NIH grant: Mechanisms and dynamics of genome plasticity in Candida species (1R01AI196684-01A1)

retained text

NIH grant 1R01AI196684-01A1: Mechanisms and dynamics of genome plasticity in Candida species
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Anna M. Selmecki. Award: $713383.
Start: 2026-07-10T00:00:00.
ABSTRACT
 Antifungal drug-resistant Candida species pose a significant threat to global health, with invasive
infections resulting in mortality rates exceeding 40%. The evolution of antifungal resistance in Candida is often
linked to genome plasticity. We discovered novel large DNA amplification events in Candida albicans that occur
during adaptation to azole antifungals, amplifying hundreds of genes simultaneously. Additionally, we have
identified recurrent aneuploid chromosomes and large structural variation in clinical isolates of C. albicans,
Candida glabrata and Candida auris obtained from patients undergoing antifungal therapy. Our research aims
to uncover the molecular mechanisms driving genome plasticity in Candida and its impact on adaptive evolution.
 The dynamics of adaptive evolution are influenced by the rate at which beneficial mutations occur and
their corresponding fitness effects. Importantly, the diverse mutation types that Candida species acquire during
adaptation to antifungal drugs and physiologically relevant stress, for example aneuploidy versus single
nucleotide polymorphisms, have very different rates and fitness effects. How these diverse mutation types within
a population affect evolutionary dynamics is not known. We have developed single-cell and population-level
genomic approaches to quantify the frequency and dynamics of genomic changes during adaptive evolution. We
will use experimental evolution and novel simulation-based inference methods to assess the rate and fitness
effects of diverse Candida genotypes in different environments. We aim to determine in what contexts and to
what extent aneuploidy is beneficial to Candida and how aneuploidy impacts the rate of adaptation to those
environments.
 Despite the prevalence of aneuploidy and DNA copy number variation in diverse Candida species, the
mechanisms underlying genome plasticity remain poorly understood. We propose a targeted mechanistic
analysis of the effect of azole-induced reactive oxygen species on genome plasticity in two diploid Candida
species, C. albicans and C. parapsilosis. Additionally, we are uniquely positioned to conduct the first genome-
wide screen for genes affecting chromosome stability in C. albicans, utilizing our single-cell flow cytometry
system to detect chromosome gain and loss events combined with new genome-wide CRISPR tools for gene
repression and activation. We will identify genes that promote genome plasticity in C. albicans both in the
presence and absence of stress, including chromosome-specific and ploidy-specific mechanisms of plasticity.
The outcomes of these experiments will reveal the mechanisms of rapid evolution in Candida species and identify
novel targets to mitigate the emergence of drug-resistant fungal infections.

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