A computational framework to explore large-scale biosynthetic diversity.

Abstract

Genome mining has become a key technology to exploit natural product diversity. While 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. Here, we provide a streamlined computational workflow consisting of two new software tools: The ‘Biosynthetic Gene Similarity Clustering And Prospecting Engine’ (BiG-SCAPE) facilitates fast and interactive sequence similarity network analysis of biosynthetic gene clusters and gene cluster families. ‘CORe Analysis of Syntenic Orthologues to prioritize Natural product gene clusters’ (CORASON) elucidates phylogenetic relationships within and across these families. We validate BiG-SCAPE by correlating its output to metabolomic data across 363 actinobacterial strains and demonstrate the discovery potential of CORASON by comprehensively mapping biosynthetic diversity across a range of detoxin/rimosamide-related gene cluster families, culminating in the characterization of seven novel analogues.