Biology subjects

Dilks, C. M.

Publications and source records attributed to Dilks, C. M..

7 recordsLinked to original sources

bioRxiv2026

Global genomic diversity of the selfing nematode Caenorhabditis tropicalis correlates with geography

Self-fertilization reduces genetic diversity compared to outcrossing and hypothetically decreases the ability to adapt to diverse environments. Among Caenorhabditis nematodes, self-fertilization evolved three times independently in Caenorhabditis elegans, Caenorhabditis briggsae, and the more recently discovered Caenorhabditis tropicalis. To survey C. tropicalis genetic relatedness, the influence of geography and niche on species-wide variation, and the signatures of selection, we collected 785 wild strains, sequenced their genomes, and identified 622 distinct genotypes (isotypes). In contrast to C. elegans and C. briggsae, C. tropicalis relatedness shows substantial association with geography and no transcontinental selective sweeps or broadly sampled isotypes. Populations from the Hawaiian Islands or Taiwan harbor more genetic variation than populations from the Caribbean or Americas, suggesting a Pacific species origin similar to other members of the Elegans subclade. Punctuated genomic regions of extreme genetic variation pervade the genome. These hyper-divergent regions (HDRs) comprise less than 6% of the reference genome in any given strain despite harboring 73% of all variant sites and are enriched for genes likely involved in environmental adaptation. HDRs represent a shared genomic feature of self-fertilizing Caenorhabditis nematodes despite their independent evolutionary origins and suggest a mechanism to explain worldwide distributions despite low species-wide levels of genetic variation.

genomics↗

bioRxiv2025

Caenorhabditis briggsae ancestral genomic hyper-diversity contrasts with globally distributed genome-wide haplotypes

Comparative genomics provides a powerful framework to uncover the molecular and evolutionary mechanisms that shape genetic diversity within and across species, revealing how shared and lineage-specific processes influence their evolutionary trajectories through time. The nematode Caenorhabditis briggsae is distributed world-wide and is a comparative model to Caenorhabditis elegans in the biology of development, cellular mechanisms, neurobiology, genetic mappings of complex traits, and genome evolution. Following massive collection efforts by the nematode research community, we present the isolation of over 2,000 wild strains and analyses of genome sequences that catalog over six million single-nucleotide and insertion-deletion variants. This genome and strain resource provide a powerful means to interrogate the causal genetic bases of phenotypic variation for diverse traits. Additionally, we describe its global population structure and discover new and genetically distinct groups within this primarily self-fertilizing species, including groups of highly related strains that were sampled across different continents. We leverage expansive genetic variation to decipher the effects of linkage and selection on the distribution of genetic diversity across the genome and across geographic regions. Within the species, we find genomic regions with extremely high levels of genetic variation similar to hyper-divergent regions found in C. elegans and other species. These regions harbor new genes and variation enriched for environmental sensing and pathogen responses. In comparison to the outbreeding sister species Caenorhabditis nigoni, we conclude that long-term balancing selection has maintained substantial functional variation since the divergence from their outbreeding ancestor, likely in response to differences in the ecological niche. Overall, this massive strain resource enables future comparative genetics and genomics studies, including genome-wide association studies between Caenorhabditis species.

genomics↗

bioRxiv2024

Naturally occurring variation in a cytochrome P450 modifies thiabendazole responses independent of beta-tubulin

Widespread anthelmintic resistance has complicated the management of parasitic nematodes. Resistance to the benzimidazole (BZ) drug class is nearly ubiquitous in many species and is associated with mutations in beta-tubulin genes. However, mutations in beta-tubulin alone do not fully explain all BZ resistance. We performed a genome-wide association study using a genetically diverse panel of Caenorhabditis elegans strains to identify loci that contribute to resistance to the BZ drug thiabendazole (TBZ). We identified a quantitative trait locus (QTL) on chromosome V independent of all beta-tubulin genes and overlapping with two promising candidate genes, the cytochrome P450 gene cyp-35d1 and the nuclear hormone receptor nhr-176, identified by another mapping technique. Both genes were previously demonstrated to play a role in TBZ metabolism. NHR-176 binds TBZ and induces the expression of CYP-35D1, which metabolizes TBZ. We generated single gene deletions of nhr-176 and cyp-35d1 and found that both genes play a role in TBZ response. A predicted high-impact lysine-to-glutamate substitution at position 267 (K267E) in CYP-35D1 was identified in a sensitive parental strain, and reciprocal allele replacement strains in both genetic backgrounds were used to show that the lysine allele conferred increased TBZ resistance. Using competitive fitness assays, we found that neither allele is deleterious, but the lysine allele is selected in the presence of TBZ. Additionally, we found that the lysine allele significantly increased the rate of TBZ metabolism compared to the glutamate allele. Moreover, yeast expression assays showed that the lysine version of CYP-35D1 had twice the enzymatic activity of the glutamate allele. To connect our results to parasitic nematodes, we analyzed four Haemonchus contortus cytochrome P450 orthologs but did not find variation at the 267 position in fenbendazole-resistant populations. Overall, we confirmed that variation in this cytochrome P450 gene is the first locus independent of beta-tubulin to play a role in BZ resistance. Author SummaryBenzimidazoles (BZs) are the most common drug class used to control parasitic nematodes, but because of overuse, resistance is widespread. The known genetic causes of BZ resistance are associated with mutations in beta-tubulin and are the most well understood of any anthelmintic class. However, BZ response varies significantly and differential levels of resistance likely require mutations in genes independent of beta-tubulin. We used the free-living model nematode Caenorhabditis elegans to identify and characterize a novel cytochrome P450 gene, cyp-35d1, associated with natural resistance to the BZ drug thiabendazole (TBZ). We demonstrated that a lysine at position 267 confers TBZ resistance and is selected over multiple generations after TBZ treatment. This allele significantly increased the rate of TBZ metabolism in both C. elegans and yeast. In conclusion, we have characterized the role of variation in a cytochrome P450 that contributes to TBZ resistance, independent of mutations in beta-tubulin.

genetics↗

bioRxiv2023

Praziquantel inhibits Caenorhabditis elegans development and species-wide differences might be cct-8-dependent

Anthelmintic drugs are used to treat parasitic roundworm and flatworm infections in humans and other animals. Caenorhabditis elegans is an established model to investigate anthelmintics used to treat roundworms. In this study, we use C. elegans to examine the mode of action and the mechanisms of resistance against the flatworm anthelmintic drug praziquantel (PZQ), used to treat trematode and cestode infections. We found that PZQ inhibited development and that this developmental delay varies by genetic background. Interestingly, both enantiomers of PZQ are equally effective against C. elegans, but only the left-handed PZQ (S-PZQ) is effective against schistosome infections. We conducted a genome-wide association mapping with 74 wild C. elegans strains to identify a region on chromosome IV that is correlated with differential PZQ susceptibility. Five candidate genes in this region: cct-8, znf-782, Y104H12D.4, Y104H12D.2, and cox-18, might underlie this variation. The gene cct-8, a subunit of the protein folding complex TRiC, has variation that causes a putative protein coding change (G226V), which is correlated with reduced developmental delay. Gene expression analysis suggests that this variant correlates with slightly increased expression of both cct-8 and hsp-70. Acute exposure to PZQ caused increased expression of hsp-70, indicating that altered TRiC function might be involved in PZQ responses. To test if this variant affects development upon exposure to PZQ, we used CRISPR-Cas9 genome editing to introduce the V226 allele into the N2 genetic background (G226) and the G226 allele into the JU775 genetic background (V226). These experiments revealed that this variant was not sufficient to explain the effects of PZQ on development. Nevertheless, this study shows that C. elegans can be used to study responses to PZQ to identify mode of action and resistance mechanisms. Additionally, we show that the TRiC complex requires further evaluation for PZQ responses in C. elegans.

genetics↗

bioRxiv2022

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

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. AUTHOR SUMMARYParasitic nematodes infect most animal species and significantly impact human and animal health. Control of parasitic nematodes in host species relies on a limited collection of anthelmintic drugs. However, anthelmintic resistance is widespread, which threatens our ability to control parasitic nematode populations. Here, we used the non-parasitic roundworm Caenorhabditis elegans as a model to study anthelmintic resistance across 26 anthelmintics that span ten drug classes. We leveraged the genetic diversity of C. elegans to quantify anthelmintic responses across a range of doses, estimate dose-response curves, fit strain-specific model parameters, and calculate the contributions of genetics to these parameters. We found that genetic variation within a species plays a considerable role in anthelmintic responses within and across drug classes. Our results emphasize how the incorporation of genetically diverse C. elegans strains is necessary to understand anthelmintic response variation found in natural populations. These results highlight drugs to prioritize in future mapping studies to identify genes involved in anthelmintic resistance. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=125 HEIGHT=200 SRC="FIGDIR/small/518036v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@6222bborg.highwire.dtl.DTLVardef@d635a6org.highwire.dtl.DTLVardef@15c3935org.highwire.dtl.DTLVardef@1afe3fe_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2022

Interactions of C. elegans -tubulins with the microtubule inhibitor albendazole

Parasitic nematodes are major human and agricultural pests, and benzimidazoles are amongst the most important broad spectrum anthelmintic drug class used for their control. Benzimidazole resistance is now widespread in many species of parasitic nematodes in livestock globally and an emerging concern for the sustainable control of human soil transmitted helminths. {beta}-tubulin is the major benzimidazole target, although other genes may influence resistance. Among the six C. elegans {beta}-tubulin genes, loss of ben-1 causes resistance without other apparent defects. Here, we explored the genetics of C. elegans {beta}-tubulin genes in relation to the response to the benzimidazole derivative albendazole. The most highly expressed {beta}-tubulin isotypes, encoded by tbb-1 and tbb-2, were known to be redundant with each other for viability, and their products are predicted not to bind benzimidazoles. We found that tbb-2 mutants, and to a lesser extent tbb-1 mutants, were hypersensitive to albendazole. The double mutant tbb-2 ben-1 is uncoordinated and dumpy, resembling the wild type exposed to albendazole, but the tbb-1 ben-1 double mutant did not show the same phenotype. These results suggest that tbb-2 is a modifier of ABZ sensitivity. To better understand how BEN-1 mutates to cause benzimidazole resistance, we isolated mutants resistant to albendazole and found that 15 of 16 mutations occurred in ben-1. Mutations ranged from likely nulls to hypomorphs, and several corresponded to residues that cause resistance in other organisms. Null alleles of ben-1 are albendazole-resistant and BEN-1 shows high sequence identity with tubulins from other organisms, suggesting that many amino acid changes could cause resistance. However, our results suggest that missense mutations conferring resistance are not evenly distributed across all possible conserved sites. Independent of their roles in benzimidazole resistance, tbb-1 and tbb-2 may have specialized functions as null mutants of tbb-1 or tbb-2 were cold or heat sensitive, respectively.

genetics↗

bioRxiv2021

Local adaptation and spatiotemporal patterns of genetic diversity revealed by repeated sampling of Caenorhabditis elegans across the Hawaiian Islands

The nematode Caenorhabditis elegans is among the most widely studied organisms, but relatively little is known about its natural ecology. Wild C. elegans have been isolated from both temperate and tropical climates, where they feed on bacteria associated with decomposing plant material. Genetic diversity is low across much of the globe but high in the Hawaiian Islands and across the Pacific Rim. The high genetic diversity found there suggests that: (1) the origin of the species lies in Hawaii or the surrounding Pacific Rim; and (2) the ancestral niche of the species is likely similar to the Hawaiian niche. A recent study of the Hawaiian niche found that genetically distinct groups appeared to correlate with elevation and temperature, but the study had a limited sample size. To better characterize the niche and genetic diversity of C. elegans on the Hawaiian Islands and to explore how genetic diversity might be influenced by local adaptation, we repeatedly sampled nematodes over a three-year period, measured various environmental parameters at each sampling site, and whole-genome sequenced the C. elegans isolates that we identified. We found that the typical Hawaiian C. elegans niche is moderately moist native forests at high elevations (500 to 1500 meters) where temperatures are cool (15 to 20{degrees}C). We measured levels of genetic diversity and differentiation among Hawaiian strains and found evidence of seven genetically distinct groups distributed across the islands. Then, we scanned these genomes for signatures of local adaptation and identified 18 distinct regions that overlap with hyperdivergent regions, which are likely maintained by balancing selection and enriched for genes related to environmental sensing, xenobiotic detoxification, and pathogen resistance. These results provide strong evidence of local adaptation among Hawaiian C. elegans and a possible genetic basis for this adaptation.

ecology↗