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A notable feature of this natural product class is the existence of chemical hybrids that combine core moieties from different polyketide structures. To understand the prevalence, biosynthetic basis, and evolutionary patterns of this phenomenon, we developed <jats:italic>trans<\/jats:italic>PACT, a phylogenomic algorithm to automate global classification of <jats:italic>trans<\/jats:italic>-AT PKS modules across bacteria and applied it to 1782 <jats:italic>trans<\/jats:italic>-AT PKS gene clusters. These analyses reveal widespread exchange patterns suggesting recombination of extended PKS module series as an important mechanism for metabolic diversification in this natural product class. For three plant-associated bacteria, i.e., the root colonizer <jats:italic>Gynuella sunshinyii<\/jats:italic> and the pathogens <jats:italic>Xanthomonas cannabis<\/jats:italic> and <jats:italic>Pseudomonas syringae<\/jats:italic>, we demonstrate the utility of this computational approach for uncovering cryptic relationships between polyketides, accelerating polyketide mining from fragmented genome sequences, and discovering polyketide variants with conserved moieties of interest. As natural combinatorial hybrids are rare among the more commonly studied <jats:italic>cis<\/jats:italic>-AT PKSs, this study paves the way towards evolutionarily informed, rational PKS engineering to produce chimeric <jats:italic>trans<\/jats:italic>-AT PKS-derived\u00a0polyketides.<\/jats:p>","DOI":"10.1038\/s41467-021-21163-x","type":"journal-article","created":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T11:09:58Z","timestamp":1614769798000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Evolution of combinatorial diversity in trans-acyltransferase polyketide synthase assembly lines across bacteria"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8751-3279","authenticated-orcid":false,"given":"Eric J. 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