Stern Cardinale: Response to Price, Carter, and Sanford on Genetic Entropy

I have been critiquing Dr. John Sanford’s “genetic entropy” hypothesis for some time, leveling a number of specific, and often technical criticisms against the idea.

See here for a list of links to those critiques: Reddit - Dive into anything

I’ve also debated this topic with Sal Cordova on two occasions, and further explained my critiques in video, all of which can be found here:

Paul Price and Drs. Rob Carter and John Sanford of CMI have seen fit to respond to a number of specific critiques of the genetic entropy hypothesis, including several that I have made, in a recent piece “Responding to supposed refutations of genetic entropy from the ‘experts’, which can be found here:

In this piece, they describe and respond to six specific criticisms of genetic entropy. I am specifically referenced in three of them, so I will respond to those three items below.

Comments on Style and Tone

Before getting into the specifics, I want to comment on the style and tone of this piece. Dr. Sanford, I believe, would like for genetic entropy to be taken seriously as a scientific idea. For that to happen, proponents of that idea need to meaningfully engage with critics in good faith, take the arguments seriously, and respond specifically to them.

What we see throughout this piece instead is what I read as basically that the authors are affronted that anyone would have the nerve to dispute such obviously correct ideas, along with a number of slights at critics, everything from the scare quotes in the title (‘experts’), to Dr. Sanford’s repeated accusations that the critics have not actually thought through what they are saying.

And speaking personally, I want to note that it’s pretty rich for a non-scientist (Price), a marine biologist (Carter), and a plant geneticist (Sanford) to say:

The ‘experts’ mentioned below are very well-credentialed scientists. Yet, they are not experts on the specific topic at hand. They have not spent the last twenty years studying the problem of mutation accumulation.

Mutation accumulation and fitness was one of the subjects of my Ph.D. thesis; part of my work involved a novel approach to inducing error catastrophe in populations of bacteriophages. So I am an expert in this very specific topic, thanks for asking. (That’s to say nothing of the absurdity saying Dr. Joseph Felsenstein is not an expert in population genetics, which is ultimately what “genetic entropy” comes down to.)

So let’s get into the specific responses.

1. Mutations & Equilibrium

Price, Carter, and Sanford (PCS going forward) first respond to the argument that, if we accept Sanford’s premise that all mutations have a constant fitness value (which is wrong but we’re granting it for the sake of argument), as deleterious mutations accumulate, the frequency of future deleterious mutations declines and the frequency of future beneficial mutations increases.

An analogy illustrating this dynamic might involve 10 lights that could be either red or green that change colors randomly one at a time with equal probability. If all the lights start out as red, the frequency of a change from green to red is zero. But after two lights have turned green, that frequency is now 0.2, and the frequency of red-to-green changes has declined to 0.8. Once five lights are green, the system is at equilibrium and there will be no directional trend towards either color on net. So too must be the case with deleterious and beneficial mutations, if we accept Sanford’s premises.

PCS respond to this by…responding to a different argument:

Mutation-drift equilibrium is a standard part of many evolutionary models. Given many millions of years, one would expect genomes to become saturated with mutations, reaching an equilibrium where the number of new mutations is balanced by the number of mutations lost through random genetic drift and purifying selection. (emphasis mine)

I’m not talking about drift and selection here. I’m just talking about the set of possible future mutations and how that set changes as mutations occur. They seem to acknowledge that such and equilibrium would exist mathematically (which is good, because…it has to), but then make a completely unrelated point by arguing that extinction would occur before that point.

That’s immaterial to the question. If the equilibrium exists (it does!), then Sanford’s model is wrong, because that model requires the accumulation of deleterious mutations at an approximately constant rate. So PCS can do all the hand-waving they want here, but the nature of the equilibrium is immaterial the the criticism I have leveled. If we acknowledge the equilibrium exists, then Sanford’s model is flawed.

Sanford, in his specific comments on this, does not seem to understand the critique:

Obviously, rapidly accumulating deleterious mutations do not lead to more and more beneficial mutations.

It is not the case that deleterious mutations cause more beneficial mutations. The problem (for Sanford) is that if you take his assumption of fixed fitness values for each specific mutation at face value, then as deleterious mutations occur, the universe of possible future mutations necessarily shifts in favor of a higher frequency of beneficial mutations, and this necessarily reaches an equilibrium point at which the rates of beneficial and deleterious mutations are equal. At that point, deleterious mutations no longer accumulate.

So, on this first point, PCS don’t really address the critique, but obliquely acknowledge that it is valid (i.e. that such an equilibrium exists) before moving to the nature of that equilibrium, which is immaterial to the critique.

2. Natural selection equilibrium

The next critique they address is that, as deleterious mutations accumulate, fitness will be affected, which means those mutations can be selected against. Which means the population will not experience infinite and terminal deleterious mutation accumulation without selection operating.

PCS say that “This is essentially the ‘mutation count’ hypothesis.”

No it is not. It’s not a question of the number of mutations. It’s a question of the cumulative fitness effects of those mutations. The only way for selection to not operate on a population in which deleterious mutations are occurring would be for the relative fitness of every individual to be the same (i.e. for population-wide relative fitness to be 1). That is simply unrealistic; mutations and their fitness effects are probabilistic; it is not reasonable to posit that the accumulation of unique sets of mutations within individuals in a population will have exactly the same effects on absolute fitness in every individual. But that is what is required for selection to be unable to operate. Which means that is what is required for genetic entropy to be correct.

Sanford goes on to invoke interference between mutations making selection for or against any one mutations all but impossible, but he ignores that individual mutations are not selected; genomes, i.e. combinations of mutations, are selected for or against. The only requirement for selection to operate is that some genomes are more fit than others, meaning there are differences in relative fitness. If that is the case, then by definition selection is operating. For this to fail to occur, Sanford’s model requires completely unrealistic uniformity of mutation fitness effects.

On points 3-5

I was not specifically referenced in responses 3, 4, or 5, so I’m not going to respond to each at length. I do want to note, though, that part 5 references junk DNA, and Dr. Sanford seems to be of the opinion that there is little if any junk DNA in the human genome, which is simply not a serious position to take. Even ENCODE’s follow-up work to their well-publicized 2012 paper has shown that the human genome is largely non-functional (see, for example, their 2014 follow-up). But that’s neither here nor there, so onward to part 6.

6. Allegations regarding the research into the H1N1 virus by Sanford and Carter

The problems with C&S’s 2012 H1N1 paper (A new look at an old virus: patterns of mutation accumulation in the human H1N1 influenza virus since 1918 - PubMed) are myriad. They claimed fitness declined, but didn’t measure fitness directly. The two proxies they used, virulence and codon bias, are completely inappropriate as measures of viral fitness. They ignored pandemic dynamics and the different selection pressures imposed by intrahost and interhost competition. They asserted with no evidence that the mutations they documented were responsible for the changes in virulence, and further asserted with no evidence that these mutations “attenuated” the virus in some way (i.e. disrupted its replication mechanisms in such a way that hampered its ability to reproduce). Oh, and for good measure, the virus they claim went extinct continues to circulate.

But putting all of that aside, here we’re talking about a different problem: That for the purposes of documenting mutation accumulation in the 1918-2009 H1N1 lineage, C&S used as a reference strain a 2009pdm H1N1 genome. “pdm” here stands for “pandemic”, as in the 2009 H1N1 pandemic.

The problem is that the 2009 pandemic H1N1 lineage was unrelated to the 1918 H1N1 lineage. They do not share common ancestry as H1N1 in humans. The 2009 strain was the result of reassortment between several swine and avian influenza strains and human H3N2. So the differences between the 2009 strain and the 1918 lineage are due to recombination, not point mutations. So you can’t just count all the differences and say “relative mutation count” – a huge chunk of those differences were from a different process, and in any event, you can’t just treat two different lineages as though they are a single lineage.

PCS show part of an alignment to defend their conduct, but actually illustrate the problem:

Here is a screen shot of one of the worst sections in the alignment. This is part of the hemagglutinin (HA) gene. Strains from 1918 through 1936 are shown. The human and swine H1N1 reference genomes are also there. We see one three-letter deletion (keeping the downstream codons in-frame) and many single-nucleotide changes. There is no evidence for large-scale rearrangements, either within or among the eight segments of the H1N1 genome.

Yes, because 1918 to 1936 reflects a single lineage, and nobody has said otherwise. The problem is the 2009 pandemic clade, which is distinct from the 1918 lineage. I’m not sure why PCS thought the above quoted paragraph would address that problem.

When you do this correctly, you actually have to detect and remove recombinant and reassorted sections from your genome alignments, so the recombination doesn’t mess with your mutation calculations. There are lots of ways to do that, but despite PCS saying everyone involved was well aware that reassortment occurred, they didn’t do anything about it! Just treated those differences like any other mutations, which…no! You can’t just do that.

So the mutation counts, a foundation of that paper, are wrong.

Comments on Sanford and Carter’s Concluding Remarks

Let’s finish by looking at their concluding remarks, which I will quote in full:

In reviewing the many attempted rebuttals from these various evolutionist experts, a few general observations can be noted. First, it often takes a lot of ‘doing’ to get any straight or direct answers as to why they reject Genetic Entropy. Second, we rarely see any evidence that these detractors have actually read Dr. Sanford’s book (as many of their objections are dealt with in the book itself) or any of the papers that have come via Mendel’s Accountant. Third, it is clear they oppose any challenge to Darwinism in principle. They take it as their ‘Primary Axiom’ and consider it unassailable. Finally, it is impossible to miss the fact that, even among the experts, there is no consensus as to why Genetic Entropy is supposed to be wrong. If you ask ten experts why they reject it, you’ll likely get ten different answers, often that contradict one another. This really is a huge ‘Achilles’ heel’ for evolutionary theory! Real science disproves Darwinian speculations. Attempts to show God’s design is not needed to explain the diversity of life on our planet all fall short.

The two words for this paragraph are “gratuitous” and “unprofessional”. Accusations that critics are deliberately unclear, accusations that we haven’t read Dr. Sanford’s book, accusations that the objections are just knee-jerk defenses of “Darwinism” (Aside: “Darwinism”? What year is it?). And wow different people raise different objections? Yes. That’s because there is so much wrong with genetic entropy, different people will point out different problems, any one of which fatally undermines the idea.


The takeaway here is that this does not read like a serious attempt to engage with the specific, technical critiques of the genetic entropy hypothesis. If PCS were interested in this idea gaining widespread acceptance within the scientific community, the way to do that would be to engage with critics, and make a concerted effort to address their concerns. You can convince me I’m wrong by showing that my math is wrong, not by saying I haven’t thought this through and probably haven’t even read the book I’m critiquing.

But I suspect PCS are not interested in such conversations. I reached out to CMI to invite Mr. Price, Dr. Carter, and/or Dr. Sanford for a conversation about this response. I think face-to-face conversations are the most productive for things like this because we can clarify points of misunderstanding in the moment. None of the authors were interested in such a conversation, despite Mr. Price publicly debating this very topic on YouTube recently. I don’t know what to make of that accept that while PCS seem happy to promote their ideas to nonscientific audiences there seems to be a reluctance to engage with actual scientists in the relevant fields (or perhaps I should have invited the authors for a debate, instead). Of course, nobody is under any obligation to engage with anyone in any specific way, but if PCS ultimately want this idea taken seriously by scientists, they are making odd choices in terms of how they are going about it.


Also speaking personally, they call me a generic “molecular biologist” before they try, and fail, to rebut the points I made (basically the same as yours) about their profoundly ignorant butchering of influenza virology.

My PhD is in virology, so yes, I too have far more expertise on the specific topic than they do. That’s obvious from a basic PubMed search.

Was that an error or a deliberate attempt to deceive their readers? Maybe @PDPrice can address this.


Or use a small amount of all that CMI money to do some experiments. In 2018, they had >$2M of revenue and >$2M of assets. The money is there, if they truly believe in what they are claiming.


How are they obliquely acknowledging an equilibrium exists? As far as I understand it, they are denying an equilibrium exists because mutation generally leads to a loss of information.

They never say selection doesn’t operate. Again as far as I understand it, they say it doesn’t operate efficiently in man in any way because we’re all accumulating slightly deleterious mutations. Only the worst mutations that actually affect phenotype can possibly be selected against.

This is his ENTIRE point. Selection only happens on an organism, but he reduces the argument to the way scientists usually refer to it. Because there IS interference within the genome, they won’t affect phenotype in a way that selection can “see” the VSDMs and so they will continue to accumulate.

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“Not operating” vs. “not operating efficiently” is not a trivial difference. If it’s operating, it’s operating. If Sanford is now okay with that, then great. And see what I said about selecting against genomes as a whole. If a genome fails to reproduce, or does so at a lower frequency than others, what happens to all the mutations it contains?


Mutations do not generally lead to a loss of information.


How is that not an extremely relevant point?

Obviously it’s not a trivial difference, but that doesn’t mean you can just “make” selection do whatever just because it DOES operate.

Again, we’re talking about the genome of humans that had the worst mutations. We still have many other humans that reproduce. What happens to all the mutations they contain? They continue to accumulate. We don’t go extinct because the worst mutations that affect the organism are selected against, and humans generally aren’t inbreeding.

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Because Genetic Entropy is about fitness. That’s why Sanford is constantly referencing Kimura, Eyre-Walker and Kneightley.

By the way, you just did the infamous “bait and switch”. Changed the subject away from fitness when it was pointed out there must be an equilirium at which the ratio of beneficial to deleterious (words that refer to fitness) mutations are equal. And your response doesn’t even make logical sense. In what way is the amount of information (btw please show how, with a calculation, the information content affects the ratio of D to B mutations) relevant to the ratio of deleterious to beneficial mutations?

Show your mathematical model please.


If such an equilibrium exists, it must operate even without selection?

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Here is the relevant section from the opening post:

Do you understand why you will reach an equilibrium between red and green lights? Do you understand why this applies to beneficial and deleterious mutations? Notice that there is no selection for red or green lights, and yet they reach an equilibrium.


My point is - if there is no selection, then we should see the same principle operating in human beings today even with relaxed selection as everyone claims. If we do not, the argument is defeated.

This is true even if mutation probabilities are not symmetrical. If red-to-green has a higher probability of occurring than green-to-red, that just moves the equilibrium point a bit toward more green lights.


Before they edited it, CMI (I forget the authors) had a piece up where they kind of didn’t get this, arguing that genomes must be young because there are still GC base pairs, because the C–>T mutation bias would eliminate all of the GC pairs over long timespans. Some of the users on the r/debateevolution subreddit explained this to Paul at some length, which resulted in CMI editing the article in question without acknowledging the changes.


Exactly, this is why PCS is wrong. We would have reached an equilibrium between non-selectable deleterious mutations and non-selectable beneficial mutations a long time ago in the history of life. The non-selectable deleterious mutation that happened a long time ago in an ancestor long past is being changed back to the non-deleterious base by new mutations that happen in the present. If changing a base from A to C is deleterious, then by definition changing the that same base back from C to A is beneficial.


What data do you have that supports the existence of an equilibrium? Is it possible the existence on an equilibrium is organism dependent?

That would be simple math. See the analogy involving red and green lights. It’s just math.


Ok, then why is @dsterncardinale saying there is an equilibrium? PCS aren’t saying that. Why did he like your post if you’re telling him he’s wrong?

Incorrect. Mutations lead to increased information (entropy).


I’d had actually explained this to PDP 6 months before he published the article with the gross GC error.

He obviously thought he was right and I wrong, that “mutations aren’t chemical reactions” and hence do not have an equilibrium.

That is what happens when non-scientists try to write science articles.

He obviously did not factcheck first, or get someone with a science background to check what he wrote for gross errors.


If you transfer the analogy to a gene how would a gene reach equilibrium from random change?

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WOW! I just now had to pick up my jaw from the floor.

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1 point·10 months ago

Again, you need to study equilibria. Let us say there is a reaction A <> B If the forward reaction A > B occurs twice as fast as the reverse reaction B > A, an equilibrium is reached when 2A = B.

What are you talking about? Mutations are not chemical reactions and there is no equilibrium. Mutations are copying errors that happen due to the properties of the nucleotides themselves.

Natural selection and biased gene conversion would also help maintain relative GC:AT content. Retained GC is more likely to be functional. Biased gene conversion increases GC content.

It increases GC content by undoing damaging mutations. It’s a repair mechanism. That does nothing to help you explain the origin of the information to begin with. You’re claiming the origin is from mutations, and that means we should not see GC content to begin with since mutations are more likely to remove it. Over time, that ratio can only go down and down.

I haven’t laughed this hard in a long time.