Exploitation of phylum-spanning omics resources reveals complexity in the nematode FLP signalling system and provides insights into flp-gene evolution.

Background: Parasitic nematodes significantly undermine global human and animal health and productivity. Parasite control is reliant on anthelmintic administration however over-use of a limited number of drugs has resulted in escalating parasitic nematode resistance, threatening the sustainability of parasite control and underscoring an urgent need for the development of novel therapeutics. FMRFamide-like peptides (FLPs), the largest family of nematode neuropeptides, modulate nematode behaviours including those important for parasite survival, highlighting FLP receptors (FLP-GPCRs) as appealing putative novel anthelmintic targets. Advances in omics resources have enabled the identification of FLPs and neuropeptide-GPCRs in some parasitic nematodes, but remaining gaps in FLP-ligand libraries hinder the characterisation of receptor-ligand interactions, which are required to drive the development of novel control approaches.

Results: In this study we exploited recent expansions in nematode genome data to identify 2143 flp-genes in > 100 nematode species across free-living, entomopathogenic, plant, and animal parasitic lifestyles and representing 7 of the 12 major nematode clades. Our data reveal that: (i) the phylum-spanning flps, flp-1, -8, -14, and - 18, may be representative of the flp profile of the last common ancestor of nematodes; (ii) the majority of parasitic nematodes have a reduced flp complement relative to free-living species; (iii) FLP prepropeptide architecture is variable within and between flp-genes and across nematode species; (iv) FLP prepropeptide signatures facilitate flp-gene discrimination; (v) FLP motifs display variable length, amino acid sequence, and conservation; (vi) CLANS analysis provides insight into the evolutionary history of flp-gene sequelogues and reveals putative flp-gene paralogues and, (vii) flp expression is upregulated in the infective larval stage of several nematode parasites.

Conclusions: These data provide the foundation required for phylum-spanning FLP-GPCR deorphanisation screens in nematodes to seed the discovery and development of novel parasite control approaches.