The evolution of the gliotoxin biosynthetic gene cluster inPenicilliumfungi

Abstract

Fungi biosynthesize a diversity of secondary metabolites, small organic bioactive molecules that play diverse roles in fungal ecology. Fungal secondary metabolites are often encoded by physically clustered sets of genes known as biosynthetic gene clusters (BGCs). Fungi in the genusPenicilliumproduce diverse secondary metabolites that have been both useful (e.g., the antibiotic penicillin and the cholesterol-lowering drug mevastatin) and harmful (e.g., the mycotoxin patulin and the immunosuppressant gliotoxin) to human affairs. BGCs often also encode resistance genes that confer self-protection to the secondary metabolite-producing fungus. SomePenicilliumspecies, such asPenicillium lilacinoechinulatumandPenicillium decumbens, are known to produce gliotoxin, a secondary metabolite with known immunosuppressant activity; however, an evolutionary characterization of the BGC responsible for gliotoxin biosynthesis amongPenicilliumspecies is lacking. Here, we examine the conservation of genes involved in gliotoxin biosynthesis and resistance in 35Penicilliumgenomes from 23 species. We found homologous, less fragmented gliotoxin BGCs in 12 genomes, mostly fragmented remnants of the gliotoxin BGC in 21 genomes, whereas the remaining twoPenicilliumgenomes lacked the gliotoxin BGC altogether. In contrast, we observed broad conservation of homologs of resistance genes that reside outside the BGC acrossPenicilliumgenomes. Evolutionary rate analysis revealed that BGCs with higher numbers of genes evolve slower than BGCs with few genes. Even though the gliotoxin BGC is fragmented to varying degrees in nearly all genomes examined, ancestral state reconstruction suggests that the ancestor ofPenicilliumspecies possessed the gliotoxin BGC. Our analyses suggest that genes that are part of BGCs can be retained in genomes long after the loss of secondary metabolite biosynthesis.