A Response to My Lehigh Colleagues, Part 2
Recently two of my Lehigh University Department of Biological Sciences colleagues published a seven-page critical review of Darwin Devolves in the journal Evolution. 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 second of a three-part reply. It continues directly from Part 1.
A Limited Accounting of Degradation
Greg Lang and Amber Rice cite a number of articles to show that loss-of-function mutations are just a small minority of those found in studies of organisms.
However, the truth is that loss of function mutations account for only a small fraction of natural genetic variation. In humans only ∼3.5% of exonic and splice site variants (57,137 out of 1,639,223) are putatively loss of function, and a survey of 42 yeast strains found that only 242 of the nearly 6000 genes contain putative loss of function variants. Compared to the vast majority of natural genetic variants, loss of function variants have a much lower allele frequency distribution.
Yet those three studies they cite all search only for mutations that are pretty much guaranteed to totally kill a gene or protein. For example, one paper says:
We adopted a definition for LoF variants expected to correlate with complete loss of function of the affected transcripts: stop codon-introducing (nonsense) or splice site-disrupting single-nucleotide variants (SNVs), insertion/deletion (indel) variants predicted to disrupt a transcript’s reading frame, or larger deletions …
That’s akin to counting only burnt-out shells of wrecked cars as examples of accidents that degrade an auto, while ignoring fender benders, flat tires, and so on. There are many more mutations that would not be picked up by the researchers’ methods that nonetheless would be expected to seriously degrade or even destroy the function of a protein. Since the rates leading to the kinds of mutations in the cited papers are likely to be at least ten-fold lower than general point mutations in the gene (which, again, the study passed over) there may be many more genes — perhaps five- to ten-fold more (about a quarter to a half of mutated genes) — that have been degraded or even functionally destroyed. Further research is needed to say for sure. (I know which way I’ll bet.) The remaining fraction of mutated genes in the population is likely to consist mostly of selectively neutral changes, neither helping nor hurting the organism, and not contributing anything in themselves to the fitness of the species.
Replenishing the Gene Store
The reviewers then point to work showing that, while some genes are indeed degraded over the life of a species, new genes arise by duplication or horizontal gene transfer to replenish the supply. Thus there is a continuous supply of raw material for new evolution. But there are at least three serious problems they overlook. First, assuming a generation time of one year, the rate of duplication of any particular gene is estimated to be about one per ten million years per organism (although there is much uncertainty) and, although it is frequent in prokaryotes, in eukaryotes the rate of horizontal gene transfer is much less. The rate of any particular gene suffering a degradative mutation is expected to be about a hundred times faster than duplication. Thus every gene that could help by being degraded would have an average of 100 chances to do so for every one chance another gene would have that could help by duplicating. Second, as its name indicates, gene duplication yields just an extra copy of a gene, with the same properties as the parent gene. Thus the extra copy would have to twiddle its thumbs for another expected ten million years or so — all the while trying to dodge inactivating mutations — before acquiring a second mutation that might differentiate it a little bit in a positive way from the first — exactly like an unduplicated gene.
In their review Lang and Rice write that perhaps the very fact that there were two copies of a particular gene would itself be helpful, because of the extra activity it would add to the cell. I agree that is possible. However, it is special pleading, because most duplicated genes would not be expected to behave that way. For every extra restriction put on the gene that is supposed to duplicate (such as partial duplication, duplication that joins it to another gene, and so on), a careful study of the topic must adjust the mutation rate downward, because fewer genes/events are expected to meet those extra restrictions.
The third and most serious problem Lang and Rice overlook is that they assume without argument that a duplicated gene would be able to integrate into an organism’s biology strictly by Darwinian (or at least unintelligent) processes. Yet not all genes or functions are the same, so critical distinctions must be made. As I have written in detail in Chapter 8 of Darwin Devolves and in response to other reviewers, some genes with simpler duties may have been able to do so but others not. For example, currently duplicated genes for proteins called opsins are involved in color vision of humans. Yet all those proteins do pretty much the same thing, so duplication of an opsin gene would not be expected to disrupt an organisms’ current biology too much. On the other hand, duplicated developmental genes, such as those for Hox proteins, would be expected to have a much more difficult time of it; they would be much more likely to cause birth defects than to help.
Since the question we are discussing is not about simple common descent, but rather about whether such fantastic development as we see in life could be produced with or without intelligent guidance, then a proponent of Darwinian evolution has to show that chance could fold in genes for even the most difficult pathways, if the question is not to be begged. No one has ever even tried to show that.
A Fourth Nasty Problem
One of the papers the reviewers reference in this section is Shen et al. (2018). (16) If you look up that paper you find that two of the four “Highlights” listed on the first page are that “Reconstruction of 45 metabolic traits infers complex budding yeast common ancestor” and “Reductive evolution of traits and genes is a major mode of evolutionary diversification.” It must take Darwinian tunnel vision to cite a paper that emphasizes how a complex ancestor gave rise to simpler yeast species by losing abilities over time as support for arguing that Darwinian evolution can build complexity.
The Shen et al. (2018) results point strongly to a fourth nasty problem with the notion of gene duplication as replacement for older, degraded genes. On average, degradation would be expected to remove variety in the kinds of genes, whereas even successful duplication and integration of a new gene just increases a pre-existing gene type. Over time that will diminish gene diversity.
The Shen et al. (2018) paper isn’t alone in noticing the phenomenon of genome reduction. As sequencing data becomes more plentiful and accurate, more papers are being published that show the importance of loss-of-function from more-complex states in evolution (see here and here). As one group writes of mammalian development, “Our results suggest that gene loss is an evolutionary mechanism for adaptation that may be more widespread than previously anticipated. Hence, investigating gene losses has great potential to reveal the genomic basis underlying macroevolutionary changes.” Another group comments, “These findings are consistent with the ‘less-is-more’ hypothesis, which argues that the loss of functional elements underlies critical aspects of human evolution.”
Lang and Rice ding me for disrespecting standing variation. Standing variation consists of the mutant genes that are already present in a population and can be called upon by natural selection to help a species adapt to changed environmental circumstances, obviating the need for a new mutation. For example, the most highly selected mutant gene associated with thick- versus thin-beaked Galápagos finches did not first arise when Peter and Rosemary Grant were studying the finches in the 1970s. It actually arose about a million years ago and has been present in the group ever since. Ancient standing variation also seems to be behind the very rapid evolution of cichlid fish in Lake Victoria. I discuss both of those examples in Darwin Devolves. The reviewers write, “this does not lessen the instrumental role of standing genetic variation in adaptation to new environments.”
I heartily agree, and never wrote otherwise. There are two major problems, however, for the reviewers’ position. The first is that evolution by natural selection of standing variation does not address the primordial question that my book focused on — how complex structures arise, particularly at the molecular level. The second major problem is that standing variation nicely illustrates how preexisting slapdash mutations actively inhibit more complex ones. That is, rapid beneficial degradative mutations can become standing variation.
For example, that mutant protein that is most strongly associated with thin- versus thick-beak genes in Darwin’s finches, ALX1, has only two changed amino acid residues out of 326 compared to the wild type protein. Both of those are predicted by computer analysis to be damaging to the protein’s function.Yet apparently no better solution to the task of changing finch beak shape has come along in a million years, even though an enormous number of mutations would be expected to occur in the bird population during that time.
Why not? Well, consider that an army platoon that takes an unoccupied hill has a much easier task than an opposing force that later wants to displace them. Similarly, a likely big factor in finch evolution is that the quick and dirty mutations have already been established. So in order to supplant them a new mutation would have to be better right away than the fixed ones. That is, its selection coefficient compared to mutation-free ALX1 would have to be greater than the damaging ones. There is no known correlation, however, between the strength of the selection coefficient and whether a mutation is constructive or degradative. Thus we have no reason to think standing variation would be supplanted.
Recognizing that hurdle could go a long way toward understanding the reason for stasis in evolution or, put another way, the reason for the equilibrium in punctuated equilibrium. And the generality of punctuated equilibrium reminds us that the same situation — quick and dirty mutations either stalling or completely preventing constructive ones — is expected to be very frequent on Darwinian principles.
Lang and Rice emphasize the importance of the ecological diversification and behavioral changes of Darwin’s finches, as opposed to just changes in body shape.
Darwin’s finches are an icon of evolution for good reason, having radiated into numerous ecological niches and developed diverse resource specializations (including at least one case — feeding on mature leaves — that is, to the best of our knowledge, unknown in other bird orders, much less families). By adopting a restrictive definition of fundamental biological change, Behe dismisses all corresponding behavioral, digestive, and physiological adaptations.
Species limits and relationships of the Galápagos finches remain uncertain. Yet the massive study by Lamichhaney et al. (2015), in which the complete genomes of 120 Galápagos finches were sequenced (over 100 billion nucleotides), including representatives of every separate species and population, found that the most highly selected finch gene was ALX1, which, again, is associated with thick versus thin beaks. If those alterations of the finches’ behavioral and feeding habits required genetic changes, they eluded discovery. Perhaps the ecological changes are mostly the result of nongenetic modifications.
The authors of the review point to the example of the evolution of stickleback fish in freshwater lakes that have reduced defensive armored plates compared to saltwater varieties:
The causative variants are likely cis-regulatory changes that decreased expression of [the gene] Eda in developing armor, but not in other tissues. Darwin Devolves accepts as evidence only de novo protein evolution, a restriction Behe uses to support his “First Rule” and claim that “Darwinian evolution is self limiting.”
They have misunderstood the First Rule. There’s nothing in “Break or blunt any functional gene” that confines degradative mutations just to protein coding regions. If it would benefit a species to reduce the activity of a gene by messing up its control elements instead of its coded protein sequence, that works too. The first mutation that comes along to helpfully suppress a gene’s activity is the one with the best chance of being established in a population.
The very next sentence the reviewers write is this: “Narrow by definition and unsupported by the data, Behe’s First Rule does not stand up to scrutiny.” On the contrary, the scrutiny itself doesn’t stand up.
Photo: Lehigh University campus, by IR393DEME [CC BY-SA 3.0], via Wikimedia Commons.