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Parasitic Worm Adaptations, Gene Targets Uncovered by Comparative Genomics

NEW YORK (GenomeWeb) – An international team led by investigators in the US and the UK used genomics to uncover shared adaptations — including altered interactions with the human immune system — that have helped roundworms (nematodes) and flatworms (platyhelminths) evolve parasitic lifestyles.

"Parasitic worms are some of our oldest foes, and have evolved over millions of years to be expert manipulators of the human immune system," co-senior and co-corresponding author Makedonka Mitreva, an internal medicine researcher affiliated with Washington University's McDonnell Genome Institute, said in a statement. "This study will lead to a better understanding of the biology of these important organisms, but could also help us better understand how our immune systems can be harnessed or controlled."

Mitreva and other members of the International Helminth Genomes Consortium sequenced draft genomes for dozens of parasitic and non-parasitic roundworm or flatworm species, comparing the sequences to one another and to genomes sequenced in the past, in an effort to untangle the gene families and pathways behind adaptations to parasitic lifestyles. The findings, published online today in Nature Genetics, revealed new genes, gene family expansions, and altered host interactions in the parasites profiled.

"All the parasites evolved from free living ancestors, and comparing their genomes has shown the changes that happen when a species becomes a parasite," co-author Mark Blaxter, an immunity, infection, and evolution researcher at the University of Edinburgh, said in a statement.

For their analyses, the researchers considered 81 worm genomes, including sequences for 36 species sequenced in the past, another 36 species newly sequenced at the Sanger Institute, half a dozen species sequenced at Washington University's McDonnell Genome Institute, and three species sequenced at the University of Edinburgh's Blaxter Nematode and Neglected Genomics lab.

In the 45 new genomes, the team identified some 800,000 predicted protein-coding genes, with a range of more than 9,100 to nearly 17,300 genes per species profiled. Folding in information on another 31 parasitic and five free-living worm species described in past studies, along with 10 outgroup animals, the group tracked down 1.6 million predicted protein-coding genes falling in more than 108,300 gene families.

When they dug into these data, the researchers got a look at conserved genes as well as the genes, non-coding DNA content, repeat sequences, and metabolic features that distinguished the free-living worms from their parasitic counterparts.

Along with a phylogenetic analysis of the parasitic and non-parasitic worm species, the team identified gene family expansions at parasitism-related points in the worms' tree, along with changes expected to alter the worms' core metabolic processes or host interactions.

"[B]y focusing on lineage-specific trends rather than individual species-specific difference, our analysis was deliberately conservative," the authors noted. In particular, we have focused on large gene family expansions, supported by the best-quality data and for which functional information was available."

To complement those analyses, the researchers also devised a pipeline for performing in silico screening based on worm genome sequences and target data for compounds in the ChEMBL database, narrowing in candidate worm treatments and 40 high-priority potential drug target genes in the parasitic worms.

"We have uncovered many new genes and gene families to help understand how the worms live and migrate inside us and other animals," co-senior and co-corresponding author Matthew Berriman, a parasite genomics researcher at the Wellcome Trust Sanger Institute, said in a statement. "This dataset will catapult worm research into a new era of discovery."

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