MOLECULAR BASIS OF PHENOTYPIC SWITCHING IN 24067 MUTANT

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The goal of my research project is to better understand the molecular mechanism underlying phenotypic switching in Cryptococcus neoformans. There is evidence that phenotypic switching is a means by which this fungus escapes eradication by the host and results in persistence. I will study a variant of the laboratory strain 24067 that switches at high frequency between a "smooth" and "wrinkled" phenotype. In addition to an altered cell surface the "wrinkled" phenotype exhibits a bigger capsule, filamentous growth and an increased in vivo persistence. Thus the switch yields a complex phenotype. The switch to a "wrinkle" phenotype appears to involve the upregulation of genes that are associated with virulence in this pathogen. In addition the switch is associated with a length change of two chromosomes. The hypothesis to be tested is that chromosomal rearrangement results in differential expression of a central regulator, which in turn regulates genes, which are associated with virulence. The first part of my project will involve morphological studies of the complex phenotype. The second part is designed to clone the gene mediating this complex phenotype and the third part will aim to establish whether there is a causative relationship between chromosomal rearrangement and switching.