Giant transposons promote strain heterogeneity in a major fungal pathogen

Abstract

AbstractFungal infections are difficult to prevent and treat in large part due to heterogeneity in clinically relevant phenotypes. However, the genetic mechanisms driving pathogen variation remain poorly understood. Here, we determined the extent to whichStarships—giant transposons capable of mobilizing numerous fungal genes—generate genetic and phenotypic variability in the human pathogenAspergillus fumigatus. We analyzed 519 diverse strains, including 12 newly sequenced with long-read technology, to reveal 20 distinctStarshipsthat generate genomic heterogeneity over timescales impacting experimental reproducibility.Starship-mobilized genes encode diverse functions, including biofilm-related virulence factors and biosynthetic gene clusters, and many are differentially expressed during infection and antifungal exposure in a strain-specific manner. These findings support a new model of fungal pathogenesis whereinStarshipsmediate variation in virulence-related gene content and expression. Together, our results demonstrate thatStarshipsare a foundational mechanism generating disease-relevant genotypic and, in turn, phenotypic heterogeneity in a major human fungal pathogen.