Genome dynamics and chromosome structural variations in Histoplasma ohiense, a fungal pathogen of humans.

Histoplasma is a clinically important but understudied genus of thermally dimorphic human fungal pathogens. Histoplasma species normally transition between a multicellular sporulating hyphal form in the soil and a unicellular pathogenic yeast form in a mammalian host. Little is known about genome plasticity of Histoplasma, which we address in this study with the ultimate goal of increasing our understanding of its pathogenicity. Here we present the first telomere-to-telomere genome assemblies for Histoplasma ohiense; specifically, strains UCSF2 and UCSF3 derived from isolate G217B. We find that our 2 new assemblies differ from each other and from the previously published G217B reference genome by 2 reciprocal chromosome translocations. Analysis of short read sequencing of natural Histoplasma isolates reveals that the majority of isolates (91 of 94) match the chromosome structure of our UCSF3 assembly, which is, therefore, most representative of the original G217B isolate and H. ohiense in nature. Additionally, to determine the rate of Histoplasma genomic changes, we sequence 46 passaged isolates and calculate the mutation rate to be 2.6 × 10-10 SNP/base/doubling-the first such measurement to our knowledge within the order Onygenales, which encompasses several critical fungal pathogens. Taken together, this work highlights the plasticity of the Histoplasma genome and presents a comprehensive genome assembly that is representative of H. ohiense natural isolates.