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Ancient transcriptional regulators can easily evolve new pair-wise cooperativity


The immense diversity of life is astounding. Yet this variety is in stark contrast with life’s genetic similarity. Many of the same genes and even gene sequences are shared by much of the life on Earth. Thus, perhaps what best defines a species is not its gene complement, per se, but how those genes are used and regulated. Much of gene regulation depends on the binding of sequence specific transcription factors to cis-regulatory sites in other gene promoters. Changes in these protein factors, or the DNA sites they bind, can alter gene expression and give rise to new traits and forms of life. Likewise, these transcription factors themselves may change, gaining (or losing) functionalities that alter the organism. For example, in some budding yeast species two ancient and unrelated transcription factors – Matα2 and MCM1 – acquired the ability to bind one another and co-regulate new genes. This facilitated the emergence of a new mode of combinatorial gene control in these species. In this work, I show that this new form of regulation likely arose easily due to the promiscuous nature of the Matα2-MCM1 interaction. This promiscuity allows for many alternative ways for Matα2 to bind MCM1 and involves widespread intramolecular epistasis within Matα2. The gain of new functional protein-protein interactions between transcriptional regulators, as explored here, is believed to be a general way that life diversifies and likely has broad implications. Understanding how and why new biological traits emerge is a fundamental question in biology.

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