片段重复和超数染色体驱动耳念珠菌的抗真菌药物耐药性
Segmental duplications and supernumerary chromosomes drive antifungal drug resistance in Candida auris.
摘要(中文译文)
耳念珠菌（Candida auris）是世界卫生组织列出的关键优先真菌病原体，在全球范围内频繁引起多重耐药暴发。尽管介导抗真菌耐药的点突变已被充分表征，但结构基因组变异对抗真菌反应的贡献仍不明确。本研究整合全基因组测序、全基因组拷贝数变异（CNV）筛查、电泳核型和突变累积分析，在临床耳念珠菌分离株队列中探究结构变异对抗真菌敏感性的作用。我们识别出反复出现的CNV热点，其中片段重复是基因组变异的主要模式。包含ERG11的小片段重复以高频率出现，并常与耐药相关ERG11突变共存，共同增强唑类耐药性。此外，1号染色体包含着丝粒的大片段重复产生超数染色体，导致矛盾性生长及对棘白菌素卡泊芬净敏感性降低。在群体水平上，结构变异常与FKS1突变平行出现，提示药物敏感性降低存在多种遗传机制。总之，我们的发现确立片段重复是抗真菌耐药的主要非突变驱动因素，强调在耐药监测和临床药敏试验中需考虑结构基因组变异。
Abstract
Candida auris, a World Health Organisation-listed critical priority fungal pathogen, causes frequent multidrug-resistant outbreaks worldwide. While point mutations underlying antifungal resistance are well characterised, the contribution of structural genomic variation to antifungal responses remains poorly defined. Here, we integrate whole-genome sequencing, a genome-wide copy number variation (CNV) screen, electrophoretic karyotyping, and mutation-accumulation analyses to investigate the role of structural variation in antifungal susceptibility across a clinical cohort of C. auris isolates. We identify recurrent CNV hotspots, with segmental duplications representing a predominant mode of genome variation. Small duplications encompassing ERG11 arise at high frequency and frequently co-occur with drug resistance-associated ERG11 mutations, collectively enhancing azole resistance. In addition, large centromere-inclusive duplications of chromosome 1 generate supernumerary chromosomes, leading to paradoxical growth and reduced susceptibility to caspofungin, an echinocandin. At the population level, structural variants frequently arise in parallel to FKS1 mutations, suggesting multiple genetic mechanisms underlying reduced drug susceptibility. Together, our findings establish segmental duplication as a major, non-mutational driver of antifungal resistance, highlighting the need to consider structural genomic variation in both resistance surveillance and clinical susceptibility testing.
如何引用
AMA
Aswathy Narayanan, Sameer Joshi, Ritika Harchand, Rajendra Prasad, Shivaprakash M Rudramurthy, Koodali T Nishant, et al. Segmental duplications and supernumerary chromosomes drive antifungal drug resistance in Candida auris.. Nature communications. 2026; doi:10.1038/s41467-026-75437-3.
APA
Aswathy Narayanan, Sameer Joshi, Ritika Harchand, Rajendra Prasad, Shivaprakash M Rudramurthy, Koodali T Nishant, et al (2026). Segmental duplications and supernumerary chromosomes drive antifungal drug resistance in Candida auris.. Nature communications. https://doi.org/10.1038/s41467-026-75437-3
GB/T 7714
Aswathy Narayanan, Sameer Joshi, Ritika Harchand, Rajendra Prasad, Shivaprakash M Rudramurthy, Koodali T Nishant, et al. Segmental duplications and supernumerary chromosomes drive antifungal drug resistance in Candida auris.[J]. Nature communications, 2026 doi:10.1038/s41467-026-75437-3.
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