Two novel loci underlie natural differences in Caenorhabditis elegans abamectin responses

Abstract

Parasitic nematodes cause a massive worldwide burden on human health along with a loss of livestock and agriculture productivity. Anthelmintics have been widely successful in treating parasitic nematodes. However, resistance is increasing, and little is known about the molecular and genetic causes of resistance for most of these drugs. The free-living roundworm Caenorhabditis elegans provides a tractable model to identify genes that underlie resistance. Unlike parasitic nematodes, C. elegans is easy to maintain in the laboratory, has a complete and well annotated genome, and has many genetic tools. Using a combination of wild isolates and a panel of recombinant inbred lines constructed from crosses of two genetically and phenotypically divergent strains, we identified three genomic regions on chromosome V that underlie natural differences in response to the macrocyclic lactone (ML) abamectin. One locus was identified previously and encodes an alpha subunit of a glutamate-gated chloride channel (glc-1). Here, we validate and narrow two novel loci using near-isogenic lines. Additionally, we generate a list of prioritized candidate genes identified in C. elegans and in the parasite Haemonchus contortus by comparison of ML resistance loci. These genes could represent previously unidentified resistance genes shared across nematode species and should be evaluated in the future. Our work highlights the advantages of using C. elegans as a model to better understand ML resistance in parasitic nematodes.

From QTL to gene: C. elegans facilitates discoveries of the genetic mechanisms underlying natural variation

“…The gene scb-1, for example, underlies variation in responses to amsacrine, bleomycin, carmustine, and cisplatin, demonstrating that a single gene can affect sensitivities to multiple chemotherapeutics [67,68]. Effects of epistatic loci on phenotypic variation are more difficult to define, as most of the QTL detected so far appear to be largely additive [54,56,66,69,80]. Although this result is consistent with what is observed in many other species [139,[142][143][144][145][146], most mapping panels are underpowered to detect epistatic loci.…”

Evaluating the power and limitations of genome-wide association mapping in C. elegans

“…Traits that can be measured in high-throughput (Hahnel et al . 2018; Evans et al . 2021a) or as intermediate traits ( e.g.…”

“…Traits that can be measured in high-throughput (Hahnel et al 2018;Evans et al 2021a) or as intermediate traits (e.g., mRNA abundances) lend themselves to dissection in hundreds of strains and QTL conferring more subtle effects can be more easily resolved. At the current size of CeNDR, the primary driver of sampling depth of GWA mapping populations should be the balance between phenotyping effort for the trait of interest and the end goal of association mapping given the roughly estimated heritability of the trait (Figure 2) and the lower bound of the effect of QTL that will be detected (Figure 3).…”

“…At the current size of CeNDR, the primary driver of sampling depth of GWA mapping populations should be the balance between phenotyping effort for the trait of interest and the end goal of association mapping given the roughly estimated heritability of the trait (Figure 2) and the lower bound of the effect of QTL that will be detected (Figure 3). In many cases, evaluating the same trait using linkage mapping in complementary populations (i.e., traits segregate similarly between parental strains of the cross and in the association mapping population) can validate effect sizes and provide additional support for candidates from GWA (Zdraljevic et al 2019;Webster et al 2019;Evans et al 2021a).…”

A role for worm cutl-24 in background- and parent-of-origin-dependent ER stress resistance

“…The laboratory strain of C. elegans has been a fixture of the biology literature for decades (Nigon and Félix 2017), but dissecting natural variation in nematodes has proven to be a challenge owing to low rates of polymorphism and meiotic recombination (Hillers and Villeneuve 2003). In a few model C. elegans systems, landmark resources have been established to overcome these limitations (Li et al 2006; Reddy et al 2009; Rockman and Kruglyak 2009; McGrath et al 2009; Doroszuk et al 2009; Seidel et al 2011; Bendesky et al 2012; Ghosh et al 2012, 2015; Balla et al 2015; Andersen et al 2015; Large et al 2016; Ben-David et al 2017), including recent progress with genome-wide association scans (Webster et al 2019a; Na et al 2020; Evansid et al 2021). Despite these advances, the power of natural variation genetics remains out of reach for many nematode strains and species.…”