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Teams Scour Parasitic Worm Genome, Transcriptomes for Signs of Vulnerability

NEW YORK (GenomeWeb News) – A pair of genome sequencing studies appearing online yesterday in Genome Biology is stirring enthusiasm about the prospect of getting at the genetic roots of drug resistance in Haemonchus contortus — commonly known as the barber pole worm — and coming up with new ways to combat the sheep parasite.

"Our reference genome allows researchers to understand how H. contortus and other worms of this type acquire resistance to a wide range of anthelmintics — the drugs used to treat worm infections," the Wellcome Trust Sanger Institute's James Cotton, co-corresponding author on one of the studies, said in a statement.

Cotton and University of Calgary veterinary medicine researcher John Gilleard led a team from the UK, Canada, the US, and Japan that used Roche 454 and Illumina platforms to generate genome sequences from an H. contortus strain that is still sensitive to most main classes of anthelmintic drugs — an important distinction given the rampant drug resistance and extensive genetic diversity found in the parasitic nematode, which infects sheep and other small ruminant livestock animals.

Together with transcriptome sequences from various H. contortus tissues taken at different stages of the worm's lifestyle, the resulting 320 million base draft genome pointed to some 21,799 protein-coding genes. Among them were genes from families that have undergone expansions since H. contortus' split from its free-living, non-parasitic relative Caenorhabditis elegans, as well as other genes suspected of contributing to the worm's parasitic habits.

Through a network analysis focused on metabolic chokepoints found in H. contortus, meanwhile, the researchers identified five genes coding for metabolic enzymes that appear to be required for the barber pole worm's survival. One of these is the H. contortus version of a gene already being targeted in the Mycobacterium tuberculosis parasite, while another corresponds to a drug target in the filarial worm Brugia malayi.

"Not only is this worm closely related to many other parasites of livestock it is also similar to some species of worms in humans," the University of Calgary's Gilleard said in a statement. "Revealing new drug targets against H. contortus could provide much-needed new treatment opportunities against parasitic worms in both animals and humans."

The availability of a reference sequence for a drug-susceptible version of H. contortus also opens the door to future comparisons with sequences from H. contortus strains that can withstand one or many of the treatments already available, prompting optimism about the prospect of better understanding such resistance.

In another study in the same issue of Genome Biology, an independent California Institute of Technology- and University of Melbourne-led team described their own genome and transcriptome sequencing analysis of H. contortus, which focused on Australian strains of the parasitic worm.

That group used Illumina GAII and HiSeq platforms to generate a 320 million base genome assembly — covered to a depth of 185-fold, on average — that houses 23,610 predicted protein-coding genes.

The team's comparison between the H. contortus genome and sequences from several other nematodes highlighted a set of genes present across parasitic nematodes, but missing in C. elegans. It also turned up genes that appear to be specific to the barber pole worm.

The investigators' search for potential players in H. contortus parasitism, host interactions, and more general biology included assessments of the worm's enzyme families, its secreted proteins profiles, and the gene expression patterns that mark its various life stages, which were deciphered with the help of transcriptome sequencing.

Their analysis also considered features ranging from the genetic variant profiles and possible drug targets in the genome to the 229 apparent gene players in the barber pole worm's RNA interference system. Among the potential drug targets that they detected, meanwhile, were 260 proteins that included dozens of enzymes, channel proteins, and transport players.

"Determining the genome sequence and transcriptomes of H. contortus can accelerate post-genomic explorations of genes and gene products involved in nematode development and reproduction, future proteomic and metabolomic studies, parasite-host interactions, and pathogenesis of disease," corresponding author Robin Gasser, a veterinary science researcher at the University of Melbourne, and his colleagues concluded.

"The characterization of the RNAi machinery for H. contortus also provides a solid platform for functional genomic work in selected stages of the parasite," they noted. "Therefore, an integrated systems biology approach should provide novel strategies for parasitic intervention via drugs, vaccines, and diagnostic tests."

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