28 October 2009
Michael J. Behe
The science writer Carl Zimmer posted an invited reply http://tinyurl.com/yhpm3t7 on his blog from Joseph Thornton of the University of Oregon to my recent comments about Thornton’s work. This is the third of several posts addressing it. References will appear in the last post.
Now back to Thornton’s first point, the role of neutral mutations (which he sometimes labels “permissive” mutations). At several places in his post Thornton implies I’m unaware of the possibilities opened up by genetic drift:
“Behe’s discussion of our 2009 paper in Nature is a gross misreading because it ignores the importance of neutral pathways in protein evolution…. Behe’s first error is to ignore the fact that adaptive combinations of mutations can and do evolve by pathways involving neutral intermediates…. As Fig. 4 in our paper shows, there are several pathways back to the ancestral sequence that pass only through steps that are neutral or beneficial with respect to the protein’s functions.”
My interest in evolution by neutral mutation, however, is a matter of public record. It is an old idea that if a gene for a protein duplicates (3), then multiple mutations can accumulate in a neutral fashion in the “spare” gene copy, even if those mutations would be severely deleterious if they occurred in a single-copy gene. Four years ago David Snoke and I wrote a paper entitled “Simulating evolution by gene duplication of protein features that require multiple amino acid residues” (4) where we investigated aspects of that scenario. The bottom line is that, although by assumption of the model anything is possible, when evolution must pass through multiple neutral steps the wind goes out of Darwinian sails, and a drifting voyage can take a very, very long time indeed. But don’t just take my word for it — listen to Professor Thornton (1):
“To restore the ancestral conformation by reversing group X, the restrictive effect of the substitutions in group W must first be reversed, as must group Y. Reversal to w and y in the absence of x, however, does nothing to enhance the ancestral function; in most contexts, reversing these mutations substantially impairs both the ancestral and derived functions. Furthermore, the permissive effect of reversing four of the mutations in group W requires pairs of substitutions at interacting sites. Selection for the ancestral function would therefore not be sufficient to drive AncGR2 back to the ancestral states of w and x, because passage through deleterious and/or neutral intermediates would be required; the probability of each required substitution would be low, and the probability of all in combination would be virtually zero.” (my emphasis)
Let’s quote that last sentence again, with emphasis: “Selection for the ancestral function would therefore not be sufficient … because passage through deleterious and/or neutral intermediates would be required; the probability of each required substitution would be low, and the probability of all in combination would be virtually zero.” If Thornton himself discounts the power of genetic drift when it suits him, why shouldn’t I?
In his blog response to me Professor Thornton wants to emphasize that selection-plus-drift can sometimes lead from one nearby function to another, as it did in his work on the ancestral MR-like to the GR-like receptor transition. (2) But I and virtually everyone else already thought that was true. That’s why at the time I called those results (perhaps impolitely, but accurately) “piddling”. A surprise it was not. In his 2009 paper investigating the reverse transition, however, Thornton wants to emphasize (because it is unexpected) that in some cases selection-plus-drift can not lead (with anything like reasonable probability) even to a very similar function. Now that was surprising to me and apparently to many other folks.
The immediate, obvious implication (which he clearly wants to keep far away from) is that the 2009 results render problematic even pretty small changes in structure/function for all proteins — not just the ones he worked on. (Thornton himself is betting on this: “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….”) (1) So how, other than begging the question, are we now to know that even the small differences we see in related protein systems came about by random mutation/selection (and, yes, drift)? Quite simply, we can’t. Yet if even small changes are problematic, then larger changes will be prohibitive, and very big changes essentially unattainable. Thanks to Thornton’s impressive work, we can now see that the limits to Darwinian evolution are more severe than even I had supposed.