Linkage mapping reveals loci that underlie differences in <i>Caenorhabditis elegans</i> growth

Nyaanga, Joy; Andersen, Erik C.

doi:10.1093/g3journal/jkac207

Cited by 4 publications

(8 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To ensure that we captured small drug-affected nematodes across anthelmintics and minimized the amount of retained debris, we altered the animal length threshold to Worm_Length > 30 (100 microns). The threshold Worm_Length > 30 was previously recorded as the smallest animal length of L1 animals after an hour of feeding [68]. To confirm that we were retaining animal objects, we (1) retained the MDHD model for drugs that had small animals present at high dose concentrations (see Methods and Data Cleaning ) and (2) observed high dose well images to ensure the MDHD model was identifying nematodes.…”

Section: Methodsmentioning

confidence: 96%

“…1) Objects with a Worm_Length > 30 pixels, 100 microns, were removed from the CellProfiler data to (A) retain L1 and MDHD-sized animals and (B) remove unwanted particles [68]. Using the Worm_Length > 30 pixels threshold to retain small sensitive animals, more small objects, such as debris, were also retained (see Supplementary Information).…”

Section: Data Cleaningmentioning

confidence: 99%

Section: Small Object Removal and Data Cleaningmentioning

confidence: 99%

See 2 more Smart Citations

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

Shaver

Wit

Dilks

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Methodsmentioning

confidence: 96%

Section: Data Cleaningmentioning

confidence: 99%

Section: Small Object Removal and Data Cleaningmentioning

confidence: 99%

See 1 more Smart Citation

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

Shaver

Wit

Dilks

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Objects with a Worm_Length > 30 pixels, 100 microns, were removed from the CellProfiler data to (A) retain L1 and MDHD-sized animals and (B) remove unwanted particles [ 70 ]. Using the Worm_Length > 30 pixels threshold to retain small sensitive animals, more small objects, such as debris ( i .…”

Section: Methodsmentioning

confidence: 99%

“…1. Objects with a Worm_Length > 30 pixels, 100 microns, were removed from the CellProfiler data to (A) retain L1 and MDHD-sized animals and (B) remove unwanted particles [70].…”

Section: Data Cleaningmentioning

confidence: 99%

Variation in anthelmintic responses are driven by genetic differences among diverse C. elegans wild strains

et al. 2023

Self Cite

View full text Add to dashboard Cite

Treatment of parasitic nematode infections in humans and livestock relies on a limited 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 similar anthelmintic responses within drug classes and significant variation across drug classes. 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 laboratory reference strain, 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 before applications to helminths. Third, we quantified the levels of anthelmintic response variation caused by genetic differences among individuals (heritability) to each drug and observed a significant correlation between exposure closest to the EC10 and the exposure that exhibited the most heritable responses. These results suggest drugs to prioritize in genome-wide association studies, which will enable the identification of AR genes.

show abstract

Quantifying the fitness effects of resistance alleles with and without anthelmintic selection pressure usingCaenorhabditis elegans

Shaver,

Miller,

Schaye

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Albendazole and ivermectin are the two most commonly co-administered anthelmintic drugs in mass-drug administration programs worldwide. Despite emerging resistance, we do not fully understand the mechanisms of resistance to these drugs nor the consequences of delivering them in combination. Albendazole resistance has primarily been attributed to variation in the drug target, a beta-tubulin gene. Ivermectin targets glutamate-gated chloride channel (GluCl) genes, but it is unknown whether these genes are involved in ivermectin resistance in nature. Using Caenorhabditis elegans, we defined the fitness costs associated with loss of the drug target genes singly or in combinations of the genes that encode GluCl subunits. We quantified the loss-of-function effects on three traits: (i) multi-generational competitive fitness, (ii) fecundity, and (iii) development. In competitive fitness and development assays, we found that a deletion of the beta-tubulin gene ben-1 conferred albendazole resistance, but ivermectin resistance required loss of two GluCl genes (avr-14 and avr-15) or loss of three GluCl genes (avr-14, avr-15, and glc-1). The fecundity assays revealed that loss of ben-1 did not provide any fitness benefit in albendazole and that no GluCl deletion mutants were resistant to ivermectin. Next, we searched for evidence of multi-drug resistance across the three traits. Loss of ben-1 did not confer resistance to ivermectin, nor did loss of any single GluCl subunit or combination confer resistance to albendazole. Finally, we assessed the development of 124 C. elegans wild strains across six benzimidazoles and seven macrocyclic lactones to identify evidence of multi-drug resistance between the two drug classes and found a strong phenotypic correlation within a drug class but not across drug classes. Because each gene affects various aspects of nematode physiology, these results suggest that it is necessary to assess multiple fitness traits to evaluate how each gene contributes to anthelmintic resistance.

show abstract

Linkage mapping reveals loci that underlie differences in Caenorhabditis elegans growth

Cited by 4 publications

References 41 publications

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

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

Variation in anthelmintic responses are driven by genetic differences among diverse C. elegans wild strains

Quantifying the fitness effects of resistance alleles with and without anthelmintic selection pressure usingCaenorhabditis elegans

Contact Info

Product

Resources

About