MAESTRO uncovers tandem paralog dynamics as a core driver of fungal stress adaptation
Hsieh, P.-H.; Sasaki, Y.; Yang, C.-I.; Wu, Z.-Y.; Steindorff, A. S.; Haridas, S.; Ke, J.; Fatma, Z.; Zhao, Z.; Opulente, D. A.; Deng, S.; Hittinger, C. T.; Grigoriev, I. V.; Dien, B.; Zhao, H.; Li, Y.-P.; Yoshikuni, Y.
Show abstract
Understanding how fungi adapt to diverse stresses is critical for mitigating emerging drug resistance and harnessing their robustness for biotechnology. Pichia kudriavzevii is a stress-tolerant and intrinsically drug-resistant yeast, with dual industrial and clinical importance. We analyzed 170 strains using MAESTRO, a machine-learning-assisted GWAS pipeline optimized for small cohorts. MAESTRO identified biologically meaningful features and revealed that copy number variation (CNV) of tandem paralogs (TPs) is a core mechanism of multi-stress adaptation. TPs were recurrently linked to tolerance of industrial inhibitors (HMF, phenolics, heat) and antifungal drugs (fluconazole, azoles), and deletion of the TP pair gene4260/gene4261 confirmed pleiotropic effects across stresses. These findings support a TP CNV model where recombination-driven TP CNVs and gene fusions enable rapid stress adaptation. Importantly, our results suggest that antifungal resistance can arise through co-option of mechanisms originally evolved for environmental stressors, raising a One Health concern about the environmental origins of drug-resistant pathogens.
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