Table_1_Tetraploidy accelerates adaptation under drug selection in a fungal pathogen.docx

Baseline ploidy significantly impacts evolutionary trajectories and, specifically, tetraploidy is associated with higher rates of adaptation relative to haploidy and diploidy. While the majority of experimental evolution studies investigating ploidy use the budding yeast Saccharomyces cerivisiae, the fungal pathogen Candida albicans is a powerful system to investigate ploidy dynamics, particularly in the context of acquiring antifungal drug resistance. C. albicans laboratory and clinical strains are predominantly diploid, but have been isolated as haploid and polyploid. Here, we evolved diploid and tetraploid C. albicans for ~60 days in the antifungal drug caspofungin. Tetraploid-evolved lines adapted faster than diploid-evolved lines and reached higher levels of caspofungin resistance. While diploid-evolved lines generally maintained their initial genome size, tetraploid-evolved lines rapidly underwent genome-size reductions and did so prior to caspofungin adaptation. While clinical resistance was largely due to mutations in FKS1, these mutations were caused by substitutions in diploid, and indels in tetraploid isolates. Furthermore, fitness costs in the absence of drug selection were significantly less in tetraploid-evolved lines compared to the diploid-evolved lines. Taken together, this work supports a model of adaptation in which the tetraploid state is transient but its ability to rapidly transition ploidy states improves adaptive outcomes and may drive drug resistance in fungal pathogens.

基础倍性（ploidy）对进化轨迹具有显著影响，具体而言，相较于单倍体与二倍体，四倍体的适应性进化速率显著更高。尽管多数探究倍性的实验进化研究以出芽酵母——酿酒酵母（Saccharomyces cerevisiae）为模型，但真菌病原体白色念珠菌（Candida albicans）却是探究倍性动态的绝佳系统，尤其在抗真菌药物耐药性获得的研究场景中。白色念珠菌的实验室菌株与临床菌株多为二倍体，但也已分离得到单倍体与多倍体菌株。本研究将二倍体与四倍体白色念珠菌置于含抗真菌药物卡泊芬净（caspofungin）的培养基中开展了约60天的适应性进化实验。结果显示，四倍体进化株的适应性进化速率快于二倍体进化株，且最终达到的卡泊芬净耐药水平更高。二倍体进化株通常能够维持初始基因组大小，而四倍体进化株则会快速发生基因组尺寸缩减，且这一过程发生于卡泊芬净适应性进化之前。临床耐药性主要源于FKS1基因（FKS1）的突变：二倍体分离株的突变类型为碱基替换，而四倍体分离株则为插入缺失变异（indels）。此外，在无药物选择压力的条件下，四倍体进化株的适合度代价（fitness costs）显著低于二倍体进化株。综合以上结果，本研究支持如下适应性进化模型：四倍体状态具有暂时性，但该状态能够通过快速转换倍性提升适应性进化效果，并可能推动真菌病原体的耐药性演化。