The Emergence of Resistance to the Benzimidazole Anthlemintics in Parasitic Nematodes of Livestock Is Characterised by Multiple Independent Hard and Soft Selective Sweeps

Abstract

Anthelmintic resistance is a major problem for the control of parasitic nematodes of livestock and of growing concern for human parasite control. However, there is little understanding of how resistance arises and spreads or of the “genetic signature” of selection for this group of important pathogens. We have investigated these questions in the system for which anthelmintic resistance is most advanced; benzimidazole resistance in the sheep parasites Haemonchus contortus and Teladorsagia circumcincta. Population genetic analysis with neutral microsatellite markers reveals that T. circumcincta has higher genetic diversity but lower genetic differentiation between farms than H. contortus in the UK. We propose that this is due to epidemiological differences between the two parasites resulting in greater seasonal bottlenecking of H. contortus. There is a remarkably high level of resistance haplotype diversity in both parasites compared with drug resistance studies in other eukaryotic systems. Our analysis suggests a minimum of four independent origins of resistance mutations on just seven farms for H. contortus, and even more for T. circumincta. Both hard and soft selective sweeps have occurred with striking differences between individual farms. The sweeps are generally softer for T. circumcincta than H. contortus, consistent with its higher level of genetic diversity and consequent greater availability of new mutations. We propose a model in which multiple independent resistance mutations recurrently arise and spread by migration to explain the widespread occurrence of resistance in these parasites. Finally, in spite of the complex haplotypic diversity, we show that selection can be detected at the target locus using simple measures of genetic diversity and departures from neutrality. This work has important implications for the application of genome-wide approaches to identify new anthelmintic resistance loci and the likelihood of anthelmintic resistance emerging as selection pressure is increased in human soil-transmitted nematodes by community wide treatment programs.

Author Summary

Parasitic nematodes (roundworms) are major causes of disease in both domestic animals and humans. Strategic treatments with anthelmintic drugs have been used to control livestock parasites for several decades resulting in widespread drug resistance. Drug treatments have, until recently, been applied at a relatively low level to control human parasites. However, in recent years community wide treatment programs have been massively increased for the 1–2 billion people infected with roundworms. Hence, for both human and animal health, there is an urgent need to understand how resistance emerges and spreads and how we can detect resistance mutations in this important group of pathogens. In this study, we investigated how drug resistance mutations appear and spread in the two livestock parasites for which resistance is most widespread. We have found that resistance appears repeatedly and frequently in parasite populations, and propose a model to explain the high capacity of these pathogens to develop drug resistance. Our work suggests that anthelmintic resistance is likely to occur when repeated drug treatment is relied upon to control this group of pathogens. Our results also suggest that resistance mutations should be detectable when modern genome-wide approaches are used to scan the genomes of resistant parasites.