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Natural products and the gene cluster revolution

Omic sciences are driving natural-products research in exciting new directions. Genome sequence data, coupled with an improved understanding of the molecular genetics of natural-product biosynthesis, and online tools to facilitate computational analyses, are providing unprecedented opportunities to explore the diversity and distributions of natural-product biosynthetic gene clusters in Nature. While most of the BGCs observed in bacterial genome sequences are orphan, it remains unclear how many of these will yield new compounds (see Outstanding Questions). Synthetic biology has taken center stage in terms of discovering the products of orphan BGCs; however, we remain surprisingly unaware of the natural cues that trigger expression in the native hosts. A better understanding of the regulatory cues and ecological functions of natural products will certainly facilitate future discovery efforts. By sequencing large numbers of closely related strains, it has become clear that certain groups of bacteria maintain extensive population-level BGC diversity and that most of this diversity is rarely observed among strains. This observation suggests that most BGCs are not under strong positive selection and that maintaining an expansive and dynamic secondary metabolome maximizes opportunities for population-level responses to episodic environmental pressures. While much remains to be learned about the mechanisms by which chemical diversity is created, natural-product BGCs provide opportunities to explore secondary metabolism as it relates to the ecology and evolution of bacteria in addition to exploiting their products for useful purposes.

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