Evolution and diversity of lichen biosynthetic gene clusters: a focus on terpenes and RiPPs

Natural products and their derivatives are an essential resource for the development of pharmaceuticals. However, demand for novel drugs is ever increasing due to the increasing number of infectious diseases, resistant to existing drugs, posing an mounting pressure to explore novel taxa for bioactive natural products. Currently, genome mining has become a key technology to identify, compare, and exploit natural product diversity as it expands the possible sources of bioactive natural products to beyond culturable taxa. In recent times natural product research has made an exponential progress, thanks to rapidly increasing number of publicly available genomes and the improvements in genome mining, gene identification and comparison pipelines, which not only allow the identification of biosynthetic genes but also permit their the bioinformatic characterization and clustering to unravel the relationship between Biosynthetic Gene Clusters (BGCs) and make informed predictions about the compounds’ bioactivity. For this study, a total of 111 lichenized fungal genomes were analysed to identify terpene-related and RiPPs biosynthetic genes, and to perform phylogenetic analyses to unravel the evolution of homologous clusters across taxa. A total of 733 terpene BGCs and 1183 RiPPs BGCs were found. We found that: 1) lichenized fungi contain predominantly species-specific or taxonomically restricted biosynthetic genes 2) lichenized fungi contain two widely distributed, homologous gene clusters for both RiPPs and terpene-related BGCs 3) the terpene clans were widely distributed across lichens, containing the same core gene - squalene/phytoene synthase - but different sets of accessory genes and 4) lichenized fungal RiPPs are diverse than those found in non-lichenized fungi and probably code for novel molecules. A conserved domain was identified in the core gene of two RiPP clans, as well as in dikaritin homologs, potentially playing an important role in the mature product.