Recent gene selection and drug resistance underscore clinical adaptation across Candida species

Understanding how microbial pathogens adapt to treatments, humans and clinical environments is key to infer mechanisms of virulence, transmission and drug resistance. This may help improve therapies and diagnostics for infections with a poor prognosis, such as those caused by fungal pathogens, including Candida. Here we analysed genomic variants across approximately 2,000 isolates from six Candida species (C. glabrata, C. auris, C. albicans, C. tropicalis, C. parapsilosis and C. orthopsilosis) and identified genes under recent selection, suggesting a highly complex clinical adaptation. These involve species-specific and convergently affected adaptive mechanisms, such as adhesion. Using convergence-based genome-wide association studies we identified known drivers of drug resistance alongside potentially novel players. Finally, our analyses reveal an important role of structural variants and suggest an unexpected involvement of (para)sexual recombination in the spread of resistance. Our results provide insights on how opportunistic pathogens adapt to human-related environments and unearth candidate genes that deserve future attention.
The T.G. group acknowledges support from the Spanish Ministry of Science and Innovation (grant numbers PID2021-126067NB-I00, CPP2021-008552, PCI2022-135066-2 and PDC2022-133266-I00), cofounded by ERDF ‘A way of making Europe’, as well as support from the Catalan Research Agency (grant number SGR01551), European Union’s Horizon 2020 research and innovation programme (grant number ERC-2016-724173), Gordon and Betty Moore Foundation (grant number GBMF9742), ‘La Caixa’ Foundation (grant number LCF/PR/HR21/00737) and Instituto de Salud Carlos III (IMPACT grant number IMP/00019 and CIBERINFEC CB21/13/00061-ISCIII-SGEFI/ERDF). M.A.S.-T. received a Predoctoral Fellowship from the ‘La Caixa’ Foundation (grant number LCF/BQ/DR19/11740023). The authors thank all of the members of the Gabaldón group for key support during this work. In particular H. Hovhannisyan, V. d. Olmo, D. Fuentes, M. Schiavinato, M. Marcet-Houben, G. Torruella, J. C. Núñez, U. Chorostecki and E. Księżopolska, who provided useful feedback, which was key for the project development. In addition, we thank M. Lleal for useful feedback in designing the figures.
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