Structural variation drives praziquantel response and host adaptation in Schistosoma japonicum

Structural variation (SV) is a major yet underappreciated source of genomic diversity that drives parasite adaptation. We generated the first comprehensive SV map of Schistosoma japonicum from 72 genomes across six endemic Asian regions, identifying 12,632 high-confidence SVs spanning 3.55% of the genome that delineate population structure and adaptive trajectories. SVs are non-randomly distributed and preferentially affect regulatory regions rather than coding sequences. Geographic isolation, demography, and positive selection collectively shape the SV landscape. Convergent deletions in SCNN1A, a sodium channel gene, occur in Southeast Asian populations under long-term praziquantel (PZQ) exposure and may alter its active pocket and transport activity. Taiwan-specific SVs in SETD4, GDPD1, and PAFAH1B1 are linked to reproductive adaptation and reduced pathogenicity. Expression assays confirm stage- and sex-specific regulation of these genes under PZQ treatment. These findings establish SVs as key drivers of drug response and host adaptation in S. japonicum, offering insights for precision surveillance and next-generation anthelmintic design.