Setaria digitata is an ivory coloured, slimy filarial parasitic worm with a coiled tapering tail. It is classified under class Secernentea, order Spirurida and family Setariidae. S. digitata naturally resides in the peritoneal cavity of grazing hoofed animals. (Shin et al., 2002; Shiny et al., 2011) They cause cerebrospinal nematodiasis, a neuropathological disorder that causes dysfunction of the central nervous system leading to lumbar paralysis with eventual death of non-permissive domesticated hosts such as goats, sheep and horses. As a result, this causes substantial economic losses in animal husbandry in South East Asia and the Far East. (Wickramatunga et al., 2020) However, they are not parasitic in their natural hosts such as cattle and buffaloes, but may cause mild disease conditions like fibrinous peritonitis. Human infections have also been reported in many studies and these can cause allergic reactions, eye lesions, abscesses, enlarged lymph nodes and lung inflammation. (Taylor et al., 1999; Gunawardene et al., 2015; Sundar et al., 2015).
Most of the filarial nematodes are mutually associated with Wolbachia. Their endosymbiotic relationship carries the genes required for the metabolism of haem, riboflavin, FAD, glutathione and nucleotides whereas its filarial host does not (Werren et al., 2008; Fenn et al., 2006). Although from earlier studies on filarial genomes have already identified five biosynthetic pathways coded by Wolbachia that are involved in haem/riboflavin/FAD/glutathione and nucleotide synthesis, only a few of them are fully encoded by Wolbachia. For example, FAD and glutathione pathways are found to be complete in all nematode genomes, whereas riboflavin and haem biosynthesis pathways are missing which otherwise would allow them to be carried out by protein coding genes in the Wolbachia genome. Filarial nematodes also do not have most enzymes required for purine biosynthesis and the first enzyme required for pyrimidine synthesis. Therefore, filarial nematodes cannot synthesize nucleotides de novo (Desjardins et al., 2013). Nevertheless, Wolbachia has the complete de novo nucleotide synthesis pathway and thus supplies the host with nucleotides during periods of high metabolic demand (Darby et al., 2012). They also contain purine-pyrimidine interconversion pathways. (Lee, 2002). As it is not clear on the endosymbiont relationships, whether or not the genes responsible for the biosynthetic pathways should be present in its genome remains to be ascertained. (Voronin et al., 2015). It was earlier shown that the Wolbachia free filarial nematode Loa loa have evolved their own DNA sequences to code for haem and riboflavin biosynthetic pathways. For some pathways, they have gained partial gene sequences from Wolbachia, indicating horizontal gene transfer (HGT) within Loa loa and Wolbachia at some point during the evolution. (Desjardins et al., 2013) Therefore, independent survival of S. digitata also can be explained by HGT events leading to coding of these pathways. (Mcnulty et al., 2010) .
The use of anti-Wolbachia chemotherapy against filarial parasites is a novel approach for filarial disease control and eradication. In anti-Wolbachia chemotherapy, development, reproduction, and survival of the filarial nematodes are interfered by eliminating Wolbachia endosymbiont through antibiotic treatment. (Desjardins et al., 2013; Mcnulty et al., 2010; Lefoulon et al., 2016). However, S. digitata may not be responsive to antibiotics since it does not have Wolbachia. S. digitata is also considered as a model organism for HLF, due to their close resemblance to Wuchereria bancrofti, the primary causative agent of HLF, in morphology, histology and antigenicity (Perumal et al., 2015). Therefore, generation of a draft genome of S. digitata and complete functional analysis will pave the way to understand not only the biology of this organism but also to identify novel drug targets and/or vaccine candidates for human filariasis as well as other filarial diseases. Further, the reconstruction of complete metabolic pathways of S. digitata has not been undertaken yet and hence this study was undertaken to decipher the knowledge on how Setaria digitata acquires this metabolism. We discuss in great details the results, annotation of the genome heralding pathways.