Stress alters rates and types of loss of heterozygosity in Candida albicans.
Stress alters rates and types of loss of heterozygosity in Candida albicans.
复制标题
压力改变白色念珠菌中杂合性丧失的速率和类型。
作者：
Forche A;Abbey D;Pisithkul T;Weinzierl MA;Ringstrom T;Bruck D;Petersen K;Berman J
遗传多样性通常是在适应压力的过程中产生的，在真核生物中，这种多样性中的一些被认为是通过减数分裂期间等位基因的重组和重配而产生的。白色念珠菌是人类最常见的病原体，它没有已知的减数分裂周期，但它是一种杂合二倍体，在体细胞生长过程中经历有丝分裂重组。已经表明，临床分离株以及通过哺乳动物宿主传代一次的菌株经历增加的重组水平。在此，我们检验了应激条件增加白念珠菌有丝分裂重组率的假设，其以特定位点的杂合性缺失（洛）来衡量。我们发现，在体外暴露于氧化应激、热应激和抗真菌药物的过程中，洛率升高。此外，应激严重程度的增加与洛率的增加密切相关。洛缺失事件可以通过局部重组、染色体臂较长片段的纯合或全染色体纯合而发生。在常规实验室条件下生长的培养物中，染色体臂纯合性最普遍。重要的是，暴露于不同的应激条件影响了不同类型的洛缺失事件的水平，氧化应激导致重组增加，而氟康唑和高温导致涉及整个染色体的事件增加。因此，白色念珠菌产生增加的数量和不同类型的遗传多样性，以响应一系列的压力条件下，一个过程，我们称之为“压力诱导的洛”，这是通过提高重组率和/或增加染色体错误分离率。应激诱导的诱变促进细菌病原体的进化，并且主要由通过有丝分裂重组的遗传变化驱动。在其他生物体中对这一过程知之甚少。白色念珠菌是一种机会性真菌病原体，可引起需要适应不同宿主环境小生境的感染。我们测量了洛率和洛事件的类型，出现在缺乏和存在生理相关的压力，并发现，压力会导致洛率显着增加，这种增加是成比例的压力的程度。此外，出现的洛合性缺失事件的类型以应激依赖的方式不同，表明真核细胞响应于一系列应激条件产生增加的遗传多样性。我们认为，这种“应激诱导的洛缺失”促进了不进行减数分裂的白色念珠菌快速适应宿主内不断变化的环境。
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.