Gene flow contributes to diversification of the major fungal pathogen Candida albicans.

Elucidating population structure and levels of genetic diversity and recombination is necessary to understand the evolution and adaptation of species. Candida albicans is the second most frequent agent of human fungal infections worldwide, causing high-mortality rates. Here we present the genomic sequences of 182 C. albicans isolates collected worldwide, including commensal isolates, as well as ones responsible for superficial and invasive infections, constituting the largest dataset to date for this major fungal pathogen. Although, C. albicans shows a predominantly clonal population structure, we find evidence of gene flow between previously known and newly identified genetic clusters, supporting the occurrence of (para)sexuality in nature. A highly clonal lineage, which experimentally shows reduced fitness, has undergone pseudogenization in genes required for virulence and morphogenesis, which may explain its niche restriction. Candida albicans thus takes advantage of both clonality and gene flow to diversify.

A study of the DNA damage checkpoint in Candida albicans: uncoupling of the functions of Rad53 in DNA repair, cell cycle regulation and genotoxic stress-induced polarized growth.

In response to genotoxic stress (GS), Candida albicans can undergo polarized growth and massive genome rearrangements including loss-of-heterozygosity (LOH) events. We evaluated the contribution of the CaRad53p and CaDun1p kinases of the DNA damage checkpoint (DDCP) in these processes. Characterization of C. albicans rad53ΔΔ and dun1ΔΔ mutants revealed that the two kinases were involved in the maintenance of heterozygosity. SNP-RFLP typing and whole-genome sequencing of rad53ΔΔ isolates having undergone a LOH revealed that, according to the chromosome on which LOH had occurred, these were predominantly due to break-induced replication/mitotic cross-over or chromosome loss. Loss of CaRAD53 also resulted in frequent aneuploidies. Deletion of CaDUN1 led to an increase in recombination-dependent LOH but did not trigger aneuploidies. It also increased GS sensitivity but did not impair GS-induced polarized growth contrary to CaRAD53 deletion. Characterization of CaRad53p site-directed mutants demonstrated that its kinase activity and N-terminal phosphorylation sites were crucial for its function in the resistance to GS, maintenance of heterozygosity, cell cycle regulation and polarized growth. Moreover, using phosphomimic mutants, we revealed an uncoupling of the functions of CaRad53p in these different processes, thus providing a novel understanding of how the DDCP may regulate downstream events in response to GS.