- 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. - 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. - Moreover, network parameters are similar to those of single-species interaction networks that we constructed in the same way for S. - The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. - If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. - The unusually high level of complete- ness and quality of these assemblies makes them valuable not only for investigating these taxa, but also as mod- els of the superphylum Lophotrochozoa which remains significantly under-represented in all areas of biological research.. - This assembly was used to investigate differentially- expressed genes among different life cycle stages and regions of the adult, strobilar worm [5], and for char- acterisation of the microRNA complement [7]. - Probabilistic networks are more powerful than unweighted networks as they are annotated with a level of confidence in the evidence for each interaction by comparison with a benchmark ‘gold standard’ comprising a set of interactions believed, with high confidence, to be true interactions [30]. - We assessed the network by comparison of the major network parameters against networks of major model organisms produced using the same methods. - Blastx was then used to identify proteins from the BioGRID species which had significant similarity to those of the H. - In total, 230 data sets from 16 species were included in the final integration step (Fig. - 30% of the H. - We compared the topology of the H. - Sixteen species were included in the final network (main text Table 1b). - The human network was by far the largest of the four networks, reflecting the larger proteome and multiple tis- sue types (Table 1). - Hm_net, has the highest clustering coefficient of the four, likely due to the multiple sources of interolog evidence resulting in denser connectivity between related proteins. - The proteins with the largest number of inter- actions in the other species were the immune response E3 ubiquitin ligase TRIM25 in H. - In contrast, gei-4 has just 181 interactions, all of which are present in the final network.. - The distribution of topological parameters in all four networks were similar, with the scale of the scores reflect- ing the size and density of the networks (Figs. - Toplogically-important proteins of the high confidence network (Hm_HC_net) are involved in essential cellular processes. - The topological statistics of a network may be used to identify the most important proteins in the network. - We chose to assess the topologically-important proteins of the largest connected component of Hm_HC_net (1260 pro- teins and 3995 interactions) based on three topological scores produced by NetworkAnalyser:. - elegans Hm_net. - The network and topological statistics of the of Hm_net in comparison to single species networks. - The degree distribution of the four networks with the power law fitted (red). - The largest network hub with 88 interactions, HmN is a cell cycle division 5-like (CDC5L) protein that is involved in the G2/M transition and known to be required for pre-mRNA splicing. - Of the remaining top network hubs, a large number of the proteins were involved in gene expression;. - Five of the hubs were cullin family proteins which play an intrinsic role in post-translational modi- fication of protein via ubiquitination [39]. - Four of these cullin proteins, (HmN HmN HmN_003003610 and HmN have interac- tions resulting from the same interolog evidence, resulting in identical interactions and topological statistics in the network. - Betweenness centrality is a measure of the amount of influence a pro- tein has on information flow based on the number of shortest paths between protein pairs on which it lies. - Closeness centrality also measures information flow through a protein based on how short the shortest paths are from that protein to all other pro- teins in the network. - Of the top scoring proteins for betweenness centrality (Table 3) ten are also network hubs. - The other fifteen proteins are six involved in the cell cycle and replication,. - The distribution of betweenness centrality of the four networks with the power law fitted (red). - Four of the cell cycle proteins are transitional endoplasmic reticulum ATPases (HmN HmN_003022520 and HmN have interactions resulting from the same interolog evidence and, therefore, identical interactions and topological statistics in the network.. - The remaining high CC are a splicing factor, a chap- eronin, a SNW domain containing transcriptional pro- tein, and two proteins involved in the cell cycle and replication.. - Network clusters of the high confidence network (Hm_HC_net) correspond to biological modules and processes. - We used the MCODE algorithm to identify tightly con- nected areas of the largest component of Hm_HC_net since clusters in protein-protein networks from model species generally correspond to complexes of proteins involved in the same biological process [43]. - Eight of the ribosomal proteins of cluster 1 are network hubs. - Cluster 6 comprises six eukaryotic translation initiation factors and two subunits of the COP9 signalosome, a regu- lator of the Cullin-RING proteins. - The distribution of closeness centrality of the four networks with the power law fitted (red). - of the Lsm proteins which bind U6 snRNPs and a probable snRNP. - Finally, clusters 8, 9 and 10 are signalling and regu- latory clusters each comprising several kinases in addition to members of the 14-3-3 proteins, PAK kinases and RhoA pathways, respectively. - These suites of genes were chosen because of an interest in the developmen- tal genetics of these organisms [5], and because they have been hand-curated, making their IDs more reliable than the gene models identified solely by automated means.. - As expected, the majority of the GOIs that were present in the network, and that also showed the largest number of interactions, were signal transduction components or cell cycle regulators that are highly conserved and among the former, often operate across multiple pathways. - Among these are some of the most highly connected proteins among the GOIs, such as RhoA, a hydrolase that acts in the Wnt planar cell polarity pathway and Cal- cineurin, a protein phosphatase involved in dephosphory- lation which acts in the calcium-dependent Wnt pathway (Fig. - The distribution of clustering coefficient of the four networks. - Results predict direct interactions between the posterior morphogen Wnt1 and three of the five frizzled receptors in their genome (Fz4, Fz1/2/3/6/7 and FzC) [45]. - proteins, components of the Notch signalling pathway (discussed above) and Hox transcription factors found in Hm_net. - were found in the network, but those that were are con- nected, as expected, by other regulators of the cell cycle such as CDC5-like. - However, one of two zinc finger transcription factors putatively associated with flatworm stem cells [48] has four predicted interacting proteins, all of which are SMAD factors, the intracellular transducers of the TGF β /BMP signalling pathways.. - Only two Hox family transcription factors were found to be present in the network: a bona fide ‘posterior’. - Although the sequences of these two proteins are very divergent, both are annotated with iden- tical interacting proteins, and thus would be predicted to be playing the same role in the organism. - Interest- ingly, five of the eight associated proteins are forkhead box (FOX) transcription factors, which are known to interact with Hox genes [49], and the network results thus pro- vide predictions of which of the numerous FOX proteins in tapeworms to investigate in relation to Hox expression.. - Of 3,479 DEGs, 367 were present in the net- work, and 176 proteins formed a connected component of 668 interactions (Fig. - Several members of the network clusters (Fig. - 9) were represented in the DEG subnetwork, with protein production processes being up-regulated in lar- vae and cytoskeletal and ubiquitin-related processes up- regulated in adults. - Of the hub proteins (Table 2) fourteen. - Four of the eight proteasomal subunits of cluster 2 were also up-regulated in larvae. - A large connected group of ubiquitination-associated pro- teins were up-regulated in adult worms, with the excep- tion of four proteins at the periphery of the group, which had higher expression in larvae. - HSP90, one of the largest hubs in Hm_HC_net with 52 interactions, was also up-regulated in addition to a group of 6 casein kinases, and two histone modification proteins.. - The majority of cyclin- dependent kinases, with the exception of one of the pro- tein hubs (Table 2. - Additional file 1 Table S2), present in the DEG network were up-regulated in larvae, while Ras was up-regulated in adult worms. - Since the interologs are produced from a number of different species, these net- works can have an additional level of noise, as not all inter- actions occurring in the source organisms will occur in H. - While this would not be necessary or desirable in well-studied species, the thresholding of the network to remove low scoring interactions allows for the. - However, these approaches can come at the cost of the removal of valid and useful data [57].. - In addition, of particular interest are the 14-3-3 proteins that feature prominently in Hm_net as a clus- ter of nine proteins, three of which are found in the differential expression subnetwork (two up-regulated in adult and one in larvae) and share interaction partners.. - These signalling ligands are highly conserved in eukary- otes [58] and are found in the excretory vesicles of the Echinococcus granulosus larvae where they may be used. - This protein is involved in cell cycle arrest and is conserved between most of the species included in the interolog network build [61–63]. - Analysis of these and other network-based features has been used successfully in the prediction of essential genes across diverse organisms [64]. - For example, HmN_000742700 and HmN although un-annotated, cluster in the network with the tubulins (Fig. - The caveat to this type of approach is that the proteome of the comparison species must be as complete as that of H. - 1/3 of proteins), but nevertheless covers a larger proportion of the somatic proteome than the equivalent network for the model worm C. - Inclusion of other types of interaction has the potential to increase this coverage of the Hymenolepis microstoma somatic pro- teome. - In a new study, Montagne and colleagues used a yeast two-hybrid system and additional means to inves- tigate the downstream effectors of canonical Wnt sig- nalling in tapeworms, showing that only one of three paralogs of β -catenin interacts with components of the canonical destruction pathway [81], similar to the situ- ation in free-living planarians [82]. - This represents one of the first such studies to test protein interactions in tapeworms, illustrating the scarcity of experimental data available for these important pathogens. - P ( L ) (1) where, P(L|E) and ¬P(L|E) represent the frequencies of linkages L observed in dataset E between genes anno- tated to the same and differing BioSystems pathways, respectively, and, P(L) and ¬P(L) represent the prior expectation of linkages between genes in the same and. - higher scores indicate greater confidence in the predicted interactions. - Orthologs of the H. - microstoma proteome (version v.3) were identified with Blast+ (version 2.7.1) using the -gilist option to limit the search to NCBI identifiers from species in the BioGRID database (e-value <. - elegans proteomes were derived by integration of the unfiltered data sets spe- cific to each of those species using the same integration pipeline. - were present in the network, and where so, extracted the relevant sub-networks to examine the interologs:. - 1 Components of the Wnt, Notch and Hedgehog signalling pathways [4].. - Differential expression was calculated by re-analysing previously available RNA-seq data [5] in order to take advantage of the more complete v.3 genome assem- bly and gene models. - The proteins of the top ten clusters with in-cluster degree and MCODE. - 200 interactions) datasets extracted from V164 of the BioGRID database. - High throughput datasets extracted from V164 of the BioGRID database (>=200 interactions). - We thank Alan Tracey, Nancy Holroyd and Matt Berriman (Wellcome Trust Sanger Genome Institute), and Andrew Baillie (NHM), for production of the H.. - A systematically improved high quality genome and transcriptome of the human blood fluke Schistosoma mansoni. - Comparative genomics of the major parasitic worms. - The genome of the blood fluke Schistosoma mansoni. - Description of Hymenolepis microstoma (Nottingham strain): a classical tapeworm model for research in the genomic era. - Evolutionary rate in the protein interaction network. - BMC Genomics. - The binary protein interactome of Treponema pallidum–the syphilis spirochete. - High-betweenness proteins in the yeast protein interaction network. - Characterization of 14-3-3 isoforms expressed in the Echinococcus granulosus pathogenic larval stage. - A map of the interactome network of the metazoan C. - Empirically controlled mapping of the Caenorhabditis elegans protein-protein interactome network. - Divergent Axin and GSK-3 paralogs in the beta-catenin destruction complexes of tapeworms.
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