Dataset Information

The Impact of Gene Dosage and Heterozygosity on The Diploid Pathobiont Candida albicans.

ABSTRACT: Candida albicans is a fungal species that can colonize multiple niches in the human host where it can grow either as a commensal or as an opportunistic pathogen. The genome of C. albicans has long been of considerable interest, given that it is highly plastic and can undergo a wide variety of alterations. These changes play a fundamental role in determining C. albicans traits and have been shown to enable adaptation both to the host and to antifungal drugs. C. albicans isolates contain a heterozygous diploid genome that displays variation from the level of single nucleotides to largescale rearrangements and aneuploidy. The heterozygous nature of the genome is now increasingly recognized as being central to C. albicans biology, as the relative fitness of isolates has been shown to correlate with higher levels of overall heterozygosity. Moreover, loss of heterozygosity (LOH) events can arise frequently, either at single polymorphisms or at a chromosomal level, and both can alter the behavior of C. albicans cells during infection or can modulate drug resistance. In this review, we examine genome plasticity in this pathobiont focusing on how gene dosage variation and loss of heterozygosity events can arise and how these modulate C. albicans behavior.

SUBMITTER: Liang SH

PROVIDER: S-EPMC7151161 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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The Impact of Gene Dosage and Heterozygosity on The Diploid Pathobiont Candida albicans.

Liang Shen-Huan SH Bennett Richard J RJ

Journal of fungi (Basel, Switzerland) 20191227 1

Candida albicans is a fungal species that can colonize multiple niches in the human host where it can grow either as a commensal or as an opportunistic pathogen. The genome of C. albicans has long been of considerable interest, given that it is highly plastic and can undergo a wide variety of alterations. These changes play a fundamental role in determining C. albicans traits and have been shown to enable adaptation both to the host and to antifungal drugs. C. albicans</i ...[more]

PMID: 31892130

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Project description:Genetic diversity is often generated during adaptation to stress, and in eukaryotes some of this diversity is thought to arise via recombination and reassortment of alleles during meiosis. Candida albicans, the most prevalent pathogen of humans, has no known meiotic cycle, and yet it is a heterozygous diploid that undergoes mitotic recombination during somatic growth. It has been shown that clinical isolates as well as strains passaged once through a mammalian host undergo increased levels of recombination. Here, we tested the hypothesis that stress conditions increase rates of mitotic recombination in C. albicans, which is measured as loss of heterozygosity (LOH) at specific loci. We show that LOH rates are elevated during in vitro exposure to oxidative stress, heat stress, and antifungal drugs. In addition, an increase in stress severity correlated well with increased LOH rates. LOH events can arise through local recombination, through homozygosis of longer tracts of chromosome arms, or by whole-chromosome homozygosis. Chromosome arm homozygosis was most prevalent in cultures grown under conventional lab conditions. Importantly, exposure to different stress conditions affected the levels of different types of LOH events, with oxidative stress causing increased recombination, while fluconazole and high temperature caused increases in events involving whole chromosomes. Thus, C. albicans generates increased amounts and different types of genetic diversity in response to a range of stress conditions, a process that we term "stress-induced LOH" that arises either by elevating rates of recombination and/or by increasing rates of chromosome missegregation.Stress-induced mutagenesis fuels the evolution of bacterial pathogens and is mainly driven by genetic changes via mitotic recombination. Little is known about this process in other organisms. Candida albicans, an opportunistic fungal pathogen, causes infections that require adaptation to different host environmental niches. We measured the rates of LOH and the types of LOH events that appeared in the absence and in the presence of physiologically relevant stresses and found that stress causes a significant increase in the rates of LOH and that this increase is proportional to the degree of stress. Furthermore, the types of LOH events that arose differed in a stress-dependent manner, indicating that eukaryotic cells generate increased genetic diversity in response to a range of stress conditions. We propose that this "stress-induced LOH" facilitates the rapid adaptation of C. albicans, which does not undergo meiosis, to changing environments within the host.

Project description:In many microbes rapid mutation of highly mutable contingency genes continually replenishes a pool of variant alleles from which the most suitable are selected, assisting in rapid adaptation and evasion of the immune response. In some contingency genes mutability is achieved through DNA repeats within the coding region. The fungal human pathogen Candida albicans has 2600 repeat-containing ORFs. For those investigated (ALS genes, HYR1, HYR2, CEK1, RLM1) many protein variants with differing amino acid repeat regions exist, as expected for contingency genes. However, specific alleles dominate in different clades, which is unexpected if allele variation is used for short-term adaptation. Generation of new alleles of repeat-containing C. albicans ORFs has never been observed directly. Here we present evidence for restrictions on the emergence of new alleles in a highly mutable C. albicans repeat-containing ORF, PNG2, encoding a putative secreted or cell surface glycoamidase. In laboratory cultures new PNG2 alleles arose at a rate of 2.8x10(-5) (confidence interval 3.3x10(-6)-9. 9x10(-5)) per cell per division, comparable to rates measured for contingency genes. Among 80 clinical isolates 17 alleles of different length and 23 allele combinations were distinguishable; sequence differences between repeat regions of identical size suggest the existence of 36 protein variants. Specific allele combinations predominated in different genetic backgrounds, as defined by DNA fingerprinting and multilocus sequence typing. Given the PNG2 mutation rate, this is unexpected, unless in different genetic backgrounds selection favors different alleles. Specific alleles or allele combinations were not preferentially associated with C. albicans isolates from particular body sites or geographical regions. Our results suggest that the mutability of PNG2 is not used for short-term adaptation or evasion of the immune system. Nevertheless the large number of alleles observed indicates that mutability of PNG2 may assist C. albicans strains from different genetic backgrounds optimize their interaction with the host in the long term.

Dataset Information

The Impact of Gene Dosage and Heterozygosity on The Diploid Pathobiont Candida albicans.

Publications

The Impact of Gene Dosage and Heterozygosity on The Diploid Pathobiont <i>Candida albicans</i>.

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