Abstract

Background Cystic echinococcosis (CE), caused by the tapeworm Echinococcus granulosus sensu stricto (s.s.), is a globally distributed, zoonotic disease—recognised by the World Health Organization (WHO) as a neglected tropical disease (NTD). Despite its clinical and economic significance, nuclear genomic variation in this parasite has not been systematically characterised across global populations. Methods We conducted whole-genome sequencing of 137 E. granulosus s.s. samples from endemic regions across five continents. Using a chromosome-scale reference genome, we applied population genomic and comparative approaches to investigate nuclear genetic diversity, population structure and genome-wide patterns of variation and evolutionary constraint. Findings We identified more than one million high-quality nuclear single nucleotide polymorphisms (SNPs), with heterozygosity ranging from 46% to 93% per sample. Genome-wide analyses revealed two major clades associated with geographical origin. Distinct regions of high genetic differentiation, particularly on chromosome 9, were observed, representing candidate loci potentially associated with lineage divergence. Conserved genes under purifying selection, notably those involved in glycan biosynthesis and core cellular functions, were identified as potential diagnostic or therapeutic targets. In contrast, variable genes were enriched in pathways including ribosome biogenesis. Notably, mitochondrial genotypes (G1 and G3) did not align with nuclear genomic structure, indicating evolutionary discordance between mitochondrial and nuclear lineages. Interpretation To our knowledge, this study provides the first broad atlas of nuclear genomic diversity in E. granulosus s.s., uncovering genetic diversity and population structure. The findings have important implications for molecular epidemiology, genomic surveillance, and translational development of diagnostics and vaccines. Incorporating genomic data into CE control programs could enhance WHO-aligned efforts to reduce the burden of this NTD. Funding This study was supported by the Australian Research Council (ARC) and the Estonian Ministry of Education and Research.