Research seminars Centromere-driven genomic innovations and the emergence of anti-fungal drug resistance

A The fungal kingdom comprises a minimum of 2.5 million eukaryotic species. Fungi can adapt to various selection pressure by changing their karyotypes. The unusual karyotype plasticity of fungal pathogens plays a significant role in driving reproductive isolation and increased resistance to antifungal drugs. A growing body of evidence suggests that the centromere locus is one of the most significant hubs involved in karyotype diversity. 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. 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 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 the echinocandin caspofungin. At the population level, these structural variants frequently arise alongside mutations in FKS1, suggesting coordinated genetic mechanisms underlying reduced drug susceptibility. Together, our findings establish segmental aneuploidy 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.