The evolution and molecular epidemiology of variation in antigen coding genes of the zoonotic parasite Schistosoma japonicum

The broad host range of the Asian blood fluke Schistosoma japonicum is a principal factor maintaining transmission in the face of strenuous control efforts and supports schistosomiasis re-emergence across Southeast Asia, where multi-host transmission is complex and contextspecific. The extent to which such transmission influences the genetic variability of S. japonicum antigen coding genes (SjACGs) has yet to be investigated, despite its relevance to parasite survival, evolution, control, and vaccine development. In this thesis, molecular techniques and bioinformatic approaches are used to explore the molecular epidemiology and evolutionary processes driving inter- and intra-definitive host variability of SjACGs, as well as SjACG variation, across China. Through application of molecular clocks, and changes to SjACG allele frequency spectra, SjACG divergence was dated to ~1.7-0.66 MYA, before modern humans arrived in China, suggesting animal hosts have been, and remain, important for SjACG evolution. Whole genome sequencing and comparative genomics with the closely-related S. mekongi facilitates assessment of antigen diversity between Asian schistosomes, providing further insight into schistosome antigen evolution. Population genetic analyses revealed SjACGs to be highly diverse across China, and within/between definitive host species. Overall, 10-20 unique SjACG variants were identified from the sampled hosts. Across SjTSP-23, SjVAL-7, and SjTAL-1, seven, six and 12 host-specific, and three, four, and eight shared antigen variants were identified, highlighting the importance of certain host species in the generation and maintenance of SjACG diversity, and the importance of zoonotic transmission in disseminating that diversity. Human-host derived/sampled SjACGs had the greatest overall diversity and shared variants with all host species, supporting their suggested role as ‘genetic mixing bowls’. Concurrently, antigen variants specific to humans were most abundant (4-7), supporting their capacity as ‘antigenic sinks’. Selection-driven antigen diversification was predicted to impact the structure, function, and antigenic propensity of detected antigen variants. Given that some variants may be host-specific, adaptive antigen evolution to specific hosts, and variation in the immunomodulatory competency between variants is proposed. Collectively, the results have theoretical and applied implications for zoonotic schistosomiasis control in China, and elsewhere, and improve our understanding of the impact of zoonotic transmission on the co-evolutionary processes driving antigenic variability.