title: Characterization and comparative analysis of the complete Haemonchus contortus β-tubulin gene family and implications for benzimidazole resistance in strongylid nematodes.
abstract: Parasitic nematode β-tubulin genes are of particular interest because they are the targets of benzimidazole drugs. However, in spite of this, the full β-tubulin gene family has not been characterized for any parasitic nematode to date. Haemonchus contortus is the parasite species for which we understand benzimidazole resistance the best and its close phylogenetic relationship with Caenorhabditis elegans potentially allows inferences of gene function by comparative analysis. Consequently, we have characterized the full β-tubulin gene family in H. contortus. Further to the previously identified Hco-tbb-iso-1 and Hco-tbb-iso-2 genes, we have characterized two additional family members designated Hco-tbb-iso-3 and Hco-tbb-iso-4. We show that Hco-tbb-iso-1 is not a one-to-one orthologue with Cel-ben-1, the only β-tubulin gene in C. elegans that is a benzimidazole drug target. Instead, both Hco-tbb-iso-1 and Hco-tbb-iso-2 have a complex evolutionary relationship with three C. elegans β-tubulin genes: Cel-ben-1, Cel-tbb-1 and Cel-tbb-2. Furthermore, we show that both Hco-tbb-iso-1 and Hco-tbb-iso-2 are highly expressed in adult worms; in contrast, Hco-tbb-iso-3 and Hco-tbb-iso-4 are expressed only at very low levels and are orthologous to the Cel-mec-7 and Cel-tbb-4 genes, respectively, suggesting that they have specialized functional roles. Indeed, we have found that the expression pattern of Hco-tbb-iso-3 in H. contortus is identical to that of Cel-mec-7 in C. elegans, being expressed in just six "touch receptor" mechano-sensory neurons. These results suggest that further investigation is warranted into the potential involvement of strongylid isotype-2 β-tubulin genes in mechanisms of benzimidazole resistance.
authors: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, 464 Bearsden Road, Glasgow, Scotland G61 1QH, UK.
authors: Gary Ian
authors: GI
authors: Saunders
authors: James David
authors: JD
authors: Wasmuth
authors: Robin
authors: R
authors: Beech
authors: Roz
authors: R
authors: Laing
authors: Martin
authors: M
authors: Hunt
authors: Hardeep
authors: H
authors: Naghra
authors: James A
authors: JA
authors: Cotton
authors: Matt
authors: M
authors: Berriman
authors: Collette
authors: C
authors: Britton
authors: John Stuart
authors: JS
authors: Gilleard
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000235:genetics; D016000:Cluster Analysis; D004351:Drug Resistance; D020869:Gene Expression Profiling; D006189:Haemonchus / Q000187:drug effects* / Q000235:genetics*; D008969:Molecular Sequence Data; D005810:Multigene Family; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D017385:Sequence Homology; D014404:Tubulin / Q000235:genetics*
chemical_list: D000871:Anthelmintics; D001562:Benzimidazoles; D014404:Tubulin; C031000:benzimidazole