Haploidy, diploidy and evolution of antifungal drug resistance in Saccharomyces cerevisiae
Haploidy, diploidy and evolution of antifungal drug resistance in Saccharomyces cerevisiae
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DOI：
10.1534/genetics.104.033266
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发表时间：
2004-12-01
期刊：
影响因子：
3.3
通讯作者：
Ricker, N
中科院分区：
文献类型：
--
作者：
Anderson, JB;Sirjusingh, C;Ricker, N
我们测试了抗真菌药物耐药性演变的时间过程取决于真菌倍性的假设。实验的目的是测量初始响应的选择施加的抗真菌药物氟康唑，并包括固定的第一个耐药突变的酿酒酵母菌群。在低药物浓度的条件下，PDR 1和PDR 3基因的突变是有利的，PDR 1和PDR 3基因调节与氟康唑耐药性有关的ABC转运蛋白。在这种环境中，确定大小的二倍体群体始终比单倍体群体更快地固定抗性突变。操纵群体大小的实验表明，二倍体的这种优势是由于相对于单倍体的突变可用性增加;实际上，二倍体具有两倍于单倍体的突变靶点数量，因此具有减少的突变发生的等待时间。在高药物浓度的条件下，有利于ERG 3的隐性突变，其通过改变固醇合成而导致抗性。在这种环境中，单倍体始终比二倍体更快地获得抗性。当29个单倍体和29个二倍体群体在低药物浓度下进化100代时，二倍体群体中固定的突变均为显性，而单倍体群体中固定的突变为隐性（16个群体）或显性（13个群体）。此外，在序列水平上鉴定的53个非同义突变的谱在单倍体和二倍体之间是不同的。这些结果符合现有的理论，单倍体和二倍体的相对能力，以适应和真菌病原体的倍性有很强的影响氟康唑耐药性的演变。
We tested the hypothesis that the time course of the evolution of antifungal drug resistance depends on the ploidy of the fungus. The experiments were designed to measure the initial response to the selection imposed by the antifungal drug fluconazole up to and including the fixation of the first resistance mutation in populations of Saccharomyces cerevisiae. Under conditions of low drug concentration, mutations in the genes PDR1 and PDR3, which regulate the ABC transporters implicated in resistance to fluconazole, are favored. In this environment, diploid populations of defined size consistently became fixed for a resistance mutation sooner than haploid populations. Experiments manipulating population sizes showed that this advantage of diploids was due to increased mutation availability relative to that of haploids; in effect, diploids have twice the number of mutational targets as haploids and hence have a reduced waiting time for mutations to occur. Under conditions of high drug concentration, recessive mutations in ERG3, which result in resistance through altered sterol synthesis, are favored. In this environment, haploids consistently achieved resistance much sooner than diploids. When 29 haploid and 29 diploid populations were evolved for 100 generations in low drug concentration, the mutations fixed in diploid populations were all dominant, while the mutations fixed in haploid populations were either recessive (16 populations) or dominant (13 populations). Further, the spectrum of the 53 nonsynonymous mutations identified at the sequence level was different between haploids and diploids. These results fit existing theory on the relative abilities of haploids and diploids to adapt and suggest that the ploidy of the fungal pathogen has strong impact on the evolution of fluconazole resistance.