"Fungi are particularly challenging pathogens; because they and their human hosts are eukaryotes. We will study how new traits such as drugR arise rapidly using Candida albicans, the most prevalent fungal pathogen of humans. The work explores the ground-breaking concept that alterations in genome ploidy are prevalent in drugR isolates because these genome states promote persistence and drug resistance.We recently found that C. albicans, thought to be an “obligate diploid”, can form haploids. This represents a major paradigm shift both technologically and conceptually. We are poised to exploit this unique opportunity to reinvent genomic approaches for C. albicans by leveraging next generation sequencing, high throughput analyses and more traditional genetics. Because haploids are much less fit than heterozygous diploids, our working hypothesis is that changes in ploidy, including whole genome ploidy and aneuploidy, occur frequently under drug stress and that they make major contributions to the rapid appearance of genotypic and phenotypic diversity, in part by promoting persistence.The objectives of this proposal are to develop next-generation technologies that leverage haploids; to characterize the conditions and genes that promote ploidy transitions, especially in the presence of drug, in vitro and in vivo and to analyze their fitness consequences. This multi-disciplinary research program will integrate = approaches at the genetic, genomic, molecular, cellular and population levels and includes computational approaches to model evolutionary processes.The project will lead to unparalleled advances in tools for the research community, and important insights concerning how diversity arises rapidly. It will assist in efforts to design diagnostic and therapeutic strategies for preventing and treating fungal diseases, prividing insights into the rapid appearance of drug resistance in eukaryotic pathogens, and chemotherapy resistance in cancer cells."