Linking secondary metabolites to gene clusters through genome sequencing of six diverse Aspergillus species

Inge Kjærbølling, Tammi C. Vesth, Jens C. Frisvad, Jane L. Nybo, Sebastian Theobald, Alan Kuo, Paul Bowyer, Yudai Matsuda, Stephen Mondo, Ellen K. Lyhne, Martin E. Kogle, Alicia Clum, Anna Lipzen, Asaf Salamov, Chew Yee Ngan, Chris Daum, Jennifer Chiniquy, Kerrie Barry, Kurt LaButti, Sajeet Haridas, Blake A. Simmons, Jon K. Magnuson, Uffe H. Mortensen, Thomas O. Larsen, Igor V. Grigoriev, Scott E. Baker, Mikael R. Andersen

The fungal genus of Aspergillus is highly interesting, containing everything from industrial cell factories, model organisms, and human pathogens. In particular, this group has a prolific production of bioactive secondary metabolites (SMs). In this work, four diverse Aspergillus species (A. campestris, A. novofumigatus, A. ochraceoroseus, and A. steynii) have been whole-genome PacBio sequenced to provide genetic references in three Aspergillus sections. A. taichungensis and A. candidus also were sequenced for SM elucidation. Thirteen Aspergillus genomes were analyzed with comparative genomics to determine phylogeny and genetic diversity, showing that each presented genome contains 15-27% genes not found in other sequenced Aspergilli. In particular, A. novofumigatus was compared with the pathogenic species A. fumigatus This suggests that A. novofumigatus can produce most of the same allergens, virulence, and pathogenicity factors as A. fumigatus, suggesting that A. novofumigatus could be as pathogenic as A. fumigatus Furthermore, SMs were linked to gene clusters based on biological and chemical knowledge and analysis, genome sequences, and predictive algorithms. We thus identify putative SM clusters for aflatoxin, chlorflavonin, and ochrindol in A. ochraceoroseus, A. campestris, and A. steynii, respectively, and novofumigatonin, ent-cycloechinulin, and epi-aszonalenins in A. novofumigatus Our study delivers six fungal genomes, showing the large diversity found in the Aspergillus genus; highlights the potential for discovery of beneficial or harmful SMs; and supports reports of A. novofumigatus pathogenicity. It also shows how biological, biochemical, and genomic information can be combined to identify genes involved in the biosynthesis of specific SMs.