The tapeworm interactome: inferring confidence scored protein-protein interactions from the proteome of Hymenolepis microstoma

Abstract

Background: Reference genome and transcriptome assemblies of helminths have reached a level of completion whereby secondary analyses that rely on accurate gene estimation or syntenic relationships can be now conducted with a high level of confidence. Recent public release of the v.3 assembly of the mouse bile-duct tapeworm, Hymenolepis microstoma, provides chromosome-level characterisation of the genome and a stabilised set of protein coding gene models underpinned by bioinformatic and empirical data. However, interactome data have not been produced. Conserved protein-protein interactions in other organisms, termed interologs, can be used to transfer interactions between species, allowing systems-level analysis in non-model organisms. Results: Here, we describe a probabilistic, integrated network of interologs for the H. microstoma proteome, based on conserved protein interactions found in eukaryote model species. Almost a third of the 10,139 gene models in the v.3 assembly could be assigned interaction data and assessment of the resulting network indicates that topologically-important proteins are related to essential cellular pathways, and that the network clusters into biologically meaningful components. Moreover, network parameters are similar to those of single-species interaction networks that we constructed in the same way for S. cerevisiae, C. elegans and H. sapiens, demonstrating that information-rich, system-level analyses can be conducted even on species separated by a large phylogenetic distance from the major model organisms from which most protein interaction evidence is based. Using the interolog network, we then focused on sub-networks of interactions assigned to discrete suites of genes of interest, including signalling components and transcription factors, germline multipotency genes, and genes differentially-expressed between larval and adult worms. Results show not only an expected bias toward highly-conserved proteins, such as components of intracellular signal transduction, but in some cases predicted interactions with transcription factors that aid in identifying their target genes. Conclusions: With key helminth genomes now complete, systems-level analyses can provide an important predictive framework to guide basic and applied research on helminths and will become increasingly informative as new protein-protein interaction data accumulate.

Complete representation of a tapeworm genome reveals chromosomes capped by centromeres, necessitating a dual role in segregation and protection

“…The hybrid assembly has stabilised estimates of the proteome and non-coding regions and represents a resource effectively free from sampling error. The release thus provides a robust platform to begin systems-level analyses in parasitic flatworms and to this end has been recently used to infer protein-protein interactions based on functional data gathered from major model systems [49]. Producing a fully resolved assembly revealed several unexpected features.…”

Expanding Interactome Analyses beyond Model Eukaryotes

“…Conserved interactions, termed 'interologs' (direct), 'associologs' (functional) or 'regulogs' (regulatory), can therefore be transferred between species [68][69][70][71][72][73][74] providing systems-level network analysis in organisms that lack empirical interaction data (Figure 1). Co-expression patterns are also conserved between species [75,76] allowing microarray and RNA-seq data to be used to predict functional links between species in the same way [75,77].…”

“…This resource was later extended to allow exploration of the network using gene expression data [391]. Finally, a probabilisitic functional integrated network of interologs was produced for the mouse bile duct tapeworm, Hymenolepis microstoma [74]. Although there is little interactome data for these species (Table 9), interactomics has the potential to expand our understanding of parasitism in the future.…”

“…It's clear from yeast interactomes that there can be low overlap between species; S. cerevsiae is well characterised but the C. albicans and S. pombe interactomes are different in a number of respects [191,193,204,407]. Combining different computational methods [86,105,106,310], and experimental data if available [232,235,376,408], can give a fuller picture of the interactome and mitigate the effect of data noise by using a probabilistic framework [74,198].…”

Segmentation in tapeworms as a modified form of flatworm posterior regeneration involving Wnt and Hedgehog signalling

“…Here we extend investigations of PCG expression in tapeworms to the strobilar phase of the life cycle of the mouse bile-duct tapeworm Hymenolepis microstoma [20]. This classical mouse/beetle-hosted laboratory model has been the subject of a series of genomic [21][22][23][24], transcriptomic [25,26] and developmental studies [5,27] that underpin its utility as a contemporary model and is now supported by the first fully complete, chromosome-level genome assembly of a spiralian [28]. We use single and double fluorescent whole-mount in situ hybridisation (FISH) to examine the expression domains of genes encoding Wnt ligands (wnt1, wnt11a, wnt11b), inhibitors (sfrp, sfl, notum) and receptors (fz4, fz5/8, fz1/2/3/6 /7) involved in the canonical Wnt pathway, as well as of a gene encoding a Hedgehog ligand, an upstream regulator of Wnt signalling in planarians [29].…”