Natural variation in Caenorhabditis elegans responses to the anthelmintic emodepside

Wit, Janneke; Rodriguez, Briana; Andersen, Erik C.

doi:10.1016/j.ijpddr.2021.04.001

Cited by 17 publications

(13 citation statements)

References 54 publications

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“…The time the detector is interrupted is equated to the length of the nematode. Illustration adapted from (Wit, Rodriguez, et al, 2021). C) Distribution of GFP fluorescence of animals is shown.…”

Section: Methodsmentioning

confidence: 99%

Benzimidazoles cause lethality by inhibiting the function of Caenorhabditis elegans neuronal beta-tubulin

Gibson¹,

Ness-Cohn²,

Andersen³

2022

Preprint

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Parasitic nematode infections cause an enormous global burden to both human and livestock populations. Resistance to the limited arsenal of anthelmintic drugs used to combat these infections is widespread, including resistance to benzimidazole (BZ) compounds commonly found in livestock parasites. Previous studies using the free-living nematode Caenorhabditis elegans to model parasitic nematode resistance have shown that loss-of-function mutations in the beta-tubulin gene ben-1 confer resistance to BZ drugs. However, the mechanism of resistance and the tissue-specific susceptibility are not well known in any nematode species. To identify in which tissue(s) ben-1 function underlies BZ susceptibility, transgenic strains that express ben-1 in different tissues, including hypodermis, muscles, neurons, intestine, and ubiquitous expression were generated. High-throughput fitness assays were performed to measure and compare the quantitative responses to BZ compounds among different transgenic lines. Significant BZ susceptibility was observed in animals expressing ben-1 in neurons, comparable to expression using the ben-1 promoter. This result suggests that ben-1 function in neurons underlies susceptibility to BZ. Subsetting neuronal expression of ben-1 based on neurotransmitter system further restricted ben-1 function in cholinergic neurons to cause BZ susceptibility. These results better inform our current understanding of the cellular mode of action of BZ and also suggest additional treatments that might potentiate the effects of BZs.

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Section: Methodsmentioning

confidence: 99%

Benzimidazoles cause lethality by inhibiting the function of Caenorhabditis elegans neuronal beta-tubulin

Gibson¹,

Ness-Cohn²,

Andersen³

2022

Preprint

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“…Heritability estimates were calculated for each of the 25,849 traits used for eQTL mapping as previously described 88 . Narrow-sense heritability ( h 2 ) was calculated with the phenotype file and pruned genotypes in eQTL mapping using the functions mmer() and pin() in the R package sommer (v4.1.2) 89 .…”

Section: Methodsmentioning

confidence: 99%

An atlas of gene expression variation across the Caenorhabditis elegans species

Zhang

Roberto

Lee

et al. 2022

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Phenotypic variation in diverse organism-level traits have been studied in Caenorhabditis elegans wild strains, but differences in gene expression and the underlying variation in regulatory mechanisms are largely unknown. Here, we use natural variation in gene expression to connect genetic variants to differences in organismal-level traits, including drug and toxicant responses. We performed transcriptomic analysis on 207 genetically distinct C. elegans wild strains to study natural regulatory variation of gene expression. Using this massive dataset, we performed genome-wide association mappings to investigate the genetic basis underlying gene expression variation and revealed complex genetic architectures. We found a large collection of hotspots enriched for expression quantitative trait loci across the genome. We further used mediation analysis to understand how gene expression variation could underlie organism-level phenotypic variation for a variety of complex traits. These results reveal the natural diversity in gene expression and possible regulatory mechanisms in this keystone model organism, highlighting the promise of gene expression variation in shaping phenotypic diversity.

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“…Differences in responses were measured by the change in developmental rate, as measured by animal length. Nematodes grow longer over time, and anthelmintics have been shown to slow this development [9,10,[18][19][20][21].…”

Section: Anthelmintic Drugsmentioning

confidence: 99%

Variation in anthelmintic responses are driven by genetic differences among diverseC. eleganswild strains

Shaver

Wit

Dilks

et al. 2022

Preprint

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Treatment of parasitic nematode infections in humans and livestock relies on a small arsenal of anthelmintic drugs that have historically reduced parasite burdens. However, anthelmintic resistance (AR) is increasing, and little is known about the molecular and genetic causes of resistance for most drugs. The free-living roundworm Caenorhabditis elegans has proven to be a tractable model to understand AR, where studies have led to the identification of molecular targets of all major anthelmintic drug classes. Here, we used genetically diverse C. elegans strains to perform dose-response analyses across 26 anthelmintic drugs that represent the three major anthelmintic drug classes (benzimidazoles, macrocyclic lactones, and nicotinic acetylcholine receptor agonists) in addition to seven other anthelmintic classes. First, we found that C. elegans strains displayed significant variation in anthelmintic responses across drug classes. Dose-response trends within a drug class showed that the C. elegans strains elicited similar responses within the benzimidazoles but variable responses in the macrocyclic lactones and nicotinic acetylcholine receptor agonists. Next, we compared the effective concentration estimates to induce a 10% maximal response (EC10) and slope estimates of each dose-response curve of each strain to the reference strain, N2, which enabled the identification of anthelmintics with population-wide differences to understand how genetics contribute to AR. Because genetically diverse strains displayed differential susceptibilities within and across anthelmintics, we show that C. elegans is a useful model for screening potential nematicides. Third, we quantified the heritability of responses to each anthelmintic and observed a significant correlation between exposure closest to the EC10 and the exposure that exhibited the most heritable responses. Heritable genetic variation can be explained by strain-specific anthelmintic responses within and across drug classes. These results suggest drugs to prioritize in genome-wide association studies, which will enable the identification of AR genes.

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Natural variation in Caenorhabditis elegans responses to the anthelmintic emodepside

Cited by 17 publications

References 54 publications

Benzimidazoles cause lethality by inhibiting the function of Caenorhabditis elegans neuronal beta-tubulin

Benzimidazoles cause lethality by inhibiting the function of Caenorhabditis elegans neuronal beta-tubulin

An atlas of gene expression variation across the Caenorhabditis elegans species

Variation in anthelmintic responses are driven by genetic differences among diverseC. eleganswild strains

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