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Genome mining has become a key technology to exploit natural product diversity. Although initially performed on a single-genome basis, the process is now being scaled up to mine entire genera, strain collections and microbiomes. However, no bioinformatic framework is currently available for effectively analyzing datasets of this size and complexity. In the present study, a streamlined computational workflow is provided, consisting of two new software tools: the ‘biosynthetic gene similarity clustering and prospecting engine’ (BiG-SCAPE), which facilitates fast and interactive sequence similarity network analysis of biosynthetic gene clusters and gene cluster families; and the ‘core analysis of syntenic orthologues to prioritize natural product gene clusters’ (CORASON), which elucidates phylogenetic relationships within and across these families. BiG-SCAPE is validated by correlating its output to metabolomic data across 363 actinobacterial strains and the discovery potential of CORASON is demonstrated by comprehensively mapping biosynthetic diversity across a range of detoxin/rimosamide-related gene cluster families, culminating in the characterization of seven detoxin analogues. Two bioinformatic tools, BiG-SCAPE and CORASON, enable sequence similarity network and phylogenetic analysis of gene clusters and their families across hundreds of strains and in large datasets, leading to the discovery of new natural products.

Genome mining has become a key technology to explore and exploit natural product diversity through the identification and analysis of biosynthetic gene clusters (BGCs). Initially, this was performed on a single-genome basis; currently, the process is being scaled up to large-scale mining of pan-genomes of entire genera, complete strain collections and metagenomic datasets from which thousands of bacterial genomes can be extracted at once. However, no bioinformatic framework is currently available for the effective analysis of datasets of this size and complexity. Here, we provide a streamlined computational workflow, tightly integrated with antiSMASH and MIBiG, that consists of two new software tools, BiG-SCAPE and CORASON. BiG-SCAPE facilitates rapid calculation and interactive visual exploration of BGC sequence similarity networks, grouping gene clusters at multiple hierarchical levels, and includes a ‘glocal’ alignment mode that accurately groups both complete and fragmented BGCs. CORASON employs a phylogenomic approach to elucidate the detailed evolutionary relationships between gene clusters by computing high-resolution multi-locus phylogenies of all BGCs within and across gene cluster families (GCFs), and allows researchers to comprehensively identify all genomic contexts in which particular biosynthetic gene cassettes are found. We validate BiG-SCAPE by correlating its GCF output to metabolomic data across 403 actinobacterial strains. Furthermore, we demonstrate the discovery potential of the platform by using CORASON to comprehensively map the phylogenetic diversity of the large detoxin/rimosamide gene cluster clan, prioritizing three new detoxin families for subsequent characterization of six new analogs using isotopic labeling and analysis of tandem mass spectrometric data.