Jennifer H. Wisecaver, Alexander T. Borowsky, Vered Tzin, Georg Jander, Daniel J. Kliebenstein, Antonis Rokas

Plants produce diverse specialized metabolites (SMs), but the genes responsible for their production and regulation remain largely unknown, hindering efforts to tap plant pharmacopeia. Given that genes comprising SM pathways exhibit environmentally dependent co-regulation, we hypothesized that genes within a SM pathway would form tight associations (modules) with each other in co-expression networks, facilitating their identification. To evaluate this hypothesis, we used 10 global co-expression datasets, each a meta-analysis of hundreds to thousands of experiments, across eight plant species to identify hundreds of co-expressed gene modules per dataset. In support of our hypothesis, 15.3-52.6% of modules contained two or more known SM biosynthetic genes, and module genes were enriched in SM functions. Moreover, modules recovered many experimentally validated SM pathways, including all six known to form biosynthetic gene clusters (BGCs). In contrast, bioinformatically predicted BGCs (i.e. those lacking an associated metabolite) were no more co-expressed than the null distribution for neighboring genes. These results suggest that most predicted plant BGCs are not genuine SM pathways and argue that BGCs are not a hallmark of plant specialized metabolism. We submit that global gene co-expression is a rich, largely untapped resource for discovering the genetic basis and architecture of plant natural products.