL plasmids, while the three novel bla KPC-3 mutants identified in ST101 were on FIIk-FIA(HI1)-R plasmids. Selection also promoted multiplication of the carbapenemase gene copy number by transposition, recombination, and fusion of resident plasmids. When expressed in Escherichia coli recipient cells cloned in the high-copy number pTOPO vector, the Ω loop mutated variants showed CZA-resistant phenotype associated with susceptibility to carbapenems, while KPC variants with insertions in the 270-loop showed residual activity on carbapenems. The investigation of CZA-resistance mechanisms offered the unique opportunity to study vertical, horizontal, and oblique evolutionary trajectories of K. pneumoniae high-risk clones.

scholarly journals CG gene body DNA methylation changes and evolution of duplicated genes in cassava

2015 ◽  
Vol 112 (44) ◽  
pp. 13729-13734 ◽  
Author(s):  
Haifeng Wang ◽  
Getu Beyene ◽  
Jixian Zhai ◽  
Suhua Feng ◽  
Noah Fahlgren ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Expression Patterns ◽  
Regulation Of Gene Expression ◽  
Gene Copy ◽  
Gene Body ◽  
Duplicated Genes ◽  
Gene Body Methylation ◽  
Substantial Impact ◽  
Tropical Regions

DNA methylation is important for the regulation of gene expression and the silencing of transposons in plants. Here we present genome-wide methylation patterns at single-base pair resolution for cassava (Manihot esculenta, cultivar TME 7), a crop with a substantial impact in the agriculture of subtropical and tropical regions. On average, DNA methylation levels were higher in all three DNA sequence contexts (CG, CHG, and CHH, where H equals A, T, or C) than those of the most well-studied model plant Arabidopsis thaliana. As in other plants, DNA methylation was found both on transposons and in the transcribed regions (bodies) of many genes. Consistent with these patterns, at least one cassava gene copy of all of the known components of Arabidopsis DNA methylation pathways was identified. Methylation of LTR transposons (GYPSY and COPIA) was found to be unusually high compared with other types of transposons, suggesting that the control of the activity of these two types of transposons may be especially important. Analysis of duplicated gene pairs resulting from whole-genome duplication showed that gene body DNA methylation and gene expression levels have coevolved over short evolutionary time scales, reinforcing the positive relationship between gene body methylation and high levels of gene expression. Duplicated genes with the most divergent gene body methylation and expression patterns were found to have distinct biological functions and may have been under natural or human selection for cassava traits.

scholarly journals Collateral Toxicity Limits the Evolution of Bacterial Release Factor 2 toward Total Omnipotence

2020 ◽  
Vol 37 (10) ◽  
pp. 2918-2930
Author(s):  
Hind Abdalaal ◽  
Shreya Pundir ◽  
Xueliang Ge ◽  
Suparna Sanyal ◽  
Joakim Näsvall
Keyword(s):  
Copy Number ◽  
Gene Evolution ◽  
Gene Copy Number ◽  
In Vitro Translation ◽  
Gene Copy ◽  
Release Factor ◽  
Bacterial Growth Rate ◽  
New Genes ◽  
Peptide Release

Abstract When new genes evolve through modification of existing genes, there are often tradeoffs between the new and original functions, making gene duplication and amplification necessary to buffer deleterious effects on the original function. We have used experimental evolution of a bacterial strain lacking peptide release factor 1 (RF1) in order to study how peptide release factor 2 (RF2) evolves to compensate the loss of RF1. As expected, amplification of the RF2-encoding gene prfB to high copy number was a rapid initial response, followed by the appearance of mutations in RF2 and other components of the translation machinery. Characterization of the evolved RF2 variants by their effects on bacterial growth rate, reporter gene expression, and in vitro translation termination reveals a complex picture of reduced discrimination between the cognate and near-cognate stop codons and highlights a functional tradeoff that we term “collateral toxicity.” We suggest that this type of tradeoff may be a more serious obstacle in new gene evolution than the more commonly discussed evolutionary tradeoffs between “old” and “new” functions of a gene, as it cannot be overcome by gene copy number changes. Further, we suggest a model for how RF2 autoregulation responds to alterations in the demand not only for RF2 activity but also for RF1 activity.

scholarly journals Functional interactions between unlinked muscle genes within haploinsufficient regions of the Drosophila genome.

Genetics ◽  
1988 ◽  
Vol 119 (1) ◽  
pp. 105-121
Author(s):  
T Homyk ◽  
C P Emerson
Keyword(s):  
Muscle Development ◽  
Gene Copy Number ◽  
Large Family ◽  
Mutant Gene ◽  
Genetic Interactions ◽  
Gene Copy ◽  
Drosophila Genome ◽  
Gene Products ◽  
New Genes ◽  
Allele Specific

Abstract Mutations in 13 genes affecting muscle development in Drosophila have been examined in pairwise combinations for evidence of genetic interactions. Heterozygous combinations of mutations in five genes, including the gene coding for myosin heavy chain, result in more severe phenotypes than respective single heterozygous mutant controls. The various mutant interactions include examples showing allele-specific intergenic interactions, gene specific interactions, and allele-specific intragenic complementations, suggesting that some interactions result from the manner in which mutant gene products associate. Interactions that result from alterations in "+" gene copy number were also uncovered, suggesting that normal myofibril development requires that the relative amounts of respective gene products produced be tightly regulated. The importance of the latter parameter is substantiated by the finding that all five interacting loci map to disperse haploinsufficient or haplolethal regions of the genome. The implications of the present findings are discussed in relation to pursuing the phenomena involving genetic interactions to identify new genes encoding interacting myofibrillar proteins, to examine the nature of intermolecular interactions in mutant and normal development and to decipher the quantitative and temporal regulation of a large family of functionally related gene products.

scholarly journals Meropenem-Vaborbactam Resistance Selection, Resistance Prevention, and Molecular Mechanisms in Mutants of KPC-Producing Klebsiella pneumoniae

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Dongxu Sun ◽  
Debora Rubio-Aparicio ◽  
Kirk Nelson ◽  
Michael N. Dudley ◽  
Olga Lomovskaya
Keyword(s):  
Klebsiella Pneumoniae ◽  
Copy Number ◽  
Molecular Mechanisms ◽  
Resistance Mutation ◽  
Gene Copy Number ◽  
Resistance Mechanisms ◽  
Gene Copy ◽  
Coding Region ◽  
Content Type ◽  
Drug Concentrations

ABSTRACT Vaborbactam (formerly RPX7009) is a new β-lactamase inhibitor based on a cyclic boronic acid pharmacophore with potent inhibitory activity against Klebsiella pneumoniae carbapenemases (KPC). It has been developed in combination with meropenem. The objective of these studies was to identify the concentrations of both agents associated with the selection or prevention of single-step mutations leading to reduced sensitivity to the combination and to characterize the selected mutations. Eighteen strains of KPC-producing Klebsiella pneumoniae with various degrees of sensitivity to meropenem (MICs, 8 to 512 μg/ml) and meropenem-vaborbactam (MICs, ≤0.06 to 32 μg/ml) and preexisting resistance mechanisms were selected from a worldwide collection of isolates recovered from surveillance studies, emphasizing strains for which MICs were in the upper range of the meropenem-vaborbactam MIC distribution. Meropenem and vaborbactam at 8 μg/ml each suppressed the drug resistance mutation frequency to <1 × 10−8 in 77.8% (14/18) of strains, and all strains were inhibited when the meropenem concentration was increased to 16 μg/ml. Mutants selected at lower drug concentrations showed phenotypes associated with previously described carbapenem resistance mechanisms, including ompK36 inactivation in mutants selected from OmpK36-proficient strains and an increased bla KPC gene copy number in strains with partially functional ompK36. No mutations in the coding region of bla KPC were identified. These data indicate that the selection of mutants with reduced sensitivity to meropenem-vaborbactam from KPC-producing Klebsiella pneumoniae strains is associated with previously described mechanisms involving porin mutations and the increase in the bla KPC gene copy number and not changes in the KPC enzyme and can be prevented by the drug concentrations achieved with optimal dosing of the combination.

scholarly journals Understanding Resistance Mechanisms to Trifluralin in an Arkansas Palmer Amaranth Population

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1225
Author(s):  
Fidel González-Torralva ◽  
Jason K. Norsworthy
Keyword(s):  
Root Length ◽  
Resistance Mechanism ◽  
Gene Copy Number ◽  
Resistance Mechanisms ◽  
Palmer Amaranth ◽  
Gene Copy ◽  
Nucleotide Polymorphisms ◽  
Weed Species ◽  
Tubulin Genes ◽  
Β Tubulin

Amaranthus palmeri S. Watson (Palmer amaranth) is considered a problematic and troublesome weed species in many crops in the USA, partly because of its ability to evolve resistance to herbicides. In this study, we explored the mechanism of resistance in a trifluralin-resistant A. palmeri accession collected from Arkansas, USA. Dose-response assays using agar plates demonstrated an EC50 (effective concentration that reduces root length by 50%) of 1.02 µM trifluralin compared to 0.39 µM obtained in the susceptible accession. Thus, under these conditions, the resistant accession required 2.6 times more trifluralin to inhibit root length by 50%. Seeds in the presence or absence of the cytochrome P450-inhibitior malathion displayed a differential response with no significant influence on root length, suggesting that resistance is not P450-mediated. In addition, application of 4-chloro-7-nitrobenzofurazan (NBD-Cl), a glutathione S-transferase (GST) inhibitor, showed significant differences in root length, indicating that GSTs are most likely involved in the resistance mechanism. Sequencing of α- and β-tubulin genes revealed no single nucleotide polymorphisms (SNPs) previously described between accessions. In addition, relative gene copy number of α- and β-tubulin genes were estimated; however, both resistant and susceptible accessions displayed similar gene copy numbers. Overall, our results revealed that GST-mediated metabolism contributes to trifluralin resistance in this A. palmeri accession from Arkansas.

EPSPSGene Amplification Primarily Confers Glyphosate Resistance among Arkansas Palmer amaranth (Amaranthus palmeri) Populations

Weed Science ◽  
2018 ◽  
Vol 66 (3) ◽  
pp. 293-300 ◽  
Author(s):  
Shilpa Singh ◽  
Vijay Singh ◽  
Amy Lawton-Rauh ◽  
Muthukumar V. Bagavathiannan ◽  
Nilda Roma-Burgos
Keyword(s):  
Copy Number ◽  
Gene Copy Number ◽  
Glyphosate Resistance ◽  
Resistance Mechanisms ◽  
Palmer Amaranth ◽  
Gene Copy ◽  
Amaranthus Palmeri ◽  
Resistance Level ◽  
Relative Copy Number ◽  
Gene Copies

AbstractResearch was conducted to determine whether resistance to glyphosate among Palmer amaranth (Amaranthus palmeriS. Watson) populations within the U.S. state of Arkansas was due solely to increasedEPSPSgene copy number and whether gene copy number is correlated with resistance level to glyphosate. One hundred and fifteenA. palmeriaccessions were treated with 840 g ae ha−1glyphosate. Twenty of these accessions, selected to represent a broad range of responses to glyphosate, underwent further testing. Seven of the accessions were controlled with this dose; the rest were resistant. The effective dose to cause 50% injury (ED50) for susceptible accessions ranged from 28 to 207 g ha−1. The glyphosate-resistant (GR) accessions had ED50values ranging from 494 to 1,355 g ha−1, a 3- to 48-fold resistance level compared with the susceptible standard (SS). The 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene relative copy number was determined for 20 accessions, 4 plants accession−1. Resistant plants from five GR accessions (38% of resistant plants tested) did not have increasedEPSPSgene copies. Resistant plants from the remaining eight GR accessions (62% of resistant plants tested) had 19 to 224 moreEPSPSgene copies than the SS. Among the accessions tested, injury declined 4% with every additionalEPSPScopy. ED50values were directly correlated withEPSPScopy number. The highly resistant accession MIS11-B had an ED50of 1,355 g ha−1and 150 gene copies. Partial sequences ofEPSPSfrom GR accessions withoutEPSPSamplification did not contain any of the known resistance-conferring mutations. Nearly 40% of GR accessions putatively harbor non–target site resistance mechanisms. Therefore, elevatedEPSPSgene copy number is associated with glyphosate resistance amongA. palmerifrom Arkansas.

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