Global population genomics of two subspecies ofCryptosporidium hominisduring 500 years of evolution

AbstractCryptosporidiosis is a major global health problem and a primary cause of diarrhoea, particularly in young children in low- and middle-income countries (LMICs). The zoonoticCryptosporidium parvumand anthroponoticC. hominiscause most human infections. Here, we present a comprehensive whole-genome study ofC. hominis, comprising 114 isolates from 16 countries within five continents. We detect two lineages with distinct biology and demography, which diverged circa 500 years ago. We consider these lineages two subspecies and propose the namesC. hominis hominisandC. hominis aquapotentis(gp60subtype IbA10G2). In our study,C. h. hominisis almost exclusively represented by isolates from LMICs in Africa and Asia and appears to have undergone recent population contraction. In contrast,C. h. aquapotentiswas found in high-income countries, mainly in Europe, North America and Oceania, and appears to be expanding. Notably,C. h. aquapotentisis associated with high rates of direct human-to-human transmission, which may explain its success in countries with well-developed environmental sanitation infrastructure. Intriguingly, we detected genomic regions of introgression following secondary contact between the subspecies. This resulted in high diversity and divergence in genomic islands of putative virulence genes (GIPVs), includingmuc5(CHUDEA2_430) and a hypothetical protein (CHUDEA6_5270). This diversity is maintained by balancing selection, suggesting a coevolutionary arms race with the host. Lastly, we find that recent gene flow fromC. h. aquapotentistoC. h. hominis, likely associated with increased human migration, may be driving evolution of more virulentC. hominisvariants.