Understanding aneuploid fitness for L sorbose utilization due to chromosome 5 monosomy in Candida albicans

Abstract

The major opportunistic fungal pathogen C. albicans has been shown to undergo a parasexual cycle both in vivo and in-vitro resulting in generation of wide spectrum of karyotypic alterations including but not limited to singe nucleotide polymorphisms (SNPs) duplications, deletions, translocations, whole chromosome aneuploidy and segmental aneuploidy. Aneuploidy or chromosomal numerical variations (CNVS) are proven to promote major pathogenic traits like drug resistance and non canonical carbon assimilation in C. albicans. For example, euploid C. albicans strains cannot metabolize secondary carbon sources such as L-sorbose or D-arabinose. However, C. albicans strains monosomic for Chr5 and Chr6 can metabolize L-sorbose and D-arabinose, respectively. Similarly, Chr4 monosomy and Chr4 trisomy promote resistance to fluconazole and 5-fluoroorotic acid (5-FOA), whereas euploids are sensitive to both fluconazole and 5-FOA. This phenomenon where loss or gain of specific chromosome promotes a selective advantage for survival in conditions hampering the growth of euploids is called aneuploid fitness. L-sorbose utilization due to Chr5 monosomy is the first and foremost observed aneuploid fitness mechanism in C. albicans. Euploid C. albicans strains cannot utilize L-sorbsoe and are hence designated Sou-. But C. albicans strains lacing one homologue of Chr5 can utilize L-sorbose and are hence designated Sou+. Further analysis of this phenomenon established that growth on L-sorbose for Chr5 monosomic strain is due to hemizygous loss of 5 dispersed regions called A, B, C, 135 and 139 scattered in ~ 341 kb region of Chr5 proximal to right telomere. Further, it is also shown that hemizygous loss of these regions completely or independent combinations as A (CSU51) + C+ 139 or A + B+ 135 resulted in growth of C. albicans on L-sorbose due to de-repression of single target gene called SOU1 encoding sorbose reductase located on Chr4. Also it is shown that expressing SOU1 gene in a replicative plasmid in euploid C.