Expanding the genomic encyclopedia of Actinobacteria with 824 isolate reference genomes

The phylum Actinobacteria includes important human pathogens like Mycobacterium tuberculosis and Corynebacterium diphtheriae and renowned producers of secondary metabolites of commercial interest, yet only a small part of its diversity is represented by sequenced genomes. Here, we present 824 actinobacterial isolate genomes in the context of a phylum-wide analysis of 6,700 genomes including public isolates and metagenome-assembled genomes (MAGs). We estimate that only 30%–50% of projected actinobacterial phylogenetic diversity possesses genomic representation via isolates and MAGs. A comparison of gene functions reveals novel determinants of host-microbe interaction as well as environment-specific adaptations such as potential antimicrobial peptides. We identify plasmids and prophages across isolates and uncover extensive prophage diversity structured mainly by host taxonomy. Analysis of >80,000 biosynthetic gene clusters reveals that horizontal gene transfer and gene loss shape secondary metabolite repertoire across taxa. Our observations illustrate the essential role of and need for high-quality isolate genome sequences. • 824 new actinobacterial isolate genomes from diverse environments • Only a third of actinobacterial diversity has genome representation • New niche-specific gene determinants highlighted, such as new antimicrobial peptides • Secondary metabolite gene clusters shaped by horizontal gene transfer Seshadri et al. contribute 824 new genomes of cultivated Actinobacteria , which are important for drug discovery. They observe that the genes responsible for producing such compounds often move around between microbes, making them harder to capture without high-quality genomes. They highlight interesting adaptations such as an experimentally verified antimicrobial peptide.