In the new scientific volume Biological Information: New Perspectives, Michael Behe has a paper titled “Getting There First: An Evolutionary Rate Advantage for Adaptive Loss-of-Function Mutations.” This paper elaborates on some of Behe’s arguments from his 2010 Quarterly Review of Biology paper, in which he reviewed molecular mechanisms involved in adaptations in microorganisms documented in the literature. He found there that such adaptations almost always involved loss or diminishment of function. In this new paper in the Biological Information: New Perspectives volume, Behe explores the implications of these observations for population genetics, and finds they pose a major challenge to Darwinian evolution.
Gain of Function vs. Loss of Function
Behe begins by observing that at the molecular level, far more mutations will cause loss-of function (LOF) than will cause a gain-of-function (GOF):
It is very often possible to eliminate a molecular function by a variety of mutations. GOF mutations, on the other hand, are generally much more specific, sometimes being produced in only one way.
The reason for this is simple. Behe explores various potential molecular mechanisms that can confer resistance to malaria in humans. One molecular mechanism involves creating a new binding site — which Behe calls a GOF mutation. This requires very specific mutations. But other mechanisms work because they prevent production of a functional protein. Behe observes that there are many mutations that prevent the gene from functioning. This example helps explain why LOF mutations are far more common than GOF mutations:
Research over the past fifty years has shown that many genetic elements consist of multiple nucleotides. Protein coding regions can be thousands of nucleotides in length; RNA genes can be hundreds of nucleotides; regulatory elements and processing signals can be several nucleotides to dozens of nucleotides long. A substantial portion of possible mutations in these elements will result in the diminution or loss of their function. Thus, as a class, LOF mutations for a particular genetic element will occur at a rate from several times to several-orders-of-magnitude times the basic nucleotide substitution rate.
That is not the case for GOF mutations. Consider two examples: First, a transcription factor binding site that is 10 nucleotides in length, and a second DNA sequence which has 9 of 10 nucleotides that are necessary to form a second regulatory site. Suppose that in response to a new selective pressure an adaptive effect could be secured either by mutating the first site so that it lost its function or by mutating the single mismatching residue of the second site so that it gained function. The LOF mutation would on average appear at 10-times the nucleotide substitution rate, simply because there are multiple ways to break the functioning element. The GOF mutation, however, would appear at even less than the basic rate of nucleotide substitution (because for a currently-nonfunctional, potential genetic element there it is possible that one of the “correct” nucleotides in the sequence will mutate before the “incorrect” one).
He concludes: “Because of the many ways in which a gene can be altered to lose function, the LOF mutation would have a rate several orders of magnitude greater than that of the GOF mutation for the duplicated gene.” What are the implications for neo-Darwinian evolution?
If different types of mutations (say, GOF mutations or LOF mutations) can confer some particular advantage on an organism, the LOF mutation is likely to become fixed before the GOF mutation since “LOF mutations always possess a rate advantage over GOF mutations if the respective selection coefficients are equal.” After reviewing various molecular adaptations observed in experiments reported in the literature, Behe concludes:
Both experimental laboratory work over the past few decades and recent genomic studies of adaptation in natural populations attest to the importance, even dominance, of LOF mutations in short term evolutionary episodes.
Behe’s work helps make sense of this situation:
The work presented in this paper helps show why this should be the case. Functional genetic elements such as genes and regulatory regions are built of multiple nucleotides, and a substantial fraction of mutations to these elements will cause them to lose their function. Thus the LOF mutation rate can be orders of magnitude greater than the nucleotide substitution rate. On the other hand, GOF mutations tend to be quite specific. So the rate for adaptive GOF mutations tends to be equal or very similar to the nucleotide mutation rate. As shown here, for some population size regions and for some values for the ratio of selection coefficients, the greater rate of mutation to the adaptive state for LOF versus GOF gives adaptive LOF mutations an intrinsic edge over adaptive GOF mutations.
This is an interesting result. It suggests that when Darwinian evolution is at work, it tends to diminish or destroy molecular functions rather than creating them.
Behe closes with a quote from two biologists who observe that “there clearly are complex structures that are gained during evolution … and we currently know little about how this process takes place.” The implication, of course, is that a process like Darwinian evolution, which tends to break or diminish functional molecular elements, is not a viable explanation for how these complex structures arose in the first place.