We explore how whole-genome duplications (WGDs) may have given rise to complex innovations in cellular networks, innovations that could not have evolved through sequential single-gene duplications. We focus on two classical WGD events, one in bakers’ yeast and the other at the base of vertebrates (i.e., two rounds of whole-genome duplication: 2R-WGD). Two complex adaptations are discussed in detail: aerobic ethanol fermentation in yeast and the rewiring of the vertebrate developmental regulatory network through the 2R-WGD. These two examples, derived from diverged branches on the eukaryotic tree, boldly underline the evolutionary potential of WGD in facilitating major evolutionary transitions. We close by arguing that the evolutionary importance of WGD may require updating certain aspects of modern evolutionary theory, perhaps helping to synthesize a new evolutionary systems biology. 1. Introduction Characteristic changes in karyotype number have allowed researchers to infer polyploidy events for many decades [1]. It was thus with a reasonably long history of research that Susumo Ohno was able to suggest that polyploidy was a vital route to evolutionary innovation [2]. Ohno was of course a forceful proponent of a general role for duplication in evolution: writing that “[if evolution occurred only through changes allele frequencies] … from a bacterium only numerous forms of bacteria would have emerged […B]ig leaps in evolution required the creation of new gene loci with previously nonexistent functions” [2]. What is less obvious on first reading is his distinction between the role played by WGD and that played by other, smaller scale, duplications (or SSDs). While the differences in the scales of these events are self-evident, there are at least two other features of WGD that are critical in giving rise to these differing roles. The first is that, as many authors have reported, particular functional classes of genes (e.g., transcription factors, kinases, ribosomal proteins, and cyclins) are duplicated by WGD more frequently than by SSD [3–8]. Ohno had in fact explored the most likely reason for this difference: “hub” genes with many interactions with other loci, be those interactions regulatory, protein interaction or metabolic, will tend to respond poorly to a change in copy number. As a result, they will tend to survive in duplicate after WGD but will not survive after smaller scale events [2, 5, 9–11]. This idea has now been termed the dosage balance hypothesis [12–14]. The second difference between single-gene and genome duplication is the kind of
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