title: Sequence variation in the Trichuris trichiura beta-tubulin locus: implications for the development of benzimidazole resistance.
abstract: Benzimidazole resistance has evolved in a variety of organisms and typically results from mutations in the beta-tubulin locus at specific amino acid sites. Despite widespread treatment of human intestinal nematodes with benzimidazole drugs, there have been no unambiguous reports of resistance. However, since beta-tubulin mutations conferring resistance are generally recessive, frequencies of resistance alleles less than 30% would be difficult to detect on the basis of drug treatment failures. Here we investigate sequence variation in a 1079 bp segment of the beta-tubulin locus in the human whipworm Trichuris trichiura from 72 individual nematodes from seven countries. We did not observe any alleles with amino acid mutations indicative of resistance, and of 40 point mutations there were only four non-synonymous mutations all of which were singletons. Estimated effective population sizes are an order of magnitude lower than those from another nematode species in which benzimidazole resistance has developed (Haemonchus contortus). Both the lower diversity and reduced population sizes suggest that benzimidazole resistance is likely to evolve less rapidly in Trichuris than in trichostrongyle parasites of livestock. We observed moderate levels of population subdivision (Phi(ST)=0.26) comparable with that previously observed in Ascaris lumbricoides, and identical alleles were frequently found in parasites from different continents, suggestive of recent admixture. A particularly interesting feature of the data is the high nucleotide diversities observed in nematodes from the Caribbean. This genetic complexity may be a direct result of extensive admixture and complex history of human populations in this region of the world. These data should encourage (but not make complacent) those involved in large-scale benzimidazole treatment of human intestinal nematodes.
authors.affiliation: Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College, St Mary's Campus, Old Medical School, Norfolk Place, W2 1PG, London, UK. a.bennett@ic.ac.uk
authors.forename: A B
authors.initials: AB
authors.lastname: Bennett
authors.forename: T J C
authors.initials: TJ
authors.lastname: Anderson
authors.forename: G C
authors.initials: GC
authors.lastname: Barker
authors.forename: E
authors.initials: E
authors.lastname: Michael
authors.forename: D A P
authors.initials: DA
authors.lastname: Bundy
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics*; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D017238:Genes, Helminth / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D009154:Mutation; D011110:Polymorphism, Genetic / Q000235:genetics; D011156:Population Density; D014258:Trichuris / Q000187:drug effects* / Q000235:genetics*; D014404:Tubulin / Q000235:genetics*
chemical_list: D000977:Antiparasitic Agents; D001562:Benzimidazoles; D014404:Tubulin; C031000:benzimidazole