Systematic analysis of copy number variations in the pathogenic yeast candida parapsilosis identifies a gene amplification in RTA3 that is associated with drug resistance Journal Article
| Authors: | Bergin, S. A.; Zhao, F.; Ryan, A. P.; Müller, C. A.; Nieduszynski, C. A.; Zhai, B.; Rolling, T.; Hohl, T. M.; Morio, F.; Scully, J.; Wolfe, K. H.; Butler, G. |
| Article Title: | Systematic analysis of copy number variations in the pathogenic yeast candida parapsilosis identifies a gene amplification in RTA3 that is associated with drug resistance |
| Abstract: | We analyzed the genomes of 170 C. parapsilosis isolates and identified multiple copy number variations (CNVs). We identified two genes, RTA3 (CPAR2_104610) and ARR3 (CPAR2_601050), each of which was the target of multiple independent amplification events. Phylogenetic analysis shows that most of these amplifications originated only once. For ARR3, which encodes a putative arsenate transporter, 8 distinct CNVs were identified, ranging in size from 2.3 kb to 10.5 kb with 3 to 23 copies. For RTA3, 16 distinct CNVs were identified, ranging in size from 0.3 kb to 4.5 kb with 2 to ~50 copies. One unusual amplification resulted in a DUP-TRP/INV-DUP structure similar to some human CNVs. RTA3 encodes a putative phosphatidylcholine (PC) floppase which is known to regulate the inward translocation of PC in Candida albicans. We found that an increased copy number of RTA3 correlated with resistance to miltefosine, an alkylphosphocholine drug that affects PC metabolism. Additionally, we conducted an adaptive laboratory evolution experiment in which two C. parapsilosis isolates were cultured in increasing concentrations of miltefosine. Two genes, CPAR2_303950 and CPAR2_102700, coding for putative PC flippases homologous to S. cerevisiae DNF1 gained homozygous protein-disrupting mutations in the evolved strains. Overall, our results show that C. parapsilosis can gain resistance to miltefosine, a drug that has recently been granted orphan drug designation approval by the United States Food and Drug Administration for the treatment of invasive candidiasis, through both CNVs or loss-of-function alleles in one of the flippase genes. © 2022 Bergin et al. |
| Keywords: | genetics; gene amplification; antifungal agent; drug resistance; saccharomyces cerevisiae; genomics; antifungal agents; phosphatidylcholine; phylogeny; dna copy number variations; copy number variation; candida; phosphatidylcholines; drug resistance, fungal; antifungal resistance; candida parapsilosis; miltefosine; invasive candidiasis; humans; human; drug resistance evolution; arsenic acid derivative; arsenates; candidiasis, invasive |
| Journal Title: | mBio |
| Volume: | 13 |
| Issue: | 5 |
| ISSN: | 2150-7511 |
| Publisher: | American Society for Microbiology |
| Date Published: | 2022-09-01 |
| Start Page: | e0177722 |
| Language: | English |
| DOI: | 10.1128/mbio.01777-22 |
| PUBMED: | 36121151 |
| PROVIDER: | scopus |
| PMCID: | PMC9600344 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2022 -- Source: Scopus |
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