Preventive chemotherapy has long been practiced against nematode parasites of livestock, leading to widespread drug resistance, and is increasingly being adopted for eradication of human parasitic nematodes even though it is similarly likely to lead to drug resistance. Given that the genetic architecture of resistance is poorly understood for any nematode, we have analyzed multidrug resistant Teladorsagia circumcincta, a major parasite of sheep, as a model for analysis of resistance selection. We introgressed a field-derived multiresistant genotype into a partially inbred susceptible genetic background (through repeated backcrossing and drug selection) and performed genome-wide scans in the backcross progeny and drug-selected F2 populations to identify the major genes responsible for the multidrug resistance. We identified variation linking candidate resistance genes to each drug class. Putative mechanisms included target site polymorphism, changes in likely regulatory regions and copy number variation in efflux transporters. This work elucidates the genetic architecture of multiple anthelmintic resistance in a parasitic nematode for the first time and establishes a framework for future studies of anthelmintic resistance in nematode parasites of humans.

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Divergent breeding lines of Romney sheep, selected as lambs for consistently high or low faecal worm egg count (FEC) following natural multi-species challenge by nematode parasites, were established in New Zealand at Wallaceville Animal Research Centre in 1979 and at Rotomahana Station in 1985. In 1988 the Rotomahana lines, including an unselected control line maintained under the same management conditions, were transferred to Tokanui Station where they remained for 4 years. In 1993 elite high and low FEC animals from Tokanui, along with the controls, were transferred to Wallaceville, where merged lines have since been managed together. Selection responses from the lines at Rotomahana and Tokanui, and from a further 5 years of divergent selection in the merged lines, are reported here. For the two most recent lamb crops (1996 and 1997 birth years), log-transformed FECs of the high and low lines were 1·27 and -1·46 phenotypic standard deviation units from the control. After back-transformation to the original scale, where the FEC for control line lambs averaged 1255 eggs per g, the means for the high and low lines were 3Ό5 and 0·27 times the control mean. Animal-model restricted maximum likelihood estimates of her it ability and repeatability for single-record FEC (following separate infections) were 0·28 (s.e. 0·02) and 0·42 (s.e. 0Ό1), respectively. Correlated responses in production traits include significantly decreased post-weaning weight gain and increased dags (breech soiling) in lambs, and decreased fleece weight in yearlings and ewes in the low FEC line, compared with those in the high line. However the low FEC line had proportionally 0·11 more lambs weaned per ewe mated than the high FEC line (F < 0·01). It is concluded firstly that selection for high or low FEC in Romney s has achieved an 11-fold difference between the divergent lines. Secondly, it will generally be necessary in a commercial environment to apply index selection for a combination of increased productivity, decreased FEC and possibly decreased dags, when potential candidates are recorded under conditions of nematode challenge.

Background: Currently most pastoral farmers rely on anthelmintic drenches to control gastrointestinal parasitic nematodes in sheep. Resistance to anthelmintics is rapidly increasing in nematode populations such that on some farms none of the drench families are now completely effective. It is well established that host resistance to nematode infection is a moderately heritable trait. This study was undertaken to identify regions of the genome, quantitative trait loci (QTL) that contain genes affecting resistance to parasitic nematodes.