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Recently in the journal Evolution, two of my colleagues in the Lehigh University Department of Biological Sciences published a seven-page critical review of Darwin Devolves. As I'll show below, it pretty much completely misses the mark. Nonetheless, it is a good illustration of how sincere-yet-perplexed professional evolutionary biologists view the data, as well as how they see opposition to their views, and so it is a possible opening to mutual understanding. This is the first of a three-part reply.

I'd like to begin by enthusiastically affirming that the co-authors of the review, Greg Lang and Amber Rice, are terrific young scientists. Greg's research is on the experimental laboratory evolution of yeast, and he's an associate editor at the Journal of Molecular Evolution. Amber studies the evolutionary effects of the hybridization of two species of chickadee, and she's an associate editor for Evolution. Not surprisingly, the review is well written and the authors have done a lot of homework, not only reading the book itself but also digging into other material I have written and relevant literature. What's more, Greg and Amber are both salt-of-the-earth folks, cheerful, friendly, and great colleagues. The additional Lehigh people they cite in the Acknowledgements section share all those qualities. There is no reason for anyone to take any of the remarks in their review as anything other than their best honest professional opinions of the matter. So let's get to the substance of the review.

"Two Critical Errors of Logic"

After introductory remarks, Lang and Rice begin by deferring to the review of my book in Science and a follow-up web post to show that the book contains "a few factual errors and many errors of omission." (I along with others have dealt at length with those already; see here, here, here, here, here, and here) Instead, in their own review they focus on what they see as two logical errors of the book: 1) that I wrongly equate "the prevalence of loss of function mutations to the inevitable degradation of biological systems and the impossibility of evolution to produce novelty"; and 2) that I wrongly confuse proteins with machines, and use that misguided metaphor to mislead readers. I'll take those two points and their many subparts mostly in turn.

They begin with logical error #1 by deriding the First Rule of Adaptive Evolution as a "quality sound bite" that is "simplistic and untruthful to the data." Recall that the First Rule states, "Break or blunt any functional gene whose loss would increase the number of a species' offspring." Also recall that I explained, in both the book and the journal article where it was first published, that it is called a "rule" in the sense of being a rule of thumb, not an unbreakable law, and it is called the "first" rule because that is what we should generally expect to happen first to help a species adapt, simply because there are many more ways to break a gene than to build a new constructive feature.

As you might imagine, I have read the Evolution review closely. Yet nowhere do the authors even try to show why the First Rule isn't a correct statement. They point to mutations that are not degradative, but fail to show quantitatively that those other types will arise faster than degradative ones. In fact, the other types are expected to be orders of magnitude slower.

The reviewers agree that the First Rule is fine for explaining many results from the experimental evolution of microbes such as bacteria and yeast, but they balk at extending it beyond the lab. In fact, they actively argue that lab results really can't tell us much about the real world: "No deletion is beneficial in all environments and beneficial loss of function mutations that arise in experimental evolution are unlikely to succeed if, say, cells are required to mate, the static environment is disturbed, or glucose is temporarily depleted." All of those situations, of course, will be common outside a laboratory.

One big fly in their argument, however, is that they overlook the results from non-laboratory evolution that I give in the book. Every species that has been examined in sufficient detail so far shows the same pattern as seen in lab results. For example, I open the book with a discussion of polar bear evolution. About two-thirds to three-quarters of the most highly selected genes that separated the polar bear from the brown bear are estimated by computer methods to have experienced mutations that were functionally damaging. (Some other reviewers questioned this. I showed why they are mistaken here.) Similar results were seen for the woolly mammoth. Neither of those species evolved in the laboratory. Except for the sickle mutation (which itself is a desperate remedy), all mutations selected in the wild in humans for resistance to malaria are degradative. Dog breed evolution, which has been touted as a great stand-in for selection in the wild, is mostly degradative, and lots of breeds have health problems.

What's more, we might well ask, if it doesn't mimic the world realistically, why do federal funding agencies award grants to those who study laboratory evolution? Lang and Rice aver that it does indeed give lots of helpful information:
Collectively, experimental evolution has yielded new insights into the tempo of genotypic and phenotypic adaptation, the role of historical contingency in the evolution of new traits, second order selection on mutator alleles, the power of sex to combine favorable (and purge deleterious) mutations, the dynamics of adaptation, and the seemingly unlimited potential of adaptive evolution.
(Those phrases are press-release fodder. As I have shown in numerous posts, the results are much more modest than the headlines make them sound; see here, here, here, here, and here.) But, as the reviewers themselves insist, those results are all based on an unnatural situation - on the prevalence of degradative mutations in artificial environments - so why should we trust that the results reflect what would happen in nature? How can the reviewers with any consistency accept some of the lab results but not others?

It astounds me to see how quickly lab evolution researchers disavow the importance of their own life's work when some outsider draws an unwelcome inference. But perhaps we can still save the day. Maybe all of the researchers' results point to some important lessons about unguided evolution. In fact, there's no reason to think that many lab evolution experiments are different in relevant ways from how nature behaves.

Lab Reflects Nature

The first objection Lang and Rice raise against extrapolating results from lab evolution studies to evolution in the wild is that the environments are critically different:
[L]oss of function mutations are expected to contribute disproportionately to adaptation in experimental evolution, where selective pressures are high and conditions are constant, or nearly so.
That sounds a little off. After all, selective pressures in raw nature can be pretty stringent, too, if, for example, 85 percent of a vertebrate species died in a single year due to altered weather conditions. And, as we saw above, species in a complex changing natural environment, such as the polar bear and humans, show evolutionary behavior similar to that seen in laboratories. What's more, the conditions in lab evolution are generally far from simple or "constant." That's because by far the greatest complexity in any organism's environment is not due to the temperature or solution conditions in which it finds itself. Rather it is due to the presence of other organisms, including others of its own species. If any individual suddenly gains a selective advantage - even in otherwise quite constant environmental conditions - then its progeny have a splendid chance to outcompete the progeny of all other organisms.

Let's look at several examples from the best known lab evolution experiment - that of Richard Lenski, who has been growing E. coli for over thirty years to observe how it adapts. I'll begin with the best known mutation of that long study - the development of mutant bacteria that could eat citrate in the presence of oxygen, which the ancestor strain could not do. I'll skip over the molecular details here (I've commented elsewhere) and concentrate on the bottom line. Even though the environment had been constant, overnight the citrate mutant strain outgrew its brethren and took over the flask.

The initial citrate mutation was not degradative; rather, it involved a rearrangement of the bacterium's DNA. Nonetheless, soon after that initial non-degradative change, several additional mutations occurred in other genes in support of the citrate utilization pathway. All appear to have broken their respective genes. Thus, as the First Rule of Adaptive Evolution would lead one to expect, a helpful, non-degradative mutation that took tens of thousands of generations to appear was quickly fine-tuned by mutations that broke several genes.

Let me stress that the genes that were broken following the initial citrate mutation had been helpful to the bacterium up to that point. They were apparently doing useful tasks. However, once the citrate mutation came along, the environment changed and they became a net burden, so out they went. Thus even useful genes, when circumstances change, will easily be tossed overboard by random mutation and natural selection to maximize the net benefit of even a non-degradative change.

We can derive another important lesson from the story of the citrate mutation. At the beginning of the E. coli evolution project, the starting bacteria were genetically pretty uniform (except for marker genes and such), because they came from a pure strain. (That is indeed one source of real constancy that the reviewers may have had in mind.) The bacteria then diverged from each other mostly by degradative mutations, because those were the quickest beneficial changes to hand in the new environment in which they found themselves. Yet the aftermath of the initial citrate mutation shows the same behavior. That is, the mutant rapidly took over the flask, yielding a new pure strain, and the new strain further adapted to its new environment by beneficial degradative evolution. We should expect the same behavior after selection on any gene in any species. Any non-neutral change in any organism's genome represents a de facto new environment and, as the First Rule states, will tend strongly to be fine-tuned by the most rapidly occurring beneficial mutations. Of course, degradative mutations occur most rapidly.

(The only expected exception to this situation would be if no genes are available that can helpfully be degraded. An example may be the development of chloroquine resistance by the malaria parasite Plasmodium falciparum, which occurred mainly by multiple point mutations in the PfCRT protein.)

Mutating a Mutator

A second example of fine-tuning by degradation in the Lenski experiment can be seen in the rise and slight fall of mutator strains - that is, bacteria that have lost much of their ability to repair their DNA. It transpires that, from the beginning of the E. coli lab evolution project, Lenski separately grew a dozen different test flasks of bacteria, in order to be able to ask questions about the replicability of evolution. Six out of the twelve replicate strains eventually became mutators (because a gene involved in DNA repair broke), with mutation rates more than a hundred times those of non-mutators. There is some question about whether those loss-of-function mutations helped the bacteria directly or by making other beneficial mutations appear faster. (That's what the reviewers are referring to above as "second order selection on mutator alleles.")

Whatever the resolution of that second-order question, one mutator led to a first order effect. The Lenski lab noticed that, after a while, the mutation rate of one of the mutator strains had decreased by half. Upon investigation they determined that the mutation rate had been reduced by breaking a second gene that is involved in DNA repair. Thus a problem caused by breaking one gene was partially offset by breaking a different gene. That's what random mutation and natural selection do.

Let me emphasize that, like the genes broken to fine-tune the citrate mutation, the second gene involved in repair had been useful. It was performing a beneficial function. It was not superfluous. Nonetheless, since the environment changed with the appearance of the mutator mutation, the net benefit of getting rid of the gene apparently outweighed the benefit of keeping it. So out it went. The bacterium is now better adapted to its current environment, but certainly less flexible than it had been.

A laboratory is not nature, but we do lab experiments to understand how nature behaves. Lab evolution experiments show that whenever the environment changes, microorganisms will adjust with whatever helpful mutations come along first. Both simple math and relevant experiments indicate that by far those will be degradative mutations.