Species-specific circular RNA circDS-1 enhances adaptive evolution in Talaromyces marneffei through regulation of dimorphic transition

Thermal adaptability is a crucial characteristic for mammalian pathogenic fungi that originally inhabit natural ecosystems. Thermally dimorphic fungi have evolved a unique ability to respond to host body temperature by shifting from mycelia to yeast. The high similarity of protein-coding genes between these fungi and their relatives suggests the indispensable but often overlooked roles of non-coding elements in fungal thermal adaptation. Here, we systematically delineated the landscape of full-length circRNAs in both mycelial and yeast conditions of Talaromyces marneffei, a typical thermally dimorphic fungus causing fatal Talaromycosis, by optimizing an integrative pipeline for circRNA detection utilizing next- and third-generation sequencing. We found T. marneffei circRNA demonstrated features such as shorter length, lower abundance, and circularization-biased splicing. We then identified and validated that circDS-1, independent of its parental gene, promotes the hyphae-to-yeast transition, maintains yeast morphology, and is involved in virulence regulation. Further analysis and experiments among Talaromyces confirmed that the generation of circDS-1 is driven by a T. marneffei-specific region in the flanking intron of circDS-1. Together, our findings not only provide fresh insights into the role of circRNA in fungal thermal adaptation but also reveal a novel molecular mechanism for the adaptive evolution of functional circRNAs derived from intronic mutations.