Hemizygosity Enables a Mutational Transition Governing Fungal Virulence and Commensalism

Candida albicans is a commensal fungus of human gastrointestinal and reproductive tracts, but also causes life-threatening systemic infections. The balance between colonization and pathogenesis is associated with phenotypic plasticity, with alternative cell states producing different outcomes in a mammalian host. Here, we reveal that gene dosage of a master transcription factor regulates cell differentiation in diploid C. albicans cells, as EFG1 hemizygous cells undergo a phenotypic transition inaccessible to “wild-type” cells with two functional EFG1 alleles. Notably, clinical isolates are often EFG1 hemizygous and thus licensed to undergo this transition. Phenotypic change corresponds to high-frequency loss of the functional EFG1 allele via de novo mutation or gene conversion events. This phenomenon also occurs during passaging in the gastrointestinal tract with the resulting cell type being hypercompetitive for commensal and systemic infections. A “two-hit” genetic model therefore underlies a key phenotypic transition in C. albicans that enables adaptation to host niches. [Display omitted] •TF loss frequently occurs during murine infections and drives host adaptation•Hemizygosity of the EFG1 TF licenses a phenotypic transition in C. albicans cells•Numerous clinical isolates are EFG1 hemizygous and thus can undergo this transition•This “phenotypic switch” corresponds to mutational loss of EFG1 function Microorganisms use diverse strategies to adapt to their environment. Liang et al. reveal a two-hit genetic mechanism underlies a high-frequency phenotypic transition in the diploid fungus Candida albicans. Clinical isolates heterozygous for a key transcription factor readily lose gene function, triggering a transition that impacts both commensalism and pathogenicity.