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Mechanisms and dynamics of genome plasticity in Candida species

Award Number: R01AI196684
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/10/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Mechanisms and dynamics of genome plasticity in Candida species - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $713,383 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	1	7/10/2026	NEW	$713,383
														Subtotal = $713,383

Grand Total All Awards = $713,383

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Mechanisms and dynamics of genome plasticity in Candida species

Award Number: R01AI196684

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/10/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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