LAUSR

Significance Assembly-line polyketide synthases (PKSs) make many medicinally significant natural products. A better understanding of evolutionary mechanisms underlying polyketide diversification could open new avenues for PKS engineering and drug discovery. In the course of interrogating the role of gene conversion in assembly-line PKS evolution, we discovered not only that gene conversion is widespread in these PKSs but also that it is frequently associated with the presence of a genetic element, which we have designated GRINS (genetic repeats of intense nucleotide skew). Computational analysis suggests that the presence of GRINS may promote late-stage structural diversification of polyketide antibiotics. Our work sets the stage for further investigation of the underlying molecular mechanisms and evolutionary roles of these genetic elements. Assembly-line polyketide synthases (PKSs) are large and complex enzymatic machineries with a multimodular architecture, typically encoded in bacterial genomes by biosynthetic gene clusters. Their modularity has led to an astounding diversity of biosynthesized molecules, many with medical relevance. Thus, understanding the mechanisms that drive PKS evolution is fundamental for both functional prediction of natural PKSs as well as for the engineering of novel PKSs. Here, we describe a repetitive genetic element in assembly-line PKS genes which appears to play a role in accelerating the diversification of closely related biosynthetic clusters. We named this element GRINS: genetic repeats of intense nucleotide skews. GRINS appear to recode PKS protein regions with a biased nucleotide composition and to promote gene conversion. GRINS are present in a large number of assembly-line PKS gene clusters and are particularly widespread in the actinobacterial genus Streptomyces. While the molecular mechanisms associated with GRINS appearance, dissemination, and maintenance are unknown, the presence of GRINS in a broad range of bacterial phyla and gene families indicates that these genetic elements could play a fundamental role in protein evolution.