Last author

Evolutionary biologists have long debated whether evolution is irreversible and, if so, why. But it is difficult to verify precisely which characteristics were present in early organisms and then identify the mechanisms by which they evolved into their present states. Joseph Thornton, an evolutionary biologist at the Howard Hughes Medical Institute and the University of Oregon in Eugene, and his colleagues, used a unique approach to look at the evolution of the glucocorticoid receptor (GR) in vertebrates, a protein involved in the stress response. On page 515, they show that a class of mutations that occurred in this protein hundreds of millions of years ago rendered its evolution irreversible. Thornton tells Nature more.

How did you find that mutations made GR evolution irreversible?

We knew that the GR's specific response to the stress hormone cortisol evolved from an ancestral vertebrate protein that responded to two other hormones — aldosterone and deoxycorticosterone — as well as to cortisol. Seven ancient mutations resulted in the GR's cortisol specificity. We expected that if we reversed them, we could engineer a protein that functioned more promiscuously, like its ancestor. Instead, we got a 'dead', or non-functioning, receptor. We found that five additional 'restrictive' mutations, which emerged during early GR evolution, clashed with the protein's ancestral conformation. When we reversed these five, together with the seven key mutations, we recreated a protein just like the GR's ancestor.

How do the two classes of mutations differ?

The seven key mutations caused the evolution of cortisol specificity, but the five restrictive mutations had little or no effect on the protein's function. They did, however, burn the evolutionary bridge the protein had just traversed.

Do restrictive mutations prevent reverse evolution in other proteins?

This is the first protein that has been studied in this way, so we don't know for sure. But I predict that the GR won't be a unique case.

What are the implications for how organisms evolve?

We came from ancestors that evolved from their own, deeper predecessors. As time progresses, the conditions that made their evolution possible are continually being erased. If we turned back the clock to start again, different chance events would almost certainly occur, leading to different futures but closing the path to the present that evolved in our world. Our biology is just one of many possible rolls of the evolutionary dice.