“…In agreement with AS-PCR, the K2 sample was confirmed to be heterozygous, despite both the copy number (0.34 copies/μl) and relative frequency (0.54%) of the S allele being much lower than that of the R allele. These findings are further supported by Doyle et al (2022) , who have recently confirmed that in their previous study on the global diversity of H. contortus ( Sallé et al, 2019 ), the Kokstad isolate, unlike others, had also demonstrated fixed frequencies of the mutation S168T. Fig.…”
Section: Resultssupporting
confidence: 83%
“…This observation is further reinforced by both the FECRT, and previous molecular testing done on most of these samples. Thus, as regards hco-acr-8 and its involvement in levamisole resistance in the parasite H. contortus , in our estimation, the data presented for S168T is so far more consistent with this mutation being a likely causal or closely-linked variant, associated with resistance, in comparison to the deletion in intron 2, which was readily found in both phenotypically susceptible and resistant isolates/populations ( Chagas et al, 2016 ; Baltrušis et al, 2021 ; Doyle et al, 2022 ; Antonopoulos et al, 2022 ). However, it should also be noted that S168T alone is unlikely to explain all cases of phenotypic resistance.…”
Section: Resultssupporting
confidence: 73%
“…Up until recently, the prevailing hypothesis regarding the major mechanism responsible for levamisole resistance in H. contortus was based on the observation that some phenotypically resistant isolates appeared to express a truncated transcript of hco-acr-8 (hco-acr-8b) as a result of the (63bp) deletion in the intron 2 ( Fauvin et al, 2010 ; Barrère et al, 2014 ). However, growing interest in hco-acr-8 and its role in resistance has resulted in findings inconsistent with this hypothesis ( Chagas et al, 2016 ; Baltrušis et al, 2021 ; Doyle et al, 2022 ). The most recent data suggests that a non-synonymous mutation (A G C→A C C; protein coding strand) in the exon 4 of this gene, resulting in the S168T substitution, could, instead, be the major determinant of levamisole resistance and serve as a potential molecular marker of its identification in parasite populations ( Doyle et al, 2022 ; Antonopoulos et al, 2022 ).…”
Section: Introductionmentioning
confidence: 99%
“…However, growing interest in hco-acr-8 and its role in resistance has resulted in findings inconsistent with this hypothesis ( Chagas et al, 2016 ; Baltrušis et al, 2021 ; Doyle et al, 2022 ). The most recent data suggests that a non-synonymous mutation (A G C→A C C; protein coding strand) in the exon 4 of this gene, resulting in the S168T substitution, could, instead, be the major determinant of levamisole resistance and serve as a potential molecular marker of its identification in parasite populations ( Doyle et al, 2022 ; Antonopoulos et al, 2022 ).…”
“…In agreement with AS-PCR, the K2 sample was confirmed to be heterozygous, despite both the copy number (0.34 copies/μl) and relative frequency (0.54%) of the S allele being much lower than that of the R allele. These findings are further supported by Doyle et al (2022) , who have recently confirmed that in their previous study on the global diversity of H. contortus ( Sallé et al, 2019 ), the Kokstad isolate, unlike others, had also demonstrated fixed frequencies of the mutation S168T. Fig.…”
Section: Resultssupporting
confidence: 83%
“…This observation is further reinforced by both the FECRT, and previous molecular testing done on most of these samples. Thus, as regards hco-acr-8 and its involvement in levamisole resistance in the parasite H. contortus , in our estimation, the data presented for S168T is so far more consistent with this mutation being a likely causal or closely-linked variant, associated with resistance, in comparison to the deletion in intron 2, which was readily found in both phenotypically susceptible and resistant isolates/populations ( Chagas et al, 2016 ; Baltrušis et al, 2021 ; Doyle et al, 2022 ; Antonopoulos et al, 2022 ). However, it should also be noted that S168T alone is unlikely to explain all cases of phenotypic resistance.…”
Section: Resultssupporting
confidence: 73%
“…Up until recently, the prevailing hypothesis regarding the major mechanism responsible for levamisole resistance in H. contortus was based on the observation that some phenotypically resistant isolates appeared to express a truncated transcript of hco-acr-8 (hco-acr-8b) as a result of the (63bp) deletion in the intron 2 ( Fauvin et al, 2010 ; Barrère et al, 2014 ). However, growing interest in hco-acr-8 and its role in resistance has resulted in findings inconsistent with this hypothesis ( Chagas et al, 2016 ; Baltrušis et al, 2021 ; Doyle et al, 2022 ). The most recent data suggests that a non-synonymous mutation (A G C→A C C; protein coding strand) in the exon 4 of this gene, resulting in the S168T substitution, could, instead, be the major determinant of levamisole resistance and serve as a potential molecular marker of its identification in parasite populations ( Doyle et al, 2022 ; Antonopoulos et al, 2022 ).…”
Section: Introductionmentioning
confidence: 99%
“…However, growing interest in hco-acr-8 and its role in resistance has resulted in findings inconsistent with this hypothesis ( Chagas et al, 2016 ; Baltrušis et al, 2021 ; Doyle et al, 2022 ). The most recent data suggests that a non-synonymous mutation (A G C→A C C; protein coding strand) in the exon 4 of this gene, resulting in the S168T substitution, could, instead, be the major determinant of levamisole resistance and serve as a potential molecular marker of its identification in parasite populations ( Doyle et al, 2022 ; Antonopoulos et al, 2022 ).…”
“…If so, binding of abamectin to CRs might lead to the activation of detoxification pathways, and they might hence act as xenosensors (Ingham et al, 2020). In nematodes, the transcription factor cky-1 has been linked with ivermectin resistance, as this gene is within a locus under selection in ivermectin-resistant populations worldwide, and functional validation using knockdown experiments support the observation that cky-1 is associated with ivermectin survival (Doyle et al, 2022). In mites, transcriptional regulation could lead to the modular control and differential expression of groups of genes, and at least be partially responsible for some of the genes that are differentially expressed between parental lines.…”
Pesticide resistance relies on a myriad of mechanisms, ranging from single mutations to a complex and polygenic architecture, and it involves mechanisms such as target-site insensitivity, metabolic detoxification, or a combination of these, with either additive or synergistic effects. Several resistance mechanisms against abamectin, a macrocyclic lactone widely used in crop protection, have been reported in the cosmopolitan pest Tetranychus urticae. However, it has been shown that a single mechanism cannot account for the high levels of abamectin resistance found across different mite populations. Here, we used experimental evolution combined with bulked segregant analyses to map quantitative trait loci (QTL) associated with abamectin resistance in two genetically unrelated strains of T. urticae. In these two independent QTL mapping experiments, three and four QTLs were identified, of which three were shared between experiments. Shared QTLs contained genes encoding subunits of the glutamate-gated chloride channel (GluCl) and harboured previously reported mutations, including G314D in GluCl1 and G326E in GluCl3, but also novel resistance candidate loci, including DNA helicases and chemosensory receptors. Surprisingly, the fourth QTL, present only in only one of the experiments and thus unique for one parental resistant strain, revealed a non-functional variant of GluCl2, suggesting gene knock-out as resistance mechanism. Our study uncovers the complex basis of abamectin resistance, and it highlights the intraspecific diversity of genetic mechanisms underlying resistance in a cosmopolitan pest.
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