You Can't Go Home Again

This is a resurrected version of a steroid hormone receptor. It was derived from the modern glucocorticoid receptor (GR) gene by mutating various codons to make them like the predicted ancestral gene. When all of the mutations were introduced, the protein was expressed and its structure was determined.

Glucocorticoid receptor specifically binds cortisol but the ancient protein binds other steroids as well as cortisol. This is pretty much what you might expect. Various gene duplication events lead to a family of proteins and each family member evolved to recognize a single ligand. The fact that you can reconstruct the presumed ancestral protein and show that it bound to multiple ligands is pretty amazing. The work comes out of Joseph Thornton's lab (Ortlund et al. 2007).

Altogether there were about 60 amino acid substitutions along the lineage leading from the ancestral broad-specificity receptor to the cortisol-specific receptor but only two of these turned out to be ones that shifted the specificity. Most of the rest probably had little effect of the function or specificity of the protein. This is the expected result. Most amino acid substitutions during evolution are neutral.

If there are really only two key amino acid substitutions that change specificity then it should be possible to convert a modern glucocorticoid receptor into one that recognizes a broad range of hormones by merely changing two amino acids. In other words, you could revert to the ancient form by reversing evolution and only a few mutations should do it.

Can you go back in time this easily? Apparently not, according to a recent paper from the same lab (Bridgham et al. 2009). Carl Zimmer is on top of this story in a article he published in yesterday's issue of the New York Times "Can Evolution Run in Reverse? A Study Says It’s a One-Way Street."

There's no conceptual advances in this paper, at least for those scientists who have a proper understanding of evolution. Some of the neutral changes along the pathway prepared the way for additional changes that were not possible in the ancestor protein. In other words, strictly neutral changes can add up to significant differences in structural stability making it possible for some adaptive change to occur that could not have otherwise occurred.

This isn't a breakthrough, it's an excellent study that confirms what was predicted on the basis of what we know about evolution. Here's how the authors describe their result in the abstract ...

Using ancestral gene reconstruction, protein engineering and X-ray crystallography, we demonstrate that five subsequent ‘restrictive’ mutations, which optimized the new specificity of the glucocorticoid receptor, also destabilized elements of the protein structure that were required to support the ancestral conformation. Unless these ratchet-like epistatic substitutions are restored to their ancestral states, reversing the key functionswitching mutations yields a non-functional protein. Reversing the restrictive substitutions first, however, does nothing to enhance the ancestral function. Our findings indicate that even if selection for the ancestral function were imposed, direct reversal would be extremely unlikely, suggesting an important role for historical contingency in protein evolution.

Because of "historical contingency" you can't reverse evolution. The path that lineages follow as they evolve is determined, in part, by chance and accident and not by natural selection alone.

You can't go home again.

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Bridgham, J.T., Ortlund, E.A., and Thornton, J.W. (2009) An epistatic ratchet constrains the direction of glucocorticoid receptor evolution. Nature 461:515-519. [PDF]

Ortlund, E.A., Bridgham, J.T., Redinbo, M.R., and Thornton, J.W. (2007) Crystal structure of an ancient protein: evolution by conformational epistasis. Science 317:1544-1548. [PDF]