Gluck-Thaler Emile, Forsythe Adrian, Puerner Charles, Gutierrez-Perez Cecilia, Stajich Jason E, Croll Daniel, Cramer Robert A, Vogan Aaron A
Laboratory of Evolutionary Genetics, Institute of Biology, University of Neuchâtel, Neuchâtel, Switzerland.
Department of Plant Pathology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
mBio. 2025 Jun 11;16(6):e0109225. doi: 10.1128/mbio.01092-25. Epub 2025 May 12.
Fungal infections are difficult to prevent and treat in large part due to strain heterogeneity, which confounds diagnostic predictability. Yet, the genetic mechanisms driving strain-to-strain variation remain poorly understood. Here, we determined the extent to which -giant transposons capable of mobilizing numerous fungal genes-generate genetic and phenotypic variability in the opportunistic human pathogen . We analyzed 519 diverse strains, including 11 newly sequenced with long-read technology and multiple isolates of the same reference strain, to reveal 20 distinct that are generating genomic heterogeneity over timescales relevant for experimental reproducibility. -mobilized genes encode diverse functions, including known 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 evolution wherein help generate variation in genome structure, gene content, and expression among fungal strains. Together, our results demonstrate that are a previously hidden mechanism generating genotypic and, in turn, phenotypic heterogeneity in a major human fungal pathogen.IMPORTANCENo "one size fits all" option exists for treating fungal infections in large part due to genetic and phenotypic variability among strains. Accounting for strain heterogeneity is thus fundamental for developing efficacious treatments and strategies for safeguarding human health. Here, we report significant progress toward achieving this goal by uncovering a previously hidden mechanism generating heterogeneity in the human fungal pathogen : giant transposons, called , that span dozens of kilobases and mobilize fungal genes as cargo. By conducting a systematic investigation of these unusual transposons in a single fungal species, we demonstrate their contributions to population-level variation at the genome, pangenome, and transcriptome levels. The compendium we develop will not only help predict variation introduced by these elements in laboratory experiments but will serve as a foundational resource for determining how impact clinically relevant phenotypes, such as antifungal resistance and pathogenicity.
真菌感染在很大程度上难以预防和治疗，这主要是由于菌株的异质性，这使得诊断的可预测性变得复杂。然而，驱动菌株间变异的遗传机制仍知之甚少。在这里，我们确定了能够移动众多真菌基因的巨型转座子在机会性人类病原体中产生遗传和表型变异的程度。我们分析了519个不同的菌株，包括11个用长读长技术新测序的菌株和同一参考菌株的多个分离株，以揭示20个不同的[转座子名称]，它们在与实验可重复性相关的时间尺度上产生基因组异质性。[转座子名称]移动的基因编码多种功能，包括已知的与生物膜相关的毒力因子和生物合成基因簇，并且许多基因在感染和抗真菌暴露期间以菌株特异性方式差异表达。这些发现支持了一种新的真菌进化模型，其中[转座子名称]有助于在真菌菌株之间产生基因组结构、基因含量和表达的变异。总之，我们的结果表明，[转座子名称]是一种以前隐藏的机制，在主要的人类真菌病原体中产生基因型进而表型的异质性。
重要性
由于菌株之间的遗传和表型变异性，不存在“一刀切”的真菌感染治疗方法。因此，考虑菌株异质性是开发有效治疗方法和保障人类健康策略的基础。在这里，我们通过揭示一种在人类真菌病原体中产生异质性的以前隐藏的机制，朝着实现这一目标报告了重大进展：巨型转座子，称为[转座子名称]，其跨度达数十千碱基，并将真菌基因作为货物进行移动。通过对单一真菌物种中的这些不寻常转座子进行系统研究，我们证明了它们在基因组、泛基因组和转录组水平上对群体水平变异的贡献。我们开发的[转座子名称]简编不仅将有助于预测这些元件在实验室实验中引入的变异，而且将作为确定[转座子名称]如何影响临床相关表型（如抗真菌抗性和致病性）的基础资源。
