Chromosome architecture as a determinant for biosynthetic diversity in Micromonospora.

Natural products - small molecules generated by organisms to facilitate ecological interactions - are of great importance to society and are used as antibacterial, antiviral, antifungal and anticancer drugs. However, the role and evolution of these molecules and the fitness benefits they provide to their hosts in their natural habitat remain an outstanding question. In bacteria, the genes that encode the biosynthetic proteins that generate these molecules are organised into discrete loci termed biosynthetic gene clusters (BGCs). In this work, we asked the following question: How are biosynthetic gene clusters organised at the chromosomal level? We sought to answer this using publicly available high-quality assemblies of Micromonospora, an actinomycete genus with members responsible for biosynthesizing notable natural products, such as gentamicin and calicheamicin. By orienting the Micromonospora chromosome around the origin of replication, we demonstrated that Micromonospora has a conserved origin-proximal region, which becomes progressively more disordered towards the antipodes of the origin. We then demonstrated through genome mining of these organisms that the conserved origin-proximal region and the origin-distal region of Micromonospora have distinct populations of BGCs and, in this regard, parallel the organization of Streptomyces, which possesses linear chromosomes. Specifically, the origin-proximal region contains highly syntenous, conserved BGCs predicted to biosynthesize terpenes and a type III polyketide synthase. In contrast, the ori-distal region contains a highly diverse population of BGCs, with many BGCs belonging to unique gene cluster families. These data highlight that genomic plasticity in Micromonospora is locus-specific, and highlight the importance of using high-quality genome assemblies for natural product discovery and guide future natural product discovery by highlighting that biosynthetic novelty may be enriched in specific chromosomal neighbourhoods.