An Interpreted Atlas of Biosynthetic Gene Clusters from 1000 Fungal Genomes

Abstract

Fungi are prolific producers of natural products, compounds which have had a large societal impact as pharmaceuticals, mycotoxins, and agrochemicals. Despite the availability of over 1000 fungal genomes and several decades of compound discovery efforts from fungi, the biosynthetic gene clusters (BGCs) encoded by these genomes and the associated chemical space have yet to be analyzed systematically. Here we provide detailed annotation and analyses of fungal biosynthetic and chemical space to enable genome mining and discovery of fungal natural products. Using 1037 genomes from species across the fungal kingdom (e.g., Ascomycota, Basidiomycota, and non-Dikarya taxa), 36,399 predicted BGCs were organized into a network of 12,067 gene cluster families (GCFs). Anchoring these GCFs with reference BGCs enabled automated annotation of 2,026 BGCs with predicted metabolite scaffolds. We performed parallel analyses of the chemical repertoire of Fungi, organizing 15,213 fungal compounds into 2,945 molecular families (MFs). The taxonomic landscape of fungal GCFs is largely species-specific, though select families such as the equisetin GCF are present across vast phylogenetic distances with parallel diversifications in the GCF and MF. We compare these fungal datasets with a set of 5,453 bacterial genomes and their BGCs and 9,382 bacterial compounds, revealing dramatic differences between bacterial and fungal biosynthetic logic and chemical space. These genomics and cheminformatics analyses reveal the large extent to which fungal and bacterial sources represent distinct compound reservoirs. With a >10-fold increase in the number of interpreted strains and annotated BGCs, this work better regularizes the biosynthetic potential of fungi for rational compound discovery.Significance StatementFungi represent an underexploited resource for new compounds with applications in the pharmaceutical and agriscience industries. Despite the availability of >1000 fungal genomes, our knowledge of the biosynthetic space encoded by these genomes is limited and ad hoc. We present results from systematically organizing the biosynthetic content of 1037 fungal genomes, providing a resource for data-driven genome mining and large-scale comparison of the genetic and molecular repertoires produced in fungi and compare to those present in bacteria.

Secondary metabolism drives ecological breadth in the Xylariaceae

“…In contrast, SMGC abundance in endophyte genomes appears unrelated to PCWDE content. Overall, our results provide evidence that SMGCs may play a key role in facilitating endophyte colonization of diverse hosts (e.g., through suppression or degradation of host immune responses 17,18 ), further highlighting the importance of symbioses to drive not only speciation and ecological diversification 51 , but chemical biodiversity that can be leveraged for novel pharmaceuticals and agrochemicals 52 .…”

Secondary metabolite biosynthetic diversity in the fungal family Hypoxylaceae and Xylaria hypoxylon

“…In a recent large-scale genome mining study, BGCs of around 1 000 fungal genomes were identified by an automated pipeline showing that the classes Eurotiomycetes and Sordariomycetes encode among the largest numbers of BGCs on average per species (approx. 50) ( Robey et al 2021 ). Within the Sordariomycetes dataset (n = 198), only nine members of the Xylariales were included, with four of them belonging to the Hypoxylaceae , all of which were environmental isolates only tentatively identified to the genus level.…”

The year 2020 in natural product bioinformatics: an overview of the latest tools and databases

“…A new atlas of fungal BGCs from 1000 fungal genomes, called Prospect, was also released, which includes gene cluster family assignments for these gene clusters. 31 Finally, databases with curated sets of high-quality genomes, such as the ActDES database for actinomycetes 32 released this year, will make it easier to navigate highquality data when navigating biosynthetic potential of various taxa.…”