Science Literature

Evolutionary theory does not boast of many laws, and those that do are not universal by any means. One of these is Dollo's law, which is said to date back to about 1890. It is really a hypothesis about the non-reversibility of evolutionary pathways. The authors of new research considered the relevance of the law to the molecular evolution of a protein structure and reported a significant constraint preventing reversibility.

"The extent to which our observations concerning the evolutionary reversibility of glucocorticoid receptors can be generalized to other proteins requires further research. We predict that future investigations, like ours, will support a molecular version of Dollo's law: as evolution proceeds, shifts in protein structure-function relations become increasingly difficult to reverse whenever those shifts have complex architectures [. . .]"

A few restrictive mutations meant the key would not turn (Source here)

A description of the work is provided by Carl Zimmer in The New York Times:

"Dr. Thornton and his colleagues [. . .] studied a protein called a glucocorticoid receptor that helps humans and most other vertebrates cope with stress by grabbing a hormone called cortisol and then switching on stress-defense genes. By comparing the receptor to related proteins, the scientists reconstructed its history. Some 450 million years ago, it started out with a different shape that allowed it to grab tightly to other hormones, but only weakly to cortisol. Over the next 40 million years, the receptor changed shape, so that it became very sensitive to cortisol but could no longer grab other hormones. During those 40 million years, Dr. Thornton found, the receptor changed in 37 spots, only 2 of which made the receptor sensitive to cortisol. Another 5 prevented it from grabbing other hormones. When he made these 7 changes to the ancestral receptor, it behaved just like a new glucocorticoid receptor.
Dr. Thornton reasoned that if he carried out the reverse operation, he could turn a new glucocorticoid receptor into an ancestral one. So he and his colleagues reversed these key mutations to their old form. To Dr. Thornton's surprise, the experiment failed. "All we got was a completely dead receptor," he said."

To find out why the receptor was inactive, the researchers looked for other mutations - and found 5. These were described as "restrictive" because when attempts were made to return the receptor to its supposed ancestral form, the additional mutations acted as blocks.

"Dr. Thornton argues that once the restrictive mutations evolved, they made it practically impossible for the receptor to evolve back to its original form. The five key mutations could not be reversed first, because the receptor would be rendered useless. Nor could the seven restrictive mutations be reversed first. Those mutations had little effect on how the receptor grabbed hormones. So there was no way that natural selection could favor individuals with reversed mutations."

Some significant comments on this research have been made by Michael Behe here and here. These comments are highly relevant to discussions of mechanisms of evolutionary transformation. At the outset, Behe said that the work was interesting and the conclusion was reasonable -

"but the result was exceedingly modest and well within the boundaries that an intelligent design proponent like myself would ascribe to Darwinian processes. After all, the starting point was a protein which binds several steroid hormones, and the ending point was a slightly different protein that binds the same steroid hormones with slightly different strengths. How hard could that be?"

Behe's central point is that the evolutionary pathway was relatively easily disrupted by a few other mutations, so it is not satisfactory to think that Darwinian processes can find a way over every hurdle. The conclusions of his first post are as follows:

* The central point of The Edge of Evolution was that if several amino acids of a protein must be changed before a certain selective effect is available, then that is effectively beyond the reach of Darwinian processes. Bridgham et al (2009) confirm that conclusion. [. . .]
* There is no reason to think the protein studied by Bridgham et al (2009) is unusual in its difficulty of developing a binding site for even a relatively closely-related substance. In fact, in the absence of strong opposing data, that should be the default, reasonable assumption.
* That same reasonable assumption counts strongly against any two unrelated proteins easily developing a binding site for each other.
* That reasonable assumption therefore negates all woolly Darwinian evolutionary scenarios where critical protein binding sites are assumed without justification to pop up when needed (such as, say, in the building of multiprotein structures like the cilium or flagellum).
* Thus the work strongly supports the conclusion of Edge that Darwinian processes are highly unlikely to have built the complex molecular machinery of the cell.

The conclusion of the second post is this:

"The bottom line is that, for a given evolutionary task, at best only a handful of proteins will likely be helpful to evolve, at worst none may help. To calculate the probability of, say, a helpful protein-protein interaction developing in response to any particular selective pressure, it's mistaken to gratuitously multiply odds by the total number of proteins in a cell. Combined with the point made by Bridgham et al (2009), that even tiny structural/functional changes may not be achievable by random mutation/selection, these considerations pretty much squelch the likelihood of Darwinian processes doing much of significance during evolution."

An epistatic ratchet constrains the direction of glucocorticoid receptor evolution
Jamie T. Bridgham, Eric A. Ortlund & Joseph W. Thornton
Nature 461, 515-519 (24 September 2009) | doi:10.1038/nature08249

The extent to which evolution is reversible has long fascinated biologists. Most previous work on the reversibility of morphological and life-history evolution has been indecisive, because of uncertainty and bias in the methods used to infer ancestral states for such characters. Further, despite theoretical work on the factors that could contribute to irreversibility, there is little empirical evidence on its causes, because sufficient understanding of the mechanistic basis for the evolution of new or ancestral phenotypes is seldom available. By studying the reversibility of evolutionary changes in protein structure and function, these limitations can be overcome. Here we show, using the evolution of hormone specificity in the vertebrate glucocorticoid receptor as a case-study, that the evolutionary path by which this protein acquired its new function soon became inaccessible to reverse exploration. 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 function-switching 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.

See also:

Behe, M. Nature Publishes Paper on the Edge of Evolution, Evolution News & Views, 30 September 2009

Behe, M. Nature Paper Reaches "Edge of Evolution" and Finds Darwinian Processes Lacking, Evolution News & Views, 7 October 2009

Dolgin, E. Protein burns its evolutionary bridges, Nature News, 23 September 2009 | doi:10.1038/news.2009.940