The cytochrome P450 family in the parasitic nematode Haemonchus contortus

Laing, Roz (2010) The cytochrome P450 family in the parasitic nematode Haemonchus contortus. PhD thesis, University of Glasgow.

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Haemonchus contortus, a parasitic nematode of sheep, is unsurpassed in its
ability to develop resistance to the anthelmintic drugs used as the mainstay of
its control. A reduction in drug efficacy leads to prophylactic and therapeutic
failure, resulting in loss of productivity and poor animal welfare. This situation
has reached crisis point in the sheep industry, with farms forced to close their
sheep enterprises due to an inability to control resistant nematodes.
The mechanisms of anthelmintic resistance are poorly understood for many
commonly used drugs. Altered or increased drug metabolism is a possible
mechanism, yet has received little attention despite the clear role of xenobiotic
metabolism in pesticide resistance in insects. The cytochrome P450s (CYPs) are a
large family of drug-metabolising enzymes present in all species. Their
expression is induced on exposure to their substrate and over-expression of a
single CYP has been shown to confer multi-drug resistance in insects.
The H. contortus genome is currently being sequenced and assembled at the
Wellcome Trust Sanger Institute, Cambridge. Despite the lack of a completed
genome, the public provision of read, contig and supercontig databases has
facilitated the identification of 73 partial gene sequences representing a large
family of H. contortus CYPs. Their constitutive expression is highest in larval
stages although adult expression was also detected. The majority of CYPs are
most highly expressed in the worm intestine, which is thought to be the main
organ of detoxification in nematodes and is consistent with a role in xenobiotic
metabolism. A small number of CYPs were more highly expressed in anthelmintic
resistant isolates than in an anthelmintic-susceptible isolate and may represent
candidate genes for further research. The identification of putative H. contortus
orthologues of the Caenorhabditis elegans nuclear hormone receptors controlling
CYP transcription and the cytochrome P450 reductase gene catalysing electron
transfer to CYPs suggests that regulatory and functional pathways may be
conserved between the species.
Transcriptome analysis using next generation sequencing was undertaken to
guide a pilot annotation of 590 Kb genomic sequence. A high degree of
conservation was observed between the conceptual translations of H. contortus
and C. elegans genes, although at a genomic level, H. contortus consistently had
a larger number and size of introns, which may reflect a larger genome than
previously predicted. Gene order was not conserved, although regions of
microsynteny were present and a bias for intra-chromosomal rearrangements
resulted in putative orthologues frequently residing on the corresponding
chromosome in both species. Partial conservation of a number of C. elegans
operons in H. contortus was identified. These findings have important
implications for the H. contortus genome project and the transcriptome
databases provide a valuable resource for future global comparisons of gene

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: S Agriculture > SF Animal culture > SF600 Veterinary Medicine
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
Supervisor's Name: Gilleard, Prof. John
Date of Award: 2010
Depositing User: Miss Roz Laing
Unique ID: glathesis:2010-2355
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 31 Jan 2011
Last Modified: 04 Feb 2014 08:45

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