Association of lanthipeptide genes with TnpAREP transposases in marine picocyanobacteria

Lanthipeptides are a family of ribosomally synthesized, post-translationally modified peptides that are widespread among bacteria, typically functioning as antibacterials. The marine picocyanobacteria Prochlorococcus and Synechococcus produce an unusual and diverse set of lanthipeptides of unknown function called prochlorosins. While well-studied model bacteria produce one or two different molecules of this type, a single picocyanobacterium can produce as many as 80; the community of picocyanobacteria in a single milliliter of seawater can collectively encode up to 10,000 prochlorosins. The molecular events that led to this expansion and diversification of the lanthipeptide repertoire in picocyanobacteria – the numerically dominant photosynthesizers in the oceans – is unknown. We present evidence for an unusual association between prochlorosin genes with a single-stranded DNA transposase belonging to the TnpAREP family. The genes co-occur and co-localize across the phylogeny of marine picocyanobacteria forming a distinct association pattern within genomes, most likely resulting from the transposase activity. Given the role of TnpAREP homologs in other bacteria, we propose - based on genomic structures - that they contribute to the creation of the prochlorosin structural diversity through a diversifying recombination mechanism. Post-submission note Since the original submission of this manuscript to bioRxiv, we have refined our phylogenetic analysis of the TnpA-REP transposases and we do not find strong evidence for or against a causal relationship between the presence of TnpA-REP transposases and the expansion and diversification of lanthipeptides genes. While the genetic association described in the manuscript remains valid, adjacent TnpA-REP and Prochlorosins do not appear phylogenetically linked, which might simply be the consequence of high rates of recombination for both genes. More genomic data are needed to untangle the driving force behind the lanthipeptide gene expansion in marine picocyanobacteria. IMPORTANCE Only a few mechanisms have been described that promote the diversification of a targeted gene region in bacteria. We present indirect evidence that the TnpAREP transposases associated with prochlorosins in picocyanobacteria could represent a novel such mechanism, and explain the extreme expansion and diversification of prochlorosins in this abundant marine microbe. ### Competing Interest Statement The authors have declared no competing interest.