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Polar Bear Seminar: New Evidence That Michael Behe Is Right


A major question in the ongoing debate over Darwin Devolves is whether Michael Behe was correct to claim that the polar bear gene APOB experienced degradative mutations. At first blush it may seem surprising that this particular gene has become such a focus of the debate. After all, Behe in his book provides many examples of genes experiencing adaptive yet degradative mutations. Perhaps all the attention is because APOB is one of the examples he gives at the beginning of the book. 

Whatever the reason, there are some things that are clear about APOB that most everyone agrees on, and some things that are less clear. The latter, unsurprisingly, remain disputed. Given what is known, Behe’s thesis is reasonable. It is backed up by good evidence. What follows is a review of some reasons why that is the case. This post forms a capstone of sorts to the Polar Bear Seminar series, and in it we’ll present newly uncovered evidence that powerfully supports Behe’s view. 

Where Everyone Agrees

Most everyone agrees that APOB helps regulate cholesterol in the blood. Everyone also agrees that the gene has played an important role in the evolution of polar bears from their common ancestor with brown bears. Polar bears had to evolve ways to cope with a high fat diet high, probably including lowering cholesterol. As Behe explains in Darwin Devolves:

The polar bear’s most strongly selected mutations — and thus the most important for its survival — occurred in a gene dubbed APOB, which is involved in fat metabolism in mammals, including humans. That itself is not surprising, since the diet of polar bears contains a very large proportion of fat (much higher than in the diet of brown bears) from seal blubber, so we might expect metabolic changes were needed to accommodate it.

But what precisely did the changes in polar bear APOB do to it compared to that of other mammals? 

(Darwin Devolves, pp. 16-17)

The last sentence presents the key question up for debate: Were the mutations in APOB degradative — as Behe puts it “likely to degrade or destroy the function of the protein that the gene codes for” — or were they constructive, enhancing the gene’s function and perhaps creating new biochemical functions? One problem is that no one knows exactly what APOB does in polar bears. As Behe wryly points out, it’s very difficult to do experiments on “grumpy polar bears.”

But what about APOB in humans? This post offers new evidence that apoB proteins in humans have multiple functions, including both removing cholesterol from the blood AND loading cholesterol into the blood. Many critics of Behe’s book assume that the function of APOB is to remove cholesterol from the blood, and that polar bear cholesterol is lowered by constructive mutations in APOB which enhance that function. Richard Lenski, for one, wrote that mutations in APOB

may not have damaged the protein at all, but quite possibly improved one of its activities, namely the clearance of cholesterol from the blood of a species that subsists on an extremely high-fat diet.

That is possible, but it’s far from being necessarily the case. It turns out that in humans APOB generates multiple types of proteins with different functions. One of the functions of proteins produced by APOB is to load cholesterol into the blood. Damaging the function of such a protein could lead to lower cholesterol. 

In fact, multiple medical studies have found that unequivocally damaging mutations in APOB lead to truncated and poorly functioning versions of apoB proteins that are associated with lower cholesterol — perhaps related to the sort phenotype seen in polar bears! There’s no need — indeed, no justifiable reason — for Behe’s critics to assume that the only function of APOB is to remove cholesterol from the blood, and that the only way for APOB to reduce cholesterol is via constructive mutations that enhance that function. Degradative mutations in APOB are sufficient for the job. 

But first we need to clear up some inaccurate objections being promoted by Behe’s critics. 

A Response from Joshua Swamidass

As was discussed in in an earlier post in this series, Behe in Darwin Devolves cited a 2014 Cell paper by Liu et al. The authors performed a computer study predicting that various polar bear genes were damaged by mutations. APOB, in particular, received the highest possible score — 100 percent likelihood — that the computer program could output for predicting that a gene was damaged. One of the most noteworthy findings of the paper was that “a large proportion (ca. 50%) of mutations were predicted to be functionally damaging” in positively selected polar bear genes, including APOB. 

Some critics read Liu et al. much differently. They claimed that “the authors do not expect the polar bear APOB to be broken or damaged” and that “There is no evidence for Behe’s claim that APOB is degraded or diminished in polar bears.” 

The post on APOB linked above answered these critics in great detail. Biologist Joshua Swamidass has now written a response titled “Is Polar Bear ApoB Damaged?” There, he likewise asserts that the idea that Liu et al. believe APOB to be damaged “is totally and utterly false.” His lengthy discussion is appreciated, but he did not meet our request that the critics provide language from Liu et al. where the authors contradict their own findings and state that APOB was not damaged. He instead makes a strange argument. According to Swamidass, if the abstract specifically does not include the word “damaged” when describing APOB, then the authors must not believe the gene was damaged. He writes:

Notice, that they did not call ApoB “damaged.” Why not? There is no reason to think ApoB is damaged. Abstracts are where conclusions are stated, and that is a key conclusion of this paper.

Abstracts typically include the biggest “take home” conclusions of a scientific paper. However, they are general summaries and almost never encapsulate all of the findings and results of a particular study. So while Dr. Swamidass is correct that the abstract does not specifically use the word “damaged,” this point is irrelevant. The authors do use that word in the Results and Discussion section. There they state, as noted above, that “a large proportion (ca. 50%) of mutations were predicted to be functionally damaging.” That is intended to cover mutations in the gene APOB, as Figure 4 and the paper’s context make clear. Dr. Swamidass wrongly dismisses this language as a “quote mine” and is simply incorrect to claim “they did not call APOB ‘damaged’” or “There is no reason to think ApoB is damaged.” It is certainly not “totally and utterly false” to observe that the paper predicts that the gene was damaged.

What is more, the abstract also does not say that APOB was not damaged. So if Swamidass is right that in all cases, “Abstracts are where conclusions are stated,” then by his logic the paper must not conclude that APOB was not damaged because the abstract doesn’t say that either. Here’s the key language from the abstract: 

One of the genes showing the strongest evidence of selection, APOB, encodes the primary lipoprotein component of low-density lipoprotein (LDL); functional mutations in APOB may explain how polar bears are able to cope with life-long elevated LDL levels that are associated with high risk of heart disease in humans.

The question is whether those mutations degraded or improved the function of APOB, but the abstract doesn’t address it one way or the other. Importantly, as we’ve seen, the paper is perfectly capable of explicitly addressing whether genes were “damaged” — and when it does so it always predicts that damage occurred. However, the abstract does not state that APOB was “not damaged” or “damaged”; it simply doesn’t address this particular question. 

Well, then does paper state elsewhere that APOB was NOT damaged? No, it doesn’t. 

Swamidass Tries Again

Dr. Swamidass once more quotes language from the paper — language that we already discussed extensively in our prior APOB post. He focuses on a sentence that states: “We suggest that the shift to a diet consisting predominantly of fatty acids in polar bears induced adaptive changes in APOB, which enabled the species to cope with high fatty acid intake by contributing to the effective clearance of cholesterol from the blood.” Unfortunately, as was already explained, that sentence does not conclude that APOB experienced constructive mutations. The sentence may well be fully correct, but it only says that mutations in APOB led to “effective clearance” of cholesterol from the blood. The language about “effective clearance” implies that the effective or ultimate result of the mutations in the gene is less cholesterol in the blood. But the sentence, like the rest of the paper, is silent about exactly how cholesterol is being cleared from the blood. Here’s what we wrote earlier, just to review:

When [Nathan] Lents and [Arthur] Hunt claim that the mutations in APOB “likely enhance the function of apoB,” that is their own speculation. They focus on a statement in the paper that the adaptive changes in APOB “enabled the species to cope with high fatty acid intake by contributing to the effective clearance of cholesterol from the blood.” Perhaps that is true, but the paper presents no evidence that the removal of cholesterol was accomplished by constructive mutations. Indeed, as Behe pointed out, cholesterol may be removed by decreasing the activity of APOB.

We’ll return momentarily to Behe’s point that cholesterol may be removed by damaging APOB. For now, the point is that Swamidass is putting words in the authors’ mouths when he claims they concluded that APOB was not damaged.

News from New Scientist

Dr. Swamidass then cites a news article in New Scientist. The article does not necessarily represent the views of Liu et al., but it says much the same as the paper does. Swamidass quotes one of the paper’s authors as stating: “The APOB variant in polar bears must be to do with the transport and storage of cholesterol … Perhaps it makes the process more efficient.” Like Liu et al., that statement does not claim that functional changes in APOB were the result of mutations that were degradative or constructive. Instead it uses very cautious language to speculate that “Perhaps it makes the process more efficient.” But what kinds of mutations made the process more efficient — degradative or constructive? It doesn’t say. 

At this point the critic might say, “Calling a process ‘more efficient’ implies that they believe the function is being biochemically improved or enhanced.” That’s reading too much into their words. As Michael Behe reminds us in Darwin Devolves, making a process “more efficient” can be achieved by degradative means:

[A] beneficial mutation (by itself that deletion mutation increased the cell’s growth rate by 1 to 2 percent) turned out to be a degradative mutation, one in which the loss of a preexisting genetic capacity improved the bacteria’s survival. 

How can that be? How can the loss of an ability be helpful? Well, what might be the quickest, easiest way to improve the gas mileage of your car, other considerations be damned? One way is to get rid of unneeded weight-toss out the spare tire, the hood, or even the doors or windshield. Of course, those things might be helpful in some future circumstances, but if the most important factor for your survival right now is the gas mileage, it would be beneficial to pitch whatever could be spared. If you were on a sinking ship and had to keep it afloat until it reached shore, throwing overboard any heavy unneeded equipment, no matter how sophisticated-computers, radios, cargo-is the winning survival strategy. 

(Darwin Devolves, p. 176)

The major point of Darwin Devolves is that changes that do benefit an organism — even making a process “more efficient” — can depend on degradative changes at the molecular level. Merely finding a process to be “more efficient” is no necessary contradiction of Behe’s thesis. 

Swamidass then affirmatively quotes Richard Lenski saying that APOB mutations “quite possibly improved one of its activities, namely the clearance of cholesterol from the blood.” But the very next sentence of the news article — which neither Swamidass nor his source Richard Lenski quotes — admits that we don’t even know the function of APOB in polar bears: 

It’s not clear exactly what the gene variants [of APOB] do for the polar bears, but Nielsen hopes to find out by putting them into mice and seeing what happens.

This is consistent with language from Liu et al. that states, “It remains an enigma how polar bears are able to deal with such lifelong elevated levels of cholesterol.” If we don’t know what a gene’s function is, how can we claim to know that its function was improved? Obviously, we can’t. More to the point, if a source admits that we don’t even know what exactly APOB does or how polar bears cope with high cholesterol, how can we cite that source to claim that mutations in APOB “improved one of its activities” (as Lenski wrote), or “enhance that function” (as Lents and Hunt wrote) in order to lower polar bear cholesterol? Again, we can’t.

Confusion About PolyPhen-2

Absent knowing what APOB does in polar bears and how it helps them deal with a fatty diet, the best evidence we presently have about the impact of mutations in the gene is from Liu et al.’s results with the PolyPhen-2 program, which compared the sequence of APOB in polar bears to the sequence of APOB in other organisms, and then predicted that it experienced damaging mutations. Yet according to Swamidass, the claim that Liu et al. believe APOB to be damaged “is totally and utterly false.” Well, assuming that no one in this discussion is a mind reader, when a paper reports that mutations “were predicted to be functionally damaging,” and then never contradicts that finding, it seems clear what the authors are saying. Liu et al. never express any criticisms of their PolyPhen-2 computer analysis which clearly predicted damage to the genes. Swamidass, on the other hand, does strongly criticize Liu et al.’s computer analysis. However, his arguments on this point are unconvincing because they fundamentally misstate how the program works. 

As noted, one mutation in polar bear APOB scored the program’s highest possible score — 100 percent likelihood — for predicting that a mutation was damaging. Swamidass claims that when PolyPhen-2 finds a mutation was “damaged,” that “means phenotypically damaging, not biochemically damaged” because “Polyphen does not attempt to predict ‘biochemical damage’.” That’s wrong. We have already addressed these claims, extensively quoting the literature about PolyPhen-2 which documents that the program is designed to detect amino acid changes that could biochemically damage a protein’s function. The technical literature explains that the program:

  • predicts when a mutation is “likely to destroy the hydrophobic core of a protein, electrostatic interactions, interactions with ligands or other important features of a protein”
  • predicts when a mutation is “affecting protein stability or function”
  • “predicts the possible impact of amino acid substitutions on the stability and function of human proteins using structural and comparative evolutionary considerations”
  • “predicts the effect of an nsSNP [non-synonymous single nucleotide polymorphism] on protein structure and function”

All these analyses bear precisely on whether a protein experienced biochemical damage. But we’ve already refuted Swamidass’s mistaken interpretation of PolyPhen-2. Please read it here. 

Swamidass is correct about one point: PolyPhen-2 also predicts deleterious phenotypic effects by comparing mutations in a given gene to mutations in human homologues known to cause disease. Evidence strongly supports Behe’s thesis that polar bear APOB was probably damaged. As we’re going to see, medical studies have found that mutations known to degrade apoB proteins in humans can cause diseases that dramatically lower cholesterol in humans. That may be related to what’s happening in polar bears. 

Damage to APOB Can Lower Cholesterol

At least two biologists who are ID critics, and participants in Joshua Swamidass’s online discussion forum, think that APOB either does have, or might have, a function where cholesterol would be removed from the blood by degrading that function. One commenter, “T_aquaticus,” writes:

It would appear that ApoB has two main functions: getting cholesterol into the blood stream and getting it out of the blood stream. Therefore, high or low levels of lipids in the blood stream can be affected by lipid production and lipid clearance. … Interestingly, ApoB is found in two isoforms through post-transcriptional modification: apoB-48 and apoB-100. It would appear that the smaller isoform is responsible for transferring dietary lipids into the blood stream. This may hold a key for understanding possible active sites for lipid production and lipid clearance, and the possible effects of certain mutations in those domains.

If one of the functions of APOB is getting cholesterol into the blood stream, then degrading that function would presumably decrease cholesterol. Even Nathan Lents, an ardent Behe critic who believes that mutations in APOB constructively enhanced removal of cholesterol from the blood, nonetheless concedes that “it’s possible that APOB is somehow functionally diminished in polar bears, compared to brown bears,” because such mutations in APOB could “cripple APOB-mediated loading of cholesterol into the blood.” He admits that this option would “support” Behe’s thesis. 

The Possible May Be Actual

What Lents admits is possible may in fact be actual. There is good evidence that apoB proteins are involved in bringing cholesterol into the blood stream, which means that degradative mutations could reduce cholesterol in the blood. As Liu et al. (2014) state, “ApoB enables the transport of fat molecules in blood plasma.” In discussing the gene, they cite a 2004 paper in Clinical Chemistry, “Lipid Disorders and Mutations in the APOB Gene,” noting that “[a] unique mRNA editing process enables the APOB gene to make the two structurally related but discrete isoforms that have different functions”:

Two forms of apoB are produced from the APOB gene by a unique posttranscriptional editing process: apoB-48, which is required for chylomicron production in the small intestine, and apoB-100, required for VLDL production in the liver. In addition to being the essential structural component of VLDL, apoB-100 is the ligand for LDL-receptor-mediated endocytosis of LDL particles. … ApoB-48 is required for chylomicron production, and apoB-100 is an essential structural component of VLDL and its metabolic products, intermediate-density lipoprotein (IDL) and LDL.

Thus, APOB is involved in producing lipoproteins which transport cholesterol and other lipoprotein particles through the blood. In other words, it helps load cholesterol into the blood, which is why apoB levels correlate with LDL cholesterol levels. Damage to those proteins could result in less cholesterol in the blood. In fact, this is exactly what the paper says: “APOB gene defects can lead to both hypo- and hypercholesterolemia” since “Mutations in the APOB gene causing the production of a truncated molecule can cause FHBL [familial hypobetalipoproteinemia] and hypocholesterolemia.” Both diseases entail abnormally low cholesterol levels. 

In Darwin Devolves, Behe points out that the reason genes frequently adapt via degradative mutations is that degradative mutations are so common, especially compared to constructive mutations. According to the Clinical Chemistry paper, “Approximately 50 different mutations in APOB have been described that interfere with the translation of full-length apoB,” thereby producing truncated forms of the protein. These mutations correlate with “low concentrations of LDL-cholesterol.” It’s clear from the paper that mutations that effectively reduce cholesterol are damaging:

FHBL is a rare autosomal codominant disorder of lipoprotein metabolism characterized by low plasma concentrations of total cholesterol, LDL-cholesterol, and apoB. Many nonsense, frameshift, and splicing mutations in the APOB gene leading to formation of prematurely truncated apoB forms have been reported in individuals with FHBL.

The paper specifically states that “defects” in APOB can cause lower cholesterol levels:

Defects in the APOB gene can cause either hypocholesterolemia or hypercholesterolemia, depending on the mutation.

Many other papers have affirmed these findings:

  • A paper in The Journal of Biological Chemistry notes: “Many nonsense and frameshift mutations in APOB leading to formation of prematurely truncated apoB forms have been reported in FHBL subjects,” and observes that homozygotes with these mutations have “have extremely low plasma LDL cholesterol.” This paper found a nontruncating mutation that led to the same phenotype, in which the mutation is also degradative as it “appears to impair the secretion of apoB and apoB-containing lipoproteins.”
  • A paper in the Journal of Lipid Research notes that even “Heterozygotes for hypobetalipoproteinemia typically have plasma concentrations of apoB and low density lipoprotein (LDL)-cholesterol that are one-fourth to one-half normal and are usually clinically asymptomatic” but in homozygotes, “apoB and LDL-cholesterol levels are extremely low or undetectable.” The paper observes that it has been “demonstrated that hypobetalipoproteinemia was indeed associated with defects in the apoB gene,” including “truncated” versions of the protein or insufficient amounts the protein being produced.
  • A chapter in the volume The Online Metabolic and Molecular Bases of Inherited Disease, “Disorders of the Biogenesis and Secretion of Lipoproteins Containing the B Apolipoproteins,” notes that there are two main types of apoB proteins — apoB-48 and apoB-100. When describing hypobetalipoproteinemia, the chapter observes that “defects underlying this disorder involve the gene for apo B in most cases,” frequently due to “the secretion of truncated forms of the protein.”
  • Another paper in the Journal of Lipid Research, “Familial Hypobetalipoproteinemia: a Review,” notes that the disease is characterized by “<5th percentile plasma levels of total, or LDL-cholesterol, or total apolipopotein B,” and is sometimes “caused by truncation-specifying mutations of the APOB gene.” 
  • An abstract for a medical conference published in Atherosclerosis Supplements observes that diseases characterized “by decreased plasma concentrations of apoB-containing lipoproteins” are caused by degradative mutations in APOB: “Nonsense and frame-shift mutations in the APOB gene encoding prematurely truncated apoB have been found in FHBL.”
  • Similarly, a paper in the Journal of Medical Genetics observes that FHBL is “characterised by decreased low density lipoprotein (LDL) cholesterol and apolipoprotein B (APOB) plasma levels.” The paper finds many patients with “low cholesterol levels” had “an APOB gene mutation, resulting mainly in truncated forms of APOB.” The study found that some of these mutations caused frameshifts. 
  • A paper in Nature Reviews Genetics notes that “different homozygous loss-of-function (LOF) mutations in the APOB or PCSK9 genes cause a monogenic syndrome called homozygous hypobetalipoproteinaemia (HHbL), in which almost no LDL cholesterol is present.”

Now it must be noted that polar bears seem to have high cholesterol compared to many other mammals, and in their normal state probably don’t have precise polar bear analogues of human diseases like hypocholesterolemia or FHBL. (Indeed, the literature cited above shows that damaged APOB can cause higher cholesterol too!) But given that damaged APOB is known to reduce cholesterol, and given that this would benefit polar bears in coping with a high-fat diet, it remains a serious possibility that damaged APOB in polar bears is somehow helping to reduce their cholesterol even more than it would be otherwise given their diet. Of course other genes are probably also involved in helping polar bears manage their fatty diet. It’s also possible that damaged APOB may play other roles to help polar bears cope with their fatty diet. But the point is this: 

The literature shows mutations that are unequivocally degradative — “loss-of-function” mutations and “nonsense, frameshift, and splicing mutations in the APOB gene leading to formation of prematurely truncated apoB forms” — can reduce cholesterol. What Nathan Lents concedes is “possible” is not just possible but real. It ought to lend “support” to Behe’s thesis that degradative mutations in APOB may help polar bears cope with their high-fat diet. Many studies show that degradative mutations in APOB cause decreased cholesterol. Behe’s critics are wrong.

The Mouse Study Explained

In a post for Evolution News, Behe also commented on the aforementioned New Scientist news report. He reported data from a mouse study that is consistent with studies discussed here already showing that degradative mutations in APOB can lower cholesterol levels:

[W]ithout benefit of supporting data, Lenski waxes strongly optimistic. He quotes an author of the study and then stresses his own view in bold face:

“In a news piece about this research, one of the paper’s authors, Rasmus Nielsen, said: ‘The APOB variant in polar bears must be to do with the transport and storage of cholesterol … Perhaps it makes the process more efficient.’ In other words, these mutations may not have damaged the protein at all, but quite possibly improved one of its activities, namely the clearance of cholesterol from the blood of a species that subsists on an extremely high-fat diet.”

Lenski is almost certainly wrong about the bolded text. Here’s why. In 1995 researchers knocked out (destroyed) one of the two copies of the APOB gene in a mouse model — the same gene as has been selected in polar bears. Although APOB is itself involved in the larger process of the transport of cholesterol, mice missing one copy of the APOB gene actually had lower plasma cholesterol levels than mice with two copies. (Mice missing both copies died before birth.) What’s more, the researchers noted that “When fed a diet rich in fat and cholesterol, heterozygous mice were protected from diet-induced hypercholesterolemia.”

The researchers admitted they did not know how it all came together — how that effect on the complex cholesterol-transport system resulted from breaking the gene. Nonetheless, there is no ambiguity about the mouse results. Simply by lowering the amount/activity of APOB, mice were protected from the effects of a high-fat diet. Deletion of one copy of the gene may have made the process of cholesterol removal more efficient, as Rasmus Nielsen speculated above about the polar bear, but it did so by decreasing the activity of mouse APOB.

Just to be extra clear about the relevance of the mouse results to the interpretation of the polar bear genome, let me state my reasoning explicitly. Given the experimental results with mice, it is most parsimonious to think APOB is broken or blunted in polar bears. For mice, having only half as much APOB activity protects them from a high fat diet. For polar bears, having mutated APOB genes protects them from a high fat diet. If those polar bear mutations decreased the activity of APOB by half or more, then we might expect a similar protective effect as was seen in the mouse. Given that computer analysis also estimated the APOB mutations in the polar bear as likely to be damaging, it is most reasonable to think the activity of the protein has been blunted by the mutations.

Thus there is no good reason to speculate about possible new activities of the coded protein in the polar bear. Rather, the simplest hypothesis is that the mutations in the polar bear lineage that were judged by computer analysis as likely to be damaging did indeed blunt the activity of the APOB protein in that species — that is, made it less effective. That molecular loss gave rise to a happy, higher-level phenotypic result — an increased tolerance of polar bears for their high fat diet.

The pieces are now coming together: Much like in humans, one function of APOB in mice probably involves loading cholesterol into the blood. Deleting a copy of the gene impairs this function. The mice missing one copy of APOB thus had lower plasma cholesterol and protection against a high fat diet.

Just because damaged APOB can reduce cholesterol in humans and mice doesn’t mean the same exact mechanism is at work in polar bears. But this data does establish the plausibility of damaged APOB reducing cholesterol. So why do polar bears have such high cholesterol? Well, they do have a very high-fat diet, and as with the mice, it’s also possible that damaged APOB is causing them to have lower cholesterol than they ought to, even given their fatty diet. As the mouse study stated, “When fed a diet rich in fat and cholesterol, heterozygous mice were protected from diet-induced hypercholesterolemia.” Damaged APOB may lead to lower cholesterol than you’d expect, even given a high-fat diet, clearly an adaptive benefit. It’s also possible that damaged polar bear APOB has other functions that change the effects of high cholesterol: In both polar bears and mice, having less functional APOB might in some unknown way metabolically protect against the effects of a high-fat diet. 

Addressing the Enigmas

Liu et al. stated that it’s an “enigma” how polar bears deal with high cholesterol, but they predicted that APOB was damaged and gave an advantage to polar bears in dealing with their high fat diet. We can now address a related enigma: how can a biochemically damaged protein lead to a phenotypic advantage? Swamidass seems not to appreciate this possibility, which led him to make more inaccurate claims about PolyPhen-2:

In the case of Polar Bear ApoB, we know the mutations were not phenotypically damaging (they were selected!), which is why most scientists (including the original authors) have correctly interpreted them to be “change/improvement of function” mutations, not “biochemically damaging.”

Here, Swamidass advances a mistaken dichotomy where polar bear mutations can’t be selected if PolyPhen-2 predicts they were damaged. There’s a major problem with his argument: PolyPhen-2 predicted with 100 percent certainty that APOB was damaged, yet clearly it was selected. If PolyPhen-2 only identifies phenotypic damage, how is it possible that it was selected? The answer is that PolyPhen-2 does not only identify phenotypic damage. It also identifies biochemical damage. In this case, APOB’s biochemical damage as detected by PolyPhen-2 may have led to a selectable phenotypic advantage: lower cholesterol. This model now has empirical credibility because we know that damaged APOB in humans can lead to lower cholesterol. This is just the sort of result Behe’s model would predict. 

Mysteries Remain 


Many of Behe’s critics believe, as Richard Lenski argued, that mutations in APOB “quite possibly improved one of its activities, namely the clearance of cholesterol from the blood.” But we don’t know exactly what APOB does in polar bears, and good evidence shows that its function was damaged. A better model is that mutations damaged APOB’s function to load cholesterol into the blood, helping polar bears to effectively lower cholesterol. This option is consistent with (a) the findings of the PolyPhen-2 analysis, (b) medical studies which show that damaging APOB can reduce cholesterol, and (c) the fact that polar bears must somehow cope with a high fat diet. 

Is this proposal correct? It’s plausible given what we know, but many questions remain. What exactly does APOB do in polar bears? If it helps reduce cholesterol, why do polar bears still have high cholesterol, and how do they cope with that? Polar bears don’t necessarily have something like human hypocholesterolemia, although everyone believes they have evolved mechanisms to deal with a diet of fatty seal blubber. Is damaged APOB making polar bear cholesterol levels lower than they would be even given their high-fat diet, much like in the mouse study? Is it also helping them cope with high cholesterol in some other way? What other genes are involved with helping polar bears avoid atherosclerosis? Were these mechanisms designed or did they evolve? Ultimately, any model of APOB’s evolution — including (a) those that predict it accumulated constructive mutations to better remove cholesterol from the blood and (b) those that predict that it underwent degradative mutations to reduce cholesterol and/or cope with high cholesterol — must grapple with this complicated situation. Much work remains to be done. 

It’s probably because of the many unknowns that the authors of Liu et al. (2014) did not specifically conclude that APOB experienced constructive mutations to improve some function. They observed that whatever polar bear APOB is doing, the result is “effective clearance” of cholesterol from the blood. But as the literature shows, and as even some of Behe’s critics admit, one function of APOB is loading cholesterol into the blood, and that function can be degraded by mutations in the gene, effectively lowering cholesterol. Hence Liu et al. did not claim that we know that the function of APOB was enhanced. 


Absent direct biochemical studies of the exact function of APOB in polar bears or direct empirical studies of the effects of mutations in polar bear APOB, the best we can do is what the paper Liu et al. did: Compare versions of APOB in polar bears to known homologues in other species, and predict what the likely impact would be. This is exactly what the PolyPhen-2 program did. The paper thus reported that mutations in APOB and over a dozen other polar bears genes were “predicted to be functionally damaging.” In fact, as already mentioned, one of those mutations (which converted an aspartic acid to asparagine near the middle of the protein at position 2623) was predicted with 100 percent certainty to be damaging. Was this because polar bear APOB accumulated a mutation known in humans to damage the proteins, causing diseases that involve very low cholesterol? Unfortunately the Liu et al. paper does not say. But to obtain a result of 100 percent certainty that the mutation damaged the protein makes this a serious possibility worth investigating. 

At the very least, we can now definitively reject the idea of certain Behe critics that the only way mutations in APOB could reduce cholesterol is by enhancing a function that removes cholesterol from the blood. Behe’s hypothesis that APOB experienced damaged mutations is affirmed not only by Liu et al. (2014), but is also supported by a body of peer-reviewed papers in medical journals that have found that unequivocally damaging mutations in APOB can lead to lower cholesterol. Much more work remains to be done to understand exactly how polar bears deal with their high fat diet, but in short, Behe’s proposed devolutionary model is viable. It is plausible in light of what we know, and supported by evidence.

Photo credit: Nicholas Larimer via Unsplash.