Linking geography, isolation source, and genomic diversity in a global Candida albicans phylogeny

Candida albicans is a common commensal species in the human microbiome at multiple sites and an opportunistic pathogen. Previous phylogenomic analyses identified major clades but often relied on imprecise genomic methods, limited geographic and ecological sampling, and non-standardized strategies for phylogenetic resolution. Here, we address these gaps by reconstructing a whole-genome phylogeny to examine how geography and site of isolation contribute to phylogenetic structure in C. albicans. We analyzed phased genomes from 945 global isolates obtained across diverse clinical and ecological contexts and applied an agnostic, threshold-based clustering approach to systematically define cluster boundaries and quantify intraspecific genomic features. Our analyses preserved previously defined major clusters while identifying six novel clusters, predominantly composed of highly admixed Asian isolates. Although geographic origin and isolation source were each significantly associated with cluster membership, these associations were confounded because isolates from specific regions were disproportionately derived from particular sources. However, an analysis of environmental isolates alongside a diverse strain collection from Winnipeg, Canada, highlights the potential for frequent local transmission. More than 95% of isolates were heterozygous at the mating-type locus, while aneuploidy was present in 8% of isolates distributed across the phylogeny. Analysis of the AGO1 PAZ domain involved in RNAi interference identified both known and novel RNAi variants, predominantly in a heterozygous state. Intra-host analysis of isolates from 95 individuals revealed predominantly clonal colonization, though fourteen individuals harbored isolates from different clusters. Together, these findings refine the phylogenetic structure of C. albicans and provide insights into genomic plasticity and strain transmission in this common fungal species.