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Evolutionary rewiring of the gene regulatory network controlled by Ndt80


Gene regulatory networks—composed of transcription regulators and their downstream “target” genes—have been shown to control many biological processes, and changes to either the regulators, the target genes, or the connections between them can lead to alterations in the level, timing, or patterning of gene products. However, it remains poorly understood how a complex gene regulatory network, controlling a novel phenotype, arises over evolutionary time. Here we demonstrate that the fungal transcription regulator Ndt80 has undergone a dramatic evolutionary switch in regulatory function—from an ancestral role in regulating sporulation and meiosis to a derived role in regulating biofilm formation. This switch in function, which took place along the lineage leading to the Candida clade, corresponded to a large-scale change in the genes regulated by Ndt80, as it was incorporated into a novel gene regulatory network. However, we demonstrate, through experiments in multiple extant yeast lineages, that the connections between Ndt80 and its target genes were undergoing rapid rewiring prior to the switch in Ndt80’s regulatory function. We propose that drift in the Ndt80 regulon, which occurs along all lineages examined, facilitated its dramatic switch in function along one lineage, allowing it to become integrated into a novel gene regulatory network. This idea that the promiscuity of the Ndt80 regulon could be exploited in the evolution of a novel phenotype is analogous in many ways to studies of protein evolution that have demonstrated that ancestral promiscuity in protein function can be exploited in the evolution of novel protein functions. We believe this work provides the first example of the exploitation of regulatory network promiscuity in the evolution of a novel regulatory network, and emphasizes the importance of regulatory network drift in the exploration of new network configurations and the evolution of novel phenotypes.

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