title: A systematic computational analysis of biosynthetic gene cluster evolution: lessons for engineering biosynthesis.
abstract: Bacterial secondary metabolites are widely used as antibiotics, anticancer drugs, insecticides and food additives. Attempts to engineer their biosynthetic gene clusters (BGCs) to produce unnatural metabolites with improved properties are often frustrated by the unpredictability and complexity of the enzymes that synthesize these molecules, suggesting that genetic changes within BGCs are limited by specific constraints. Here, by performing a systematic computational analysis of BGC evolution, we derive evidence for three findings that shed light on the ways in which, despite these constraints, nature successfully invents new molecules: 1) BGCs for complex molecules often evolve through the successive merger of smaller sub-clusters, which function as independent evolutionary entities. 2) An important subset of polyketide synthases and nonribosomal peptide synthetases evolve by concerted evolution, which generates sets of sequence-homogenized domains that may hold promise for engineering efforts since they exhibit a high degree of functional interoperability, 3) Individual BGC families evolve in distinct ways, suggesting that design strategies should take into account family-specific functional constraints. These findings suggest novel strategies for using synthetic biology to rationally engineer biosynthetic pathways.
authors.affiliation: Department of Microbial Physiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands; Groningen Bioinformatics Centre, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands.
authors.forename: Marnix H
authors.initials: MH
authors.lastname: Medema
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States of America; California Institute for Quantitative Biosciences, San Francisco, California, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Cimermancic
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States of America; California Institute for Quantitative Biosciences, San Francisco, California, United States of America; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Andrej
authors.initials: A
authors.lastname: Sali
authors.affiliation: Manchester Institute of Biotechnology, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Eriko
authors.initials: E
authors.lastname: Takano
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States of America; California Institute for Quantitative Biosciences, San Francisco, California, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Fischbach
mesh_terms: D057005:Bioengineering / Q000379:methods*; D019295:Computational Biology / Q000379:methods*; D019143:Evolution, Molecular; D008957:Models, Genetic; D005810:Multigene Family / Q000235:genetics*