Chromosomal rearrangements and loss of subtelomeric adhesins linked to clade-specific phenotypes in Candida auris

Abstract

11Candida auris is an emerging fungal pathogen of rising concern due to its increasing incidence, 12 its ability to cause healthcare-associated outbreaks and antifungal resistance. Genomic analysis 13 revealed that early cases of C. auris that were detected contemporaneously were 14 geographically stratified into four major clades. Clade II, also termed East Asian clade, consists 15 of the initial isolates described from cases of ear infection, is less frequently resistant to 16 antifungal drugs and to date, the isolates from this group have not been associated with 17 outbreaks. Here, we generate nearly complete genomes ("telomere-to-telomere") of an isolate 18 of this clade and of the more widespread Clade IV. By comparing these to genome assemblies 19 of the other two clades, we find that the Clade II genome appears highly rearranged, with 2 20 inversions and 9 translocations resulting in a substantially different karyotype. In addition, large 21 subtelomeric regions have been lost from 10 of 14 chromosome ends in the Clade II genomes. 22We find that shorter telomeres and genome instability might be a consequence of a naturally 23 occurring loss-of-function mutation in DCC1 exclusively found in Clade II isolates, resulting in a 24 hypermutator phenotype. We also determine that deleted subtelomeric regions might be linked 25 to clade-specific adaptation as these regions are enriched in Hyr/Iff-like cell surface proteins, 26 novel candidate cell surface proteins, and an ALS-like adhesin. The presence of these cell 27 surface proteins in the clades responsible for global outbreaks causing invasive infections 28 suggests an explanation for the different phenotypes observed between clades.29 30 IMPORTANCE 31Candida auris was unknown prior to 2009 and since then it has quickly spread around the world, 32 causing outbreaks in healthcare facilities and representing a high fraction of candidemia cases 33 in some regions. The emergence of C. auris is a major concern, since it is often multidrug-34 resistant, easily spread between patients, and causes invasive infections. While isolates from 102 103 Depleted Hyr/Iff and species-specific cell-wall protein families in C. auris Clade II 104The subtelomeric regions deleted in Clade II likely contribute to the phenotypic differences of 105 this clade, most notably by the loss of fourteen candidate adhesins present in Clades I, III and 106 IV. These include two sets of genes that contain predicted GPI anchors and secretion signals, 107 one set sharing sequence similarity to C. albicans adhesins from the Hyr/Iff family and a second 108 set of clustered genes only found in C. auris and the closely related species C. haemulonii and 109 C. duobushaemulonii (Figure 2a; Supplementary Table 2). The Hyr/Iff gene family was 110 previously noted to be the most highly enriched family in pathogenic Candida species and has 111 been associated with pathogenicity and virulence (15). Six of eight Hyr/Iff proteins found in C. 112auris contain intergenic tandem repeats, which modulate adhesion ...

Evaluation of nine surface disinfectants against Candida auris using a quantitative disk carrier method: EPA SOP-MB-35

“…9 A recent study also demonstrates that clade II isolates have large chromosomal rearrangements and are missing a number of genes present in the other 2 C. auris clades. 10 In contrast, AR 0385 from clade IV is very closely related to isolates causing outbreaks across the Americas and has chromosomal and genetic structure similar to those of clades I and III. 8 For these reasons, we chose to continue our work with AR 0385.…”

Nine Things Genomics Can Tell Us About Candida auris

“…For example, inversions and translocations of hundreds of kilobase genomic regions have been reported between Clade I (isolate B8441) and Clade III (isolate B11221) (Muñoz et al, 2018). More recent work using long-read telomere-to-telomere sequencing has shown the Clade II genome appears highly rearranged compared with the other 3 clades, with 2 inversions and 9 translocations resulting in a substantially different karyotype (Muñoz et al, 2019). It was hypothesized that these rearrangements could potentially prevent genetic exchange between those lineages (Muñoz et al, 2018).…”

“…The C. auris genome encodes several orthologs of C. albicans adhesins implicated in biofilm formation and virulence. Clade II strains of C. auris, which predominantly cause ear infections, have lost significant sections of subtelomeric regions that are enriched in putative adhesins, but are conserved in strains from Clades I, III, and IV (Muñoz et al, 2019).…”

Functional and comparative genome analysis reveals clade-specific genome innovations in the killer fungusCandida auris

“…Centromeres were numbered from 1 to 7 in the clade 4 assembly based on the decreasing sizes of the chromosomes harbouring them. Centromeres of clades 1, 2, and 3 were numbered based on synteny with clade 4 CEN s. Cross-clade comparisons revealed the genome of clade 2 to be the most rearranged one compared to the other three clades, as reported previously (Muñoz et al 2019) (fig. 2B).…”