Chromosome rearrangements shape the diversification of secondary metabolism in the cyclosporin producing fungus Tolypocladium inflatum

Abstract

BackgroundGenes involved in production of secondary metabolites (SMs) in fungi are exceptionally diverse. Even strains of the same species may exhibit differences in metabolite production, a finding that has important implications for drug discovery. Unlike in other eukaryotes, genes producing SMs are often clustered and co-expressed in fungal genomes, but the genetic mechanisms involved in the creation and maintenance of these secondary metabolite biosynthetic gene clusters (SMBGCs) remains poorly understood.ResultsIn order to address the role of genome architecture and chromosome scale structural variation in generating diversity of SMBGCs, we generated chromosome scale assemblies of six geographically diverse isolates of the insect pathogenic fungus Tolypocladium inflatum, producer of the multi-billion dollar lifesaving immunosuppressant drug cyclosporin, and utilized a Hi-C chromosome conformation capture approach to address the role of genome architecture and structural variation in generating intraspecific diversity in SMBGCs. Our results demonstrate that the exchange of DNA between heterologous chromosomes plays an important role in generating novelty in SMBGCs in fungi. In particular, we demonstrate movement of a polyketide synthase (PKS) and several adjacent genes by translocation to a new chromosome and genomic context, potentially generating a novel PKS cluster. We also provide evidence for inter-chromosomal recombination between nonribosomal peptide synthetases located within subtelomeres and uncover a polymorphic cluster present in only two strains that is closely related to the cluster responsible for biosynthesis of the mycotoxin aflatoxin (AF), a highly carcinogenic compound that is a major public health concern worldwide. In contrast, the cyclosporin cluster, located internally on chromosomes, was conserved across strains, suggesting selective maintenance of this important virulence factor for infection of insects.ConclusionsThis research places the evolution of SMBGCs within the context of whole genome evolution and suggests a role for recombination between chromosomes in generating novel SMBGCs in the medicinal fungus Tolypocladium inflatum.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5399-x) contains supplementary material, which is available to authorized users.

Fungal evolution: cellular, genomic and metabolic complexity

“…The composite nature of gene clusters opens many evolutionary possibilities. Clusters might mutate, duplicate, divide into two, combine, or lose or gain new genes, occasionally through HGT (Fischbach et al ., ; Martín & Liras, ; Slot, ; Rokas et al ., ; Olarte et al ., ). Each of these possibilities is rife with methodological complications for evolutionary studies (Bull et al ., ; Castresana, ; Fischbach et al ., ).…”

Integrative approaches for species delimitation in Ascomycota

“…Several ascomycetes, especially those in the Saccharomycotina, including the common baker's yeast Saccharomyces cerevisiae have known ancestral genome duplication events. Chromosomal translocation or the uncommon rearrangement of chromosomes also influences the incongruence in phylogeny, and it may occur more regularly in fungal genomes than earlier noticed (Olarte et al 2019). For instance, different strains of the entomopathogenic fungus Tolypocladium inflatum exhibit high diversity in production of cyclosporin and other secondary metabolites (Olarte et al 2019).…”

Genomic sequencing indicates non‐random mating ofVenturia inaequalisin a mixed cultivar orchard

“…In particular, the maintenance of separate Cox–Bramley and Cox–Worcester groupings in the Cox V. inaequalis population could be explained by chromosomal rearrangements, with the loci conferring virulence lying within an inverted or translocated region; this would give rise to lethal recombinants in crosses heterogeneous for the rearranged regions. The proportion of the genome involved in, or affected by, rearrangements would be extensive but not unprecedented (Raeside et al , ; Shi‐Kunne et al , ; Olarte et al , ). As pointed out above, such chromosomal rearrangements would, of course, also be another explanation for the aggregation of GSAs.…”