Natural Variation in a Chloride Channel Subunit Confers Avermectin Resistance in
            <i>C. elegans</i>

Ghosh, Rajarshi; Andersen, Erik C.; Shapiro, Joshua A.; Gerke, Justin P.; Kruglyak, Leonid

doi:10.1126/science.1214318

Cited by 173 publications

(205 citation statements)

References 44 publications

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“…Moreover, the behavior identified here need not be the most important one in natural settings; it may represent one of several behavioral and physiological responses that facilitate adaptation to different environments. Balancing selection may be fairly common throughout the C. elegans genome: a recent report identified 61 highly divergent regions likely to be under balancing selection that segregate among wild strains of C. elegans, including a second region 200 kb from roam-1 24,29 (Extended Data Figure 8). The composition of these regions is biased toward particular gene classes including chemoreceptors, which may act as hotspots of evolution.…”

Section: Discussionmentioning

confidence: 99%

Balancing selection shapes density-dependent foraging behaviour

Greene

Brown

Dobosiewicz

et al. 2016

Nature

126

136

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SUMMARY The optimal foraging strategy in a given environment depends on the number of competing individuals and their behavioral strategies. Little is known about the genes and neural circuits that integrate social information into foraging decisions. Here we show that ascaroside pheromones that signal population density suppress exploratory foraging in Caenorhabditis elegans, and that heritable variation in this behavior generates alternative foraging strategies. Natural C. elegans isolates differ in their sensitivity to the potent ascaroside icas#9 (IC-asc-C5). A quantitative trait locus (QTL) for icas#9 sensitivity includes srx-43, a G protein-coupled icas#9 receptor; srx-43 acts in ASI sensory neurons to suppress exploration. Two ancient haplotypes associated with this QTL confer competitive growth advantages that depend on ascaroside secretion, its detection by srx-43, and the distribution of food. These results suggest that balancing selection at the srx-43 locus generates alternative density-dependent behaviors, fulfilling a prediction of foraging game theory.

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Section: Discussionmentioning

confidence: 99%

Balancing selection shapes density-dependent foraging behaviour

Greene

Brown

Dobosiewicz

et al. 2016

Nature

126

136

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“…Hco-avr-14 and Hco-glc-5 are members of the H. contortus glutamate-gated chloride channel (GLC) family (Wolstenholme and Rogers, 2005;McCavera et al, 2007;Laing et al, 2013). Three members of this family in Caenorhabditis elegans -Cel-glc-1, Cel-avr-14 and Cel-avr-15 -have been shown to be ivermectin targets by genetic mutation and complementation studies (Dent et al, 2000;Ghosh et al, 2012). The H. contortus homologue of Cel-avr-14 -Hco-avr-14 -was implicated in ivermectin resistance by its ability to rescue ivermectin susceptibility when heterologously expressed in C. elegans, suggesting it is an ivermectin target in the parasite (McCavera et al, 2007(McCavera et al, , 2009Glendinning et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Evidence from two independent backcross experiments supports genetic linkage of microsatellite Hcms8a20, but not other candidate loci, to a major ivermectin resistance locus in Haemonchus contortus

Rezansoff

Laing

Gilleard

2016

International Journal for Parasitology

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Haemonchus contortus is the leading parasitic nematode species used to study anthelmintic drug resistance. A variety of candidate loci have been implicated as being associated with ivermectin resistance in this parasite but definitive evidence of their importance is still lacking. We have previously performed two independent serial backcross experiments to introgress ivermectin resistance loci from two H. contortus ivermectin-resistant strains - MHco4(WRS) and MHco10(CAVR) - into the genetic background of the ivermectin-susceptible genome reference strain MHco3(ISE). We have interrogated a number of candidate ivermectin resistance loci in the resulting backcross populations and assessed the evidence for their genetic linkage to an ivermectin resistance locus. These include the microsatellite marker Hcms8a20 and six candidate genes Hco-glc-5, Hco-avr-14, Hco-lgc-37 (previously designated Hco-hg-1), Hco-pgp-9 (previously designated Hco-pgp-1), Hco-pgp-2 and Hco-dyf-7. We have sampled the haplotype diversity of amplicon markers within, or adjacent to, each of these loci in the parental strains and fourth generation backcross populations to assess the evidence for haplotype introgression from the resistant parental strain into the genomic background of the susceptible parental strain in each backcross. The microsatellite Hcms8a20 locus showed strong evidence of such introgression in both independent backcrosses, suggesting it is linked to an important ivermectin resistance mutation in both the MHco4(WRS) and MHco10(CAVR) strains. In contrast, Hco-glc-5, Hco-avr-14, Hco-pgp-9 and Hco-dyf-7 showed no evidence of introgression in either backcross. Hco-lgc-37 and Hco-pgp-2 showed only weak evidence of introgression in the MHco3/4 backcross but not in the MHco3/10 backcross. Overall, these results suggest that microsatellite marker Hcms8a20, but not the other candidate genes tested, is linked to a major ivermectin resistance locus in the MHco4(WRS) and MHco10(CAVR) strains. This work also emphasises the need for genome-wide approaches to identify mutations responsible for the ivermectin resistance in this parasite.

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“…Recent studies have revealed unexpected variation in both fertility and oocyte function in wild strains of C . elegans upon exposure to high temperature [30], in responses to the anthelmintic avermectin [31], and in mitotic spindle structure and function [32]. The effects of environmental and chemical stressors, including CuO NPs, to C .…”

Section: Introductionmentioning

confidence: 99%

Copper Oxide Nanoparticles Impact Several Toxicological Endpoints and Cause Neurodegeneration in Caenorhabditis elegans

et al. 2016

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Engineered nanoparticles are becoming increasingly incorporated into technology and consumer products. In 2014, over 300 tons of copper oxide nanoparticles were manufactured in the United States. The increased production of nanoparticles raises concerns regarding the potential introduction into the environment or human exposure. Copper oxide nanoparticles commonly release copper ions into solutions, which contribute to their toxicity. We quantified the inhibitory effects of both copper oxide nanoparticles and copper sulfate on C. elegans toxicological endpoints to elucidate their biological effects. Several toxicological endpoints were analyzed in C. elegans, including nematode reproduction, feeding behavior, and average body length. We examined three wild C. elegans isolates together with the Bristol N2 laboratory strain to explore the influence of different genotypic backgrounds on the physiological response to copper challenge. All strains exhibited greater sensitivity to copper oxide nanoparticles compared to copper sulfate, as indicated by reduction of average body length and feeding behavior. Reproduction was significantly reduced only at the highest copper dose, though still more pronounced with copper oxide nanoparticles compared to copper sulfate treatment. Furthermore, we investigated the effects of copper oxide nanoparticles and copper sulfate on neurons, cells with known vulnerability to heavy metal toxicity. Degeneration of dopaminergic neurons was observed in up to 10% of the population after copper oxide nanoparticle exposure. Additionally, mutants in the divalent-metal transporters, smf-1 or smf-2, showed increased tolerance to copper exposure, implicating both transporters in copper-induced neurodegeneration. These results highlight the complex nature of CuO nanoparticle toxicity, in which a nanoparticle-specific effect was observed in some traits (average body length, feeding behavior) and a copper ion specific effect was observed for other traits (neurodegeneration, response to stress).

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Natural Variation in a Chloride Channel Subunit Confers Avermectin Resistance in C. elegans

Cited by 173 publications

References 44 publications

Balancing selection shapes density-dependent foraging behaviour

Balancing selection shapes density-dependent foraging behaviour

Evidence from two independent backcross experiments supports genetic linkage of microsatellite Hcms8a20, but not other candidate loci, to a major ivermectin resistance locus in Haemonchus contortus

Copper Oxide Nanoparticles Impact Several Toxicological Endpoints and Cause Neurodegeneration in Caenorhabditis elegans

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