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Team Interrogates Tapeworm Genomes for Treatment Clues

NEW YORK (GenomeWeb News) – Tapeworm infections may be vulnerable to some of the same compounds used in cancer chemotherapy — at least that's one of the predictions stemming from a new Nature study focused on genome sequences for four tapeworm species.

The international team used a combination of sequencing approaches to put together a high-quality reference genome assembly for the so-called fox tapeworm, Echinococcus multilocularis. Members of the group sequenced three more tapeworms, too: the dog tapeworm (E. granulosus) and pork tapeworm (Taenia solium) — which, like E. multilocularis, can infect humans — and the rodent tapeworm Hymenolepis microstoma, a popular lab model species.

From this quartet of genomes, investigators gleaned new details about the genetic features that have helped tapeworms adapt to a life of parasitism, finding gene families bolstered during this process, for example, along with genes that have been jettisoned.

Through an analysis of predicted protein coding genes in the genomes, meanwhile, the researchers put together a list of potential treatment targets, focusing in particular on genes that might be susceptible to existing drugs. At the top of that list were orthologs for genes targeted by some anti-cancer compounds — a finding that was at first surprising, but which seems to fit with certain features of the larvae-driven cysts that can grow in infected host tissues.

"The tumor-like growth, the cyst, is proliferating and … almost a tissue in its own right," co-senior author Matthew Berriman, a parasite genomics researcher with the Wellcome Trust Sanger Institute, told GenomeWeb Daily News. "So getting a drug to it that's designed to take out fast-growing cells in a cancer patient certainly makes a lot of sense."

Three groups of parasitic worms can plague humans and other mammalian hosts: roundworms, flukes, and tapeworms, he and his co-authors said. Tapeworms — which make up a class called Cestoda within the flatworm phylum — are the last to have one or more representatives with sequenced genomes, they noted. But the parasites are no less clinically relevant.

While adult tapeworms typically stay put in the guts of their hosts, the larvae can make its way into other tissue and organs where it causes debilitating and sometimes-deadly growths. The treatment for such infections is limited, prompting interest in tapeworm biology and strategies for more effectively combating tapeworm infections and the neglected tropical diseases they can cause.

For their new analysis, researchers turned to multiple platforms to sequence the tapeworm genomes — which ranged in size from around 115 million base pairs to more than 140 million base pairs.

The genome that has gotten the most scrutiny so far, that of E. multilocularis, was assessed using a combination of optical mapping, Illumina sequencing, and Roche 454 sequencing, Berriman said. With this data, researchers put together a high-quality reference assembly, mapping most of the sequences to the tapeworm's nine chromosomes.

The group subsequently set its sights on the other tapeworm species, too — namely the dog tapeworm E. granulosus and the H. microstoma, or rodent, tapeworm. Meanwhile, collaborators in Mexico and China were each sequencing different T. solium, or pork tapeworm, strains.

During the sequencing process, Berriman said, investigators came to realize just how similar the widespread E. granulosus species is to its deadlier sister species E. multilocularis. Such similarities, coupled with low genetic variation in the two Echinococcus species, made it possible to get a fairly high quality assembly for the dog tapeworm by mapping Illumina sequence data back to the newly sequenced fox tapeworm reference.

The researchers subsequently tracked down between around 10,200 and nearly 12,500 predicted protein-coding sequences in each of the four genomes with the help of RNA sequence data and some manual curation steps.

Even with the genome sequences in hand, though, some of the analyses aimed at understanding adaptations specific to tapeworms proved a bit tricky, Berriman said, mainly because tapeworms reside on a "really unexplored branch" of the flatworm tree.

"Amongst the flatworms, flukes have been explored, and free-living examples … have been explored at the genome level," he said. "But for the cestodes, which are highly derived, there's not really anything to compare them to, other than these quite distant relatives."

Nevertheless, comparisons with these somewhat far-flung outgroups — and with some sequenced model organisms such as lancelet, Caenorhabditis elegans, and Drosophila melanogaster — did provide insights into genetic features that fit with the tapeworm's life of parasitism.

In particular, the group saw extensive streamlining of the tapeworm's metabolic pathways. That included a dip in representation from redundant oxidation-reduction metabolism components, for example, along with a simplified, scavenger-like system for nabbing necessary lipids from an infected host.

The team also noticed dramatic reductions in certain gene families — most notably within families of homeobox genes that encode transcription factors contributing to precise body plan patterning in animals.

While tapeworms have a fairly complex life cycle, this loss of homeobox genes does seem to fit with the symmetrical, repetitive nature of the adult tapeworm's body plan, Berriman said, noting that such features "require less complexity in the homeobox genes."

On the other hand, the analysis revealed far more genes from a family of non-canonical heat shock protein-coding genes than usual in the tapeworm genomes — a gene family expansion that's still somewhat puzzling to researchers.

When the study's authors scoured the tapeworm's predicted protein-coding gene sets for possible drug targets, meanwhile, they unearthed a collection of genes weighted toward biosynthetic, signaling, transport, and other growth-related pathways that may be disrupted by some of the same therapies already used against cancer.

"The top of the list is highly, highly enriched for potential targets of current cancer chemotherapies," Berriman said. "So the attractive proposition is that maybe these existing drugs could really shortcut the drug discovery pipeline by several years."

To further explore that possibility, some members of the team are gearing up to test some of these compounds on lab-grown tapeworm cells.

Other follow-up analyses being planned or already underway include studies into gene gains and losses in the tapeworms, along with sequencing analyses aimed at fleshing out representation by tapeworm relatives in the flatworm tree.

"We're trying to get hold of some quite strange tapeworms that have various morphological features … for instance, tapeworms that aren't fully segmented," Berriman said. "That will allow us to explore the story of homeobox gene loss and its effect on the overall body plan."

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