Abstract

Benzimidazoles (BZ) are essential components of the limited chemotherapeutic arsenal available to control the global burden of parasitic nematodes. The emerging threat of BZ resistance among multiple nematode species necessitates the development of novel strategies to identify genetic and molecular mechanisms underlying this resistance. All detection of parasitic helminth resistance to BZ is focused on the genotyping of three variant sites in the orthologs of the β-tubulin gene found to confer resistance in the free-living nematode Caenorhabditis elegans. Because of the limitations of laboratory and field experiments in parasitic nematodes, it is difficult to look beyond these three sites to identify additional mechanisms that might contribute to BZ resistance in the field. Here, we took an unbiased genome-wide mapping approach in the free-living nematode species C. elegans to identify the genetic underpinnings of natural resistance to the commonly used BZ, albendazole (ABZ). We found a wide range of natural variation in ABZ resistance in natural C. elegans populations. In agreement with known mechanisms of BZ resistance in parasites, we found that a majority of the variation in ABZ resistance among wild C. elegans strains is caused by variation in the β-tubulin gene ben-1. This result shows empirically that resistance to ABZ naturally exists and segregates within the C. elegans population, suggesting that selection in natural niches could enrich for resistant alleles. We identified 25 distinct ben-1 alleles that are segregating at low frequencies within the C. elegans population, including many novel molecular variants. Population genetic analyses indicate that ben-1 variation arose multiple times during the evolutionary history of C. elegans and provide evidence that these alleles likely occurred recently because of local selective pressures. Additionally, we find purifying selection at all five β-tubulin genes, despite predicted loss-of-function variants in ben-1, indicating that BZ resistance in natural niches is a stronger selective pressure than loss of one β-tubulin gene. Furthermore, we used genome-editing to show that the most common parasitic nematode β-tubulin allele that confers BZ resistance, F200Y, confers resistance in C. elegans. Importantly, we identified a novel genomic region that is correlated with ABZ resistance in the C. elegans population but independent of ben-1 and the other β-tubulin loci, suggesting that there are multiple mechanisms underlying BZ resistance. Taken together, our results establish a population-level resource of nematode natural diversity as an important model for the study of mechanisms that give rise to BZ resistance.

Highlights

  • Parasitic nematodes have a tremendous impact on global health and socio-economic development, especially in the developing world [1]

  • Laboratory screens and field surveys identified β-tubulin genes as major determinants of BZ resistance in nematodes but detailed population-wide genetic analyses of resistance mechanisms are only just beginning

  • We took advantage of the free-living model organism Caenorhabditis elegans to study the genetic basis of resistance to the commonly used BZ, albendazole (ABZ) in a natural nematode population

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Summary

Introduction

Parasitic nematodes have a tremendous impact on global health and socio-economic development, especially in the developing world [1]. The main endemic areas of nematode infections are highly correlated with tropical and subtropical regions worldwide Because of their detrimental impact on human health, several nematode infections belong to a class of diseases designated by the World Health Organization (WHO) as Neglected Tropical Diseases (NTDs). The loss of disability-adjusted life years (DALY) caused by parasitic nematodes is conservatively estimated to be 10 million DALYs per year, which ranks them among the top of all NTDs [1]. Apart from this drastic impact on human health, several nematode species infect a variety of key crops and livestock causing substantial economic losses throughout the world [3]

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