Joseph Thornton and his colleagues explored why evolution rarely backtracks by studying the 450-million-year evolution of the glucocorticoid receptor (GR):
Around the time cartilaginous fish such as sharks split off from bony fish, roughly 440 million years ago, the ancestral protein that the scientists call GR1 responded to both cortisol and the hormone aldosterone. But 40 million years later, when four-legged creatures started to appear, the descendent GR2 had become cortisol-specific.During these 40 million years, 37 amino acids changed. Only two were necessary to alter the function: One put a kink in the protein’s shape, making it unresponsive to both hormones, and another allowed the restructured molecule to interact with only cortisol. Thornton’s team next wondered if they could make GR2 recognize both cortisol and aldosterone by reverting these amino acids, which they call group X, back to their GR1 state. The researchers report today in Nature that this swap not only couldn’t restore GR’s original dual function but that it also killed the protein’s ability to recognize any hormone.
So what blocked the way back? By comparing images of GR2 and a putative ancestral protein, the scientists fingered another five of the 37 GR1-to-GR2 mutations as the culprits. These changes probably occurred randomly after the X mutations and had no significant effect on the protein’s function going forward. But in reverse, when the scientists tried to iron out the GR2 kink, these mutations caused protein parts to crash into one another. For GR2 to evolve back into GR1, these five mutations must be reversed first to avoid this molecular fender-bender. But because they have no effect on which hormone the protein recognizes, there would be no selective pressure to reverse these mutations. “They burn the bridge to return back to the ancestral function,” Thornton says.