Comparative pan-genomics reveals divergent adaptations in clinically-relevant members of the Fusarium solani species complex

The Fusarium solani species complex are a group of dual-kingdom fungal pathogens capable of causing devastating disease on a wide range of host plants and life-threatening infections in humans that are difficult to treat. In this study, we generate highly contiguous genomes for three clinical isolates of Fusarium keratoplasticum and three clinical isolates of Fusarium petroliphilum and compare them with other genomes of the FSSC from plant and animal sources. We find that human pathogenicity is polyphyletic within the FSSC, including in F. keratoplasticum . Pan-genome analysis revealed a high degree of gene presence-absence in the complex, with only 41% of genes (11,079/27,068) found in all samples and the presence of accessory chromosomes encoding isolate- and species-specific genes. We also defined conserved long non-coding RNAs (lncRNAs) between F. keratoplasticum and F. petroliphilum, revealing that they show a similar low degree of presence-absence variation. Secondary metabolite analysis revealed a conserved core set of biosynthetic gene clusters across the FSSC, as well as a unique cluster potentially linked to keratitis. Transcriptomic analysis under stress conditions showed minimal differential gene expression, indicating that both F. keratoplasticum and F. petroliphilum are well adapted to human infection-relevant conditions. This study provides valuable insights into the evolutionary dynamics, genomic architecture, and potential pathogenicity mechanisms of the FSSC, with implications for understanding multi-kingdom virulence, of increasing relevance as climate change potentially increases the number of fungal species that can grow at human temperatures.