Genomic insights into multidrug-resistance, mating and virulence in Candida auris and related emerging species

Abstract

Candida auris is an emergent multidrug-resistant fungal pathogen causing increasing reports of outbreaks. While distantly related to C. albicans and C. glabrata, C. auris is closely related to rarely observed and often multidrug-resistant species from the C. haemulonii clade. Here, we analyze near complete genome assemblies for the four C. auris clades and three related species, and map intra- and inter-species rearrangements across the seven chromosomes. Using RNA-Seq-guided gene predictions, we find that most mating and meiosis genes are conserved and that clades contain either the MTLa or MTLα mating loci. Comparing the genomes of these emerging species to those of other Candida species identifies genes linked to drug resistance and virulence, including expanded families of transporters and lipases, as well as mutations and copy number variants in ERG11. Gene expression analysis identifies transporters and metabolic regulators specific to C. auris and those conserved with related species which may contribute to differences in drug response in this emerging fungal clade.

Fig. 1

Whole genome conservation, structure, and synteny. a Genome wide gene synteny among Candida auris, C. haemulonii, C. duobushaemulonii, and C. pseudohaemulonii. To determine synteny regions of conserved gene order, we identified orthologs between these isolates and then plotted chains of orthologs (gray lines). Isolate names are shown to the left of their genomes, which are represented by horizontal black lines, with vertical lines indicating scaffold borders, and their identifiers listed above (+/− = orientation). b Shared synteny regions based on whole genome alignments between C. auris B8441 and B11221. Asterisk refers to scaffolds in reverse orientation

Fig. 2

Mating-type loci (MTL) in Candida auris and closely related species. a Synteny schema depicting the orientation and conservation of the color-coded MTL idiomorphs and genes adjacent to the MTL. The putative MTL in C. auris, C. haemulonii, C. duobushaemulonii, and C. pseudohaemulonii are shown in comparison with the MTLa and MTLα idiomorphs from C. lusitaniae. b Phylogenetic analysis of the non-mating flanking genes (PIK1/OBP1/PAP1) showing the inheritance of idiomorphs of these genes within the MTLa and MTLα loci. Branch lengths indicate the mean number of changes per site. c Phylogenetic tree of C. auris isolates from Lockhart et al.. Isolates are color-coded according to the clades (I, II, III, and IV) and mating type (MTLa and MTLα). Supplementary Figure 3 shows isolates, origin, and the normalized depth read coverage of mapped positions for all isolates aligned to B8441 (MTLa) and B11221 (MTLα), supporting the classification into MTLa or MTLα

Fig. 3

Phylogenomic and gene family changes in Candida auris and related species. a Maximum likelihood phylogeny using 1570 core genes based on 1000 replicates, among 20 annotated genome assemblies, including Candida auris, C. haemulonii (B11899), C. duobushaemulonii (B09383), and C. pseudohaemulonii (B12108), and closely related species. Branch lengths indicate the mean number of changes per site. b Heatmap depicting results of protein family enrichment analysis (PFAM domains; corrected p-value < 0.05) comparing the gene content of C. auris strains representing each clade, C. haemulonii, C. duobushaemulonii, and C. pseudohaemulonii, and other closely related species, including C. lusitaniae, C. albicans, C. krusei, and C. glabrata. Values are colored along a blue (low counts) to red (high counts) color scale, with color scaling relative to the low and high values of each row. Each protein family domain has a color code (right) indicating whether expanded or depleted

Fig. 4

Phylogenetic relationships of expanded families of transporters. a, b Maximum likelihood phylogenetic trees showing expansion of oligopeptide transporters (OPT) and siderophore iron transporters (SIT) families in C. auris and C. haemulonii, C. duobushaemulonii and C. pseudohaemulonii. Each species has a color code and lineage-specific expansions (blue branches) can be seen in C. auris and closely related species relative to the close ancestor C. lusitaniae and C. albicans. Orthologs of OPT and SIT transporters in C. albicans are depicted alongside each tree. c Chromosome view depicting genes and orientation located in chromosome 6 (B8441 scaffold05). This region highlights expansion and tandem duplication of eight OPT class transporters (in red)