Phylogenetic and syntenic analyses of the 12-spanner drug:H+ antiporter family 1 (DHA1) in pathogenic Candida species: evolution of MDR1 and FLU1 genes

• The drug-H + antiporters DHA1 encoded in 25 hemiascomycetous genomes were identified.
• Sixteen DHA1 lineages were conserved during the evolution of the CTG complex species.
• Gene duplication and loss were major mechanisms in the evolution of the DHA1 genes.
• The evolutionary history of Candida albicans MDR1 and FLU1 genes was detailed.
• The biochemically uncharacterized C. albicans orf19.7148 is a FLU1 gene paralog.

Candida albicans and other pathogenic Candida species can develop resistance to clinical fungicides through active drug export mediated by multidrug efflux pumps, in particular by members of the drug:H+ antiporter family 1 (DHA1). The DHA1 proteins encoded in the genomes of 31 hemiascomycetous strains from 25 species were identified and homology relationships between these proteins and the functionally characterised DHA1 in the model yeast Saccharomyces cerevisiae were established. Gene neighbourhood analysis allowed the reconstruction of sixteen DHA1 lineages conserved during the CTG complex species evolution. The evolutionary history of C. albicans MDR1 and FLU1 genes and Candida dubliniensis, Candida tropicalis and Candida parapsilosis MDR1 genes was detailed. Candida genomes show an abundant number of MDR1 and FLU1 homologues but the chromosome environment where MDR1 homologues reside was poorly conserved during evolution. Gene duplication and loss are major mechanisms underlying the evolution of the DHA1 genes in Candida species.