A spontaneous mutation in DNA polymerase POL3 during in vitro passaging causes a hypermutator phenotype in Cryptococcus species

Boyce, Kylie J.; Cao, Chengjun; Xue, Chaoyang; Idnurm, Alexander

doi:10.1016/j.dnarep.2019.102751

Cited by 12 publications

(17 citation statements)

References 52 publications

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“…In C. neoformans VNI, MSH2 loss of function mutations produced strains with high mutation rates and extensive phenotypic variability [27]. In C. neoformans VNI and VNIV, an amino acid substitution in the DNA polymerase gene POL3 also caused rapid microevolution without an apparent fitness cost [28]. In both species, the disruption of mismatch repair mechanisms enabled development of drug resistance, demonstrating how accelerated mutation rates can enable rapid adaptation [27] [28].…”

Section: Small-scale Genetic Variation With Genome-wide Consequencesmentioning

confidence: 99%

Short-term evolution strategies for host adaptation and drug escape in human fungal pathogens

Beekman

Ene

2020

PLoS Pathog

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Research on human fungal pathogens has historically taken a backseat to other infectious diseases, perhaps due to a common misperception that fungi largely cause superficial infections [1]. In reality, fungi can be life-threatening to those who become immunocompromised during medical procedures or through conditions such as HIV and diabetes. Invasive fungal infections are estimated to kill over 1 million people every year, with mortality rates reaching 50% [2]. Significant challenges to the treatment of fungal infections include the limited availability of antifungals and the innate ability of fungi to rapidly evolve and adapt to fluctuating conditions. This adaptive ability is partially driven by extensive genomic plasticity, with many species acquiring diverse ploidy states, chromosomal rearrangements, and point mutations during host colonization [3-8]. Genetic plasticity enables rapid increases in virulence and antifungal drug resistance, which often translate to poor disease outcomes. Short-term evolution (microevolution) strategies in fungal pathogens are therefore essential for environmental adaptation in the mammalian host, and their study can inform adaptive mechanisms in other eukaryotes. Ploidy shifts enable rapid fitness jumps under stressful conditions Many clinically relevant fungi display dynamic changes in ploidy, including both karyotypic variations (number of sets of chromosomes) as well as aneuploidy (imbalance in chromosome copy number). Some fungal pathogens exist as stable haploid, diploid, or polyploid cells, but ploidy can change upon shifting conditions. Alterations in baseline ploidy have been described for some of the most prevalent genera (Candida, Cryptococcus, and Aspergillus) and are often selected for in the host or during antifungal treatment. Extra chromosomes are common in isolates from human infections [5, 6, 8, 9] and after passage through mammalian hosts during experimental microevolution [10-12]. Under nutrient starvation, Candida albicans isolates can favor either near-haploid or near-diploid states, indicating that karyotypic reduction can provide an efficient adaptive route in some conditions [13]. Aneuploidy is also common in C. albicans and in Cryptococcus neoformans lineages and has been linked to increased virulence and drug resistance [14] [15]. Chromosomal duplication can mediate adaptation through gene dosage, as transcript levels are often proportional to gene copy number [16]. This can be seen in both C. albicans and Cryptococcus species, for which antifungal treatment selects for increased copies of chromosomes or chromosomal segments containing drug targets and/or efflux pumps. Thus, clinical isolates of Cryptococcus lineages VNI and VGI that persisted during fluconazole therapy were frequently disomic for chromosome 1 [5]. Analogous in vitro fluconazole treatment of Cryptococcus lineages VNI and VNIV selected for disomy of

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Section: Small-scale Genetic Variation With Genome-wide Consequencesmentioning

confidence: 99%

Short-term evolution strategies for host adaptation and drug escape in human fungal pathogens

Beekman

Ene

2020

PLoS Pathog

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“…Although the S. cerevisiae diploids with incompatible alleles isolated from humans were not hypermutators themselves, their meiotic progeny displayed a wide range of mutation rates and included hypermutators, thus providing an opportunity to produce progeny with variable fitness under stressful conditions 47 , 48 . Another mechanism of hypermutation caused by a mutation in a DNA polymerase delta subunit was also described in C. neoformans ; this mechanism of hypermutation resulted in genome-wide increases in transition and transversion mutations but reduced viability and virulence 49 , 50 .…”

Section: Small-scale Evolution Of Fungal Genomesmentioning

confidence: 94%

Advances in understanding the evolution of fungal genome architecture

2020

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Diversity within the fungal kingdom is evident from the wide range of morphologies fungi display as well as the various ecological roles and industrial purposes they serve. Technological advances, particularly in long-read sequencing, coupled with the increasing efficiency and decreasing costs across sequencing platforms have enabled robust characterization of fungal genomes. These sequencing efforts continue to reveal the rampant diversity in fungi at the genome level. Here, we discuss studies that have furthered our understanding of fungal genetic diversity and genomic evolution. These studies revealed the presence of both small-scale and large-scale genomic changes. In fungi, research has recently focused on many small-scale changes, such as how hypermutation and allelic transmission impact genome evolution as well as how and why a few specific genomic regions are more susceptible to rapid evolution than others. High-throughput sequencing of a diverse set of fungal genomes has also illuminated the frequency, mechanisms, and impacts of large-scale changes, which include chromosome structural variation and changes in chromosome number, such as aneuploidy, polyploidy, and the presence of supernumerary chromosomes. The studies discussed herein have provided great insight into how the architecture of the fungal genome varies within species and across the kingdom and how modern fungi may have evolved from the last common fungal ancestor and might also pave the way for understanding how genomic diversity has evolved in all domains of life.

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“…In contrast to the large-scale genome alterations underpinning heteroresistance, a subset of Cryptococcus isolates have been identified as hypermutator strains 30 , 31 , which contain mutations in core genes in the DNA mismatch repair pathway, most notably MSH2 (refs 30 , 32 , 33 ) (Fig. 1 ).…”

Section: Antifungal Resistance Mechanismsmentioning

confidence: 99%

“…These mutations result in an ~200-fold higher mutation rate than in standard laboratory strains 30 and preferentially affect genes containing homopolymer runs 33 . In addition, a mutation in the proofreading domain of POL3 (encoding the catalytic subunit of DNA polymerase δ) was also shown to confer the hypermutator phenotype 31 . Whereas evolutionary theory predicts that hypermutator strains will be eliminated from populations 34 , evidence suggests that they persist in other pathogenic fungi 35 , 36 and are not detrimental to survival in vivo 30 .…”

Section: Antifungal Resistance Mechanismsmentioning

confidence: 99%

Treatment strategies for cryptococcal infection: challenges, advances and future outlook

et al. 2021

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Cryptococcus spp., in particular Cryptococcus neoformans and Cryptococcus gattii , have an enormous impact on human health worldwide. The global burden of cryptococcal meningitis is almost a quarter of a million cases and 181,000 deaths annually, with mortality rates of 100% if infections remain untreated. Despite these alarming statistics, treatment options for cryptococcosis remain limited, with only three major classes of drugs approved for clinical use. Exacerbating the public health burden is the fact that the only new class of antifungal drugs developed in decades, the echinocandins, displays negligible antifungal activity against Cryptococcus spp., and the efficacy of the remaining therapeutics is hampered by host toxicity and pathogen resistance. Here, we describe the current arsenal of antifungal agents and the treatment strategies employed to manage cryptococcal disease. We further elaborate on the recent advances in our understanding of the intrinsic and adaptive resistance mechanisms that are utilized by Cryptococcus spp. to evade therapeutic treatments. Finally, we review potential therapeutic strategies, including combination therapy, the targeting of virulence traits, impairing stress response pathways and modulating host immunity, to effectively treat infections caused by Cryptococcus spp. Overall, understanding of the mechanisms that regulate anti-cryptococcal drug resistance, coupled with advances in genomics technologies and high-throughput screening methodologies, will catalyse innovation and accelerate antifungal drug discovery.

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A spontaneous mutation in DNA polymerase POL3 during in vitro passaging causes a hypermutator phenotype in Cryptococcus species

Cited by 12 publications

References 52 publications

Short-term evolution strategies for host adaptation and drug escape in human fungal pathogens

Short-term evolution strategies for host adaptation and drug escape in human fungal pathogens

Advances in understanding the evolution of fungal genome architecture

Treatment strategies for cryptococcal infection: challenges, advances and future outlook

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