Strains used.

Heritable phenotypic switches are fundamental to the ability of cells to respond to specific conditions. Such switches are key to the success of environmental pathogens, which encounter disparate conditions as they transition between the environment and host. We determine that the copy number of chromosome seven in the thermally dimorphic fungus Histoplasma dramatically affects the rate of transition. Though Histoplasma is haploid, a second copy of this chromosome is present in natural isolates of multiple Histoplasma species and is gained and lost at a high rate. Cells carrying two copies of this chromosome exhibit aspects of the environmental transcriptome even under host-like conditions and have a competitive advantage in the transition to the environmental form. Conversely, these cells are considerably less virulent than euploid cells and have a competitive disadvantage in the mouse model of infection. Chromosome seven contains a previously unstudied transcription factor that, when expressed at higher copy number in euploid Histoplasma, is sufficient to promote some of the key phenotypes of aneuploidy. We hypothesize that rapid gain and loss of this chromosome benefits Histoplasma by increasing phenotypic variation, thus helping populations of cells survive abrupt transitions between environment and host.