Genome Organization and Copy-Number Variation Reveal Clues to Virulence Evolution in Coccidioides posadasii

The human fungal pathogen Coccidioides spp. causes valley fever, a treatment-refractory and sometimes deadly disease prevalent in arid regions of the western hemisphere. Fungal virulence in the mammalian host hinges on a switch between growth as hyphae and as large spherules containing infectious spores. How these virulence programs are encoded in the genome remains poorly understood. Drawing on Coccidioides genomic resources, we first discovered a new facet of genome organization in this system: spherule-gene islands, clusters of genes physically linked in the genome that exhibited specific mRNA induction in the spherule phase. Next, we surveyed copy-number variation genome-wide among strains of C. posadasii. Emerging from this catalog were spherule-gene islands with striking presence–absence differentiation between C. posadasii populations, a pattern expected from virulence factors subjected to different selective pressures across habitats. Finally, analyzing single-nucleotide differences across C. posadasii strains, we identified signatures of natural selection in spherule-expressed genes. Together, our data establish spherule-gene islands as candidate determinants of virulence and targets of selection in Coccidioides.