title: Evolutionary analysis of multidrug resistance genes in fungi - impact of gene duplication and family conservation.
abstract: Although the emergence of bacterial drug resistance is of great concern to the scientific community, few studies have evaluated this phenomenon systematically in fungi by using genome-wide datasets. In the present study, we assembled a large compendium of Saccharomyces cerevisiae chemical genetic data to study the evolution of multidrug resistance genes (MDRs) in the fungal lineage. We found that MDRs typically emerge in widely conserved families, most of which containing homologs from pathogenic fungi, such as Candida albicans and Coccidioides immitis, which could favor the evolution of drug resistance in those species. By integrating data from chemical genetics with protein family conservation, genetic and protein interactions, we found that gene families rarely have more than one MDR, indicating that paralogs evolve asymmetrically with regard to multidrug resistance roles. Furthermore, MDRs have more genetic and protein interaction partners than non-MDRs, supporting their participation in complex biochemical systems underlying the tolerance to multiple bioactive molecules. MDRs share more chemical genetic interactions with other MDRs than with non-MDRs, regardless of their evolutionary affinity. These results suggest the existence of an intricate system involved in the global drug tolerance phenotypes. Finally, MDRs are more likely to be hit repeatedly by mutations in laboratory evolution experiments, indicating that they have great adaptive potential. The results presented here not only reveal the main genomic features underlying the evolution of MDRs, but also shed light on the gene families from which drug resistance is more likely to emerge in fungi.
authors.affiliation: Laboratório de Química e Função de Proteínas e Peptídeos, Centro de Biociências e Biotecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, Brazil.
authors.forename: Cristiani
authors.initials: C
authors.lastname: Gossani
authors.forename: Daniel
authors.initials: D
authors.lastname: Bellieny-Rabelo
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Venancio
mesh_terms: D001483:Base Sequence; D017124:Conserved Sequence; D004271:DNA, Fungal / Q000235:genetics; D025141:Drug Resistance, Fungal / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019143:Evolution, Molecular; D020440:Gene Duplication; D005800:Genes, Fungal; D019450:Genes, MDR; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D004271:DNA, Fungal
keywords: chemical genetics; drug resistance; functional divergence; multidrug resistance genes; systems biology