Genome Instability. Population Dynamics. Drug Resistance. Evolution.
University of Minnesota Medical School
A dynamic, expandable and reversible, segmental copy number amplification on Chromosome 3 in
Candida albicans promotes acquisition of drug resistance.
Video generated from data in Todd & Selmecki, eLife, 2020
Research
Understanding the dynamics of how growth-promoting mutations arise and accumulate in a population of cells is a fundamental problem underlying our understanding of drug resistance, tumorigenesis, and the treatment of cancer. We use experimental evolution, mathematical modeling, and comparative genomics to understand the impact of mutations on the adaptation.
We employ diverse yeast model systems (Saccharomyces cerevisiae) and human fungal pathogens (Candida albicans, Candida auris, Candida glabrata, etc.) to understand how genome instability contributes to adaptation (eg. antifungal drug resistance) and determine the underlying mechanisms that promote genome instability.
Our research identified chromosome aneuploidy as a driver for the acquisition of antifungal drug resistance in C. albicans (Selmecki et al., Science 2006).
In Candida albicans, genome rearrangements resulting in copy number variation (CNV) and loss of heterozygosity (LOH) confer increased virulence and antifungal drug resistance, yet the mechanisms driving these rearrangements are not completely understood. We identified long repeat sequences that are associated with CNV, LOH, and chromosomal inversions and are a significant source of genome plasticity across diverse strain backgrounds - including clinical, environmental, and experimentally evolved C. albicans isolates. Many of these long repeat sequences encompass one or more coding sequences that are actively transcribed (Todd et al. eLife 2019 and 2020). We found that the concentration of an antifungal drug can impact the frequency and spectrum of mutations, including the formation of large, accordion-like CNVs (Todd et al., MBE 2023). In one experiment, we found that a large CNV on Chr4 provided initial adaptation to the antifungal fluconazole, which then enabled subsequent acquisition of a small LOH mutation in KSR1, causing drug resistance (Vande Zande et al., PLoS Pathogens 2024).
We develop and utilize flow cytometry-based systems that enable us to detect the acquisition and spread of beneficial mutations within populations. We found that polyploid S. cerevisiae adapted more rapidly than isogenic haploid or diploid cells in poor carbon medium, and that polyploid cells acquired more mutations, including point mutations, segmental aneuploidies, and whole chromosome aneuploidies (Selmecki et al., Nature 2015). Additionally, polyploid cells acquired a broader spectrum of beneficial mutations than lower ploidy cells (Scott et al., MBE 2017). Recently, we developed a single-cell reporter system to quantify both DNA amplification and loss events (CNV and LOH) in the diploid pathogen C. albicans. We reported the frequency and dynamics of CNV and LOH during adaptation to antifungal stress in vitro and in a mouse model of systemic infection (Zhou et al., Nature Microbiology, 2024). We continue to study how changes in DNA copy number (polyploidy, aneuploidy, CNV, and LOH) and environment affect genome stability and evolvability.
We employ diverse yeast model systems (Saccharomyces cerevisiae) and human fungal pathogens (Candida albicans, Candida auris, Candida glabrata, etc.) to understand how genome instability contributes to adaptation (eg. antifungal drug resistance) and determine the underlying mechanisms that promote genome instability.
Our research identified chromosome aneuploidy as a driver for the acquisition of antifungal drug resistance in C. albicans (Selmecki et al., Science 2006).
In Candida albicans, genome rearrangements resulting in copy number variation (CNV) and loss of heterozygosity (LOH) confer increased virulence and antifungal drug resistance, yet the mechanisms driving these rearrangements are not completely understood. We identified long repeat sequences that are associated with CNV, LOH, and chromosomal inversions and are a significant source of genome plasticity across diverse strain backgrounds - including clinical, environmental, and experimentally evolved C. albicans isolates. Many of these long repeat sequences encompass one or more coding sequences that are actively transcribed (Todd et al. eLife 2019 and 2020). We found that the concentration of an antifungal drug can impact the frequency and spectrum of mutations, including the formation of large, accordion-like CNVs (Todd et al., MBE 2023). In one experiment, we found that a large CNV on Chr4 provided initial adaptation to the antifungal fluconazole, which then enabled subsequent acquisition of a small LOH mutation in KSR1, causing drug resistance (Vande Zande et al., PLoS Pathogens 2024).
We develop and utilize flow cytometry-based systems that enable us to detect the acquisition and spread of beneficial mutations within populations. We found that polyploid S. cerevisiae adapted more rapidly than isogenic haploid or diploid cells in poor carbon medium, and that polyploid cells acquired more mutations, including point mutations, segmental aneuploidies, and whole chromosome aneuploidies (Selmecki et al., Nature 2015). Additionally, polyploid cells acquired a broader spectrum of beneficial mutations than lower ploidy cells (Scott et al., MBE 2017). Recently, we developed a single-cell reporter system to quantify both DNA amplification and loss events (CNV and LOH) in the diploid pathogen C. albicans. We reported the frequency and dynamics of CNV and LOH during adaptation to antifungal stress in vitro and in a mouse model of systemic infection (Zhou et al., Nature Microbiology, 2024). We continue to study how changes in DNA copy number (polyploidy, aneuploidy, CNV, and LOH) and environment affect genome stability and evolvability.
Recently Published
Single-cell detection of copy number changes reveals dynamic mechanisms of adaptation to antifungals in Candida albicans.
Zhou X, Hilk A, Solis NV, Scott N, Beach A, Soisangwan N, Billings CL, Burrack LS, Filler SG, Selmecki A.
Nature Microbiology. 2024 Nov;9(11):2923-2938. doi: 10.1038/s41564-024-01795-7. Epub 2024 Sep 3. PMID: 39227665; PMCID: PMC11524788.
Zhou X, Hilk A, Solis NV, Scott N, Beach A, Soisangwan N, Billings CL, Burrack LS, Filler SG, Selmecki A.
Nature Microbiology. 2024 Nov;9(11):2923-2938. doi: 10.1038/s41564-024-01795-7. Epub 2024 Sep 3. PMID: 39227665; PMCID: PMC11524788.
Step-wise evolution of azole resistance through copy number variation followed by KSR1 loss of heterozygosity in Candida albicans.
Vande Zande P, Gautier C, Kawar N, Maufrais C, Metzner K, Wash E, Beach AK, Bracken R, Maciel EI, Pereira de Sá N, Fernandes CM, Solis NV, Del Poeta M, Filler SG, Berman J, Ene IV, Selmecki A.
PLoS Pathogens. 2024 Aug 30;20(8):e1012497. doi: 10.1371/journal.ppat.1012497. PMID: 39213436; PMCID: PMC11392398.
Vande Zande P, Gautier C, Kawar N, Maufrais C, Metzner K, Wash E, Beach AK, Bracken R, Maciel EI, Pereira de Sá N, Fernandes CM, Solis NV, Del Poeta M, Filler SG, Berman J, Ene IV, Selmecki A.
PLoS Pathogens. 2024 Aug 30;20(8):e1012497. doi: 10.1371/journal.ppat.1012497. PMID: 39213436; PMCID: PMC11392398.
