Bad takes #2. Evolution by “mutation pressure”

This overly long post is part of a series focusing on bad takes on the topic of biases in the introduction of variation, covering both the theory and the evidence. For more bad takes, see:

Evolution by mutation pressure according to Haldane and Fisher

In his entertainingly combative piece entitled “The frailty of adaptive hypotheses for the origins of organismal complexity,” Lynch (2007) writes

The notion that mutation pressure can be a driving force in evolution is not new (6, 24–31)

citing works of Darwin, Morgan, Dover, Nei, Cavalier-Smith, and Stoltzfus and Yampolsky.

What does it mean to invoke evolutionary change due to a driving force of mutation pressure? This choice of terms suggests a process of population transformation by the mutational conversion of individuals, in contrast with the more typical evolutionary conception of population transformation by reproductive replacement.

That is, in a simplified world of discretely inherited types, we can imagine two general ways to transform a population from mainly type A to mainly type B. One mode is for an initially rare type B to take over the A population, over many generations, by the cumulative effects of differential reproduction, either biased (selection) or unbiased (drift). Individuals of type B over-produce, while A individuals die out, so that A individuals are replaced by unrelated B individuals. This is usually how we think about the transformation of populations: reproductive replacement.

A second possible mode of change is for a population of predominantly A individuals to change by many separate events of A-to-B conversion (either individual conversion, or the cross-generational conversion of a lineage from parent to offspring). In this case, A individuals are lost, not by death, but by conversion, and likewise, B individuals are over-produced, not by the excess reproduction of B parents, but by conversion from A individuals. This process might take a single generation or many generations, depending on the rate of conversion.

In a more complex scenario, there are other possibilities. For instance, given diploid inheritance we could consider a process of biased gene conversion by which A1A2 genotypes are converted into A2A2. Suppose that A2 is recessive so that A1A1 and A1A2 have phenotype P1, and A2A2 has P2. In this scenario, biased gene conversion can transform a predominantly P1 population into a P2 population. Dover’s ideas about molecular drive combine the cumulative effects of conversion and replacement.

One of the minor theories in Darwin’s Origin of Species is the mass transformation of individuals by direct effects of the environment. This idea was not unique to Darwin, but simply reflected 19th-century thinking by which heredity is (in effect) mediated by responsive memory-fluids that circulate in the body: after collecting bodily experiences, the memory-fluids gather in the gametes, and during reproduction, they blend, passing on a blended version of inheritance plus experience. Given this view, it was natural to suppose that, when animals or plants encounter a new environment, this results in a hereditary transformation by the cumulative effect of many environment-induced conversions.

The literature of the pre-Synthesis period includes some (typically ambiguous) references to population transformation by mutational conversion, e.g., Shull (1936) writes

If a given mutation were to happen often enough, and nothing opposed its survival, it could easily spread through the entire species, replacing all the other genes at the same locus.

In the broader context of evolutionary theorizing, the mutation pressure theory appears most prominently as a strawman rejected by Haldane (1927, 1932, 1933) and Fisher (1930). That is, Haldane and Fisher did not advocate for the importance of evolution by mutation pressure, but presented an unworkable theory as a way to reject the idea, popular among critics of neo-Darwinism, that evolutionary tendencies may reflect internal variational tendencies. In reality, the early geneticists typically argued, not for mutational transformation of populations, but for a two-step process of “mutation proposes, selection disposes” (decides); and the idea of orthogenesis was typically an appeal to what we would call “constraints” today. That is, the mutation pressure theory began as a bad take on internalist thinking.

Regardless, Haldane and Fisher worked out the implications of evolution by mutation pressure, finding it unlikely on the grounds that, because mutation rates are small, mutation is a weak pressure on allele frequencies, easily overcome by opposing selection. Haldane concluded that this pressure would not be important except in the case of neutral characters or abnormally high mutation rates.

The conclusion of Haldane (1927)

The gist of Haldane’s treatment is that, if mutation-biased evolution is happening, this is because mutation is driving alleles to fixation against the opposing pressure of selection, so that either the mutation rate has to be very high, or selection has to be practically absent (i.e., neutrality). Fisher’s (1930) reasoning on the issue was similar to Haldane’s. From the observed smallness of mutation rates, he drew a sweeping conclusion to the effect that internalist theories are incompatible with population genetics.

Provine (1978) identifies this argument (against evolution by mutation pressure) as one of the key contributions of theoretical population genetics to the Modern Synthesis, because it gave Darwin’s followers a seemingly rigorous basis to reject internalist theories (establishing the core Synthesis principle of There Is No Alternative). The argument was cited repeatedly by the architects of the Modern Synthesis (for examples, see Stoltzfus, 2017), and continues to be cited, e.g., Gould (2002) cites Fisher’s version of the argument and concludes that

Since orthogenesis can only operate when mutation pressure becomes high enough to act as an agent of evolutionary change, empirical data on low mutation rates sound the death-knell of internalism. (p. 510)

Subsequent work has partially undermined the narrow implications of the Haldane-Fisher argument, and completely undermined its broader application as a cudgel against internalism. Mutation pressure is almost never a reasonable cause of population transformation, because it would happen so slowly and take so long that other factors such as drift would intervene, as argued by Kimura (1980). The case studied by Masel and Maughan (2007) is a rare example in which evolution by mutation pressure is reasonable: the authors estimate an aggregate mutation rate of 0.003 for loss of a trait (sporulation) dependent on many loci, concluding that complex traits can be lost in a reasonable period of time due primarily to mutational degradation.

Thus, in spite of what Haldane (1927) seems to suggest, patterns of mutation bias in evolution generally do not indicate evolution by mutation pressure in the absence of selection (or evolution by mutation pressure due to abnormally high mutation rates). In the origin-fixation regime of population genetics, mutation-biased neutral evolution happens, not because mutation pressure is driving alleles to fixation in a biased way (instead, drift is the cause of fixation), but due to a bias in the origination process. And of course, Yampolsky and Stoltzfus (2001) showed that, when there is a bias in the introduction process, this can impose a bias on the course of evolutionary change even when fixations are selective, i.e., there is no requirement for neutral evolution.

In summary, the classic theory of evolution by mutation pressure is not much use in understanding evolution, and is mainly of historical interest as an influential fallacy: generations of evolutionary thinkers believed wrongly that Haldane and Fisher had proven mathematically that internalist theories are incompatible with population genetics.

Other theories

Now, with this background, we may return to consider Lynch’s bad take, which associates various authors with mutation pressure as a driving force in evolution. Of the authors cited — Darwin, Morgan, Dover, Nei, Cavalier-Smith and my colleagues and I — none of them directly propose a theory of evolution by mutation pressure. However, the ideas of Darwin and Dover depict a process reliant on mass conversion: in Dover’s case, population transformation takes place by a dual process of conversion (gene conversion or sub-genomic replication) and reproductive replacement, and in Darwin’s case, it takes place by direct inherited effects of the environment.

Nei refers to “mutation-driven” evolution (the title of his 2013 book), but this is not a reference to mutation driving alleles to fixation. Nei’s usage of “drive” is descriptive or explanatory: evolution is mutation-driven to the extent that our understanding of important aspects of the course of evolution relies on knowing which mutations happen at what times. The same meaning is used in “Mutation-Driven Parallel Evolution During Viral Adaptation” (Sackman, et al. 2017). For an explanation of this meaning of “drive,” see Bad Take #4.

Likewise, the work from my colleagues and me is not about evolution by mutation pressure. From the very beginning, we have (1) followed Provine (1978) in noting the historical importance of the Haldane-Fisher argument against evolution by mutation pressure, and (2) promoted a theory for the effects of biases in the introduction process, obviously a different theory because it contradicts the implications of the mutation pressure theory.

So, what on earth does Lynch mean when he refers to evolution driven by mutation pressure? This is unclear. The model that Lynch (2007) presents immediately after the quoted statement does not correspond to Nei’s thinking or our thinking, and is not a model of evolution by mutation pressure in the classic sense of Haldane and Fisher.

To understand this point, we must analyze the model in some detail, in comparison to the classic mutation-selection balance (also co-developed by Haldane and Fisher). The forces of population genetics are conceptualized like the laws of statistical physics, as mass-action pressures on allele frequencies due to the aggregate effect of countless individual events. In the case of mutation, countless individual events of mutational conversion from allele A1 to allele A2 result in a force or pressure of mutation shifting quantities of A1 to A2. Because there are innumerable independent events, each with an infinitesimal effect, we can represent the aggregate effect with a continuous quantity, e.g., we can write fA2‘ = fA2 + u fA1 to indicate the increase in fA2 due to mutation at rate u from allele A1, and we can write fA1‘ = (1 – u) fA1 to represent the corresponding reduction in the frequency of allele A1 due to mutation to allele A2.

In the classic conception of the mutation-selection balance, if A1 is favored over A2 by a selection coefficient s, then reproductive replacement by selection represents a pressure of magnitude s increasing fA1 and decreasing fA2, whereas mutation is a pressure of magnitude u with the opposite effect, acting by conversion (rather than reproductive replacement). The equilibrium frequency of A2 is roughly f = u / s, and this is typically a small number (much closer to 0 than to 1) because mutation rates are very small, e.g., a typical rate for a specific nucleotide mutation is 10-9 per generation. This is why Haldane concluded (above) that mutation would be unimportant unless selection is effectively absent (i.e., neutrality) or mutation rates are abnormally large (and this is how the classical mutation-selection balance is related to the classical argument against evolution by mutation pressure).

Lynch appears to reach a different answer to the same problem of the equilibrium frequency in a 2-allele system. His equation for the ratio of A1 to A2 is meS, where m is the forward-backward mutation bias favoring A1, and eS is the ratio of fixation probabilities where upper-case S = 2Ngs and lower-case s has the same meaning as above. This result actually does not represent the equilibrium frequency of A1 in a population of individuals, as for Haldane-Fisher: instead, it is the equilibrium distribution of infinitely many loci subject to an origin-fixation process, where each locus is fixed for A1 or A2, that is, meS is the expected ratio of (1) the fraction of loci fixed for A1 to (2) the fraction of loci fixed for A2.

(Figure 1 of Lynch, 2007)

This is easier to understand with a concrete example. The two cases of interest here correspond to the large-population and small-population approximations for the ratio of favored to disfavored codons in the mutation-selection-drift model of codon usage developed originally by Bulmer (1991). In a large deterministic population, each site is fixed for the favored codon, but the disfavored codon is maintained at low frequency in mutation-selection balance per Haldane-Fisher. In the small population, each site is fixed for either the favored codon or the disfavored codon, and the frequency distribution of fixed states for loci is determined by the balance of two origin-fixation rates.

Lynch’s argument gives a different result because it refers to a different kind of mass-action pressure than Haldane and Fisher conceived. The relevant pressure in Lynch’s argument is the mass-action pressure due to events of origination aggregated over an infinite distribution of loci. It is not the same as classic mutation pressure, which is the mass-action pressure due to mutational conversion events aggregated over infinitely many alleles (in a population) at the same locus.

The result of this pressure (relative to a deterministic universe with only the favored codon), is to ensure that, for small values of S = 2Ngs, a substantial fraction of loci are fixed for the disfavored state; when S = 2Ngs becomes modestly large, this fraction is negligible. That is, mutation pressure, for Lynch, refers to something that ensures the predictable presence of deleterious states. By contrast, the theory of Yampolsky and Stoltzfus (2001) is about the way that biases in origination impose biases on which path, out of many possible, is taken by adaptation.

Clearly Lynch’s model ensures the presence of deleterious states for small values of S, but it is not clear what justifies framing this as an effect of a pressure of mutation (more precisely, a pressure of origination), rather than as an effect of random drift or of origin-fixation pressure. Mutation and fixation do not act separately in the context of the argument, and drift is profoundly important in ensuring that, in Lynch’s stochastic anti-paradise, a substantial fraction of everything is in a sub-optimal state. In a world that has deterministic selection, the favored codon always wins (and the disfavored one is never fixed by chance), even in small populations, and this will be true regardless of what we assume about mutation. Metaphorically, mutation is just knocking at the door, offering bad choices: drift has to open the door and let them in. On this basis, we ought to point the finger at drift (not mutation) as the reason for non-optimality.

If all of this seems complex, that is because we have not spent enough time developing a conscious understanding of what causal forces mean and how to invoke them in explanations using precise language. Profound changes in thinking separate us from Haldane and Fisher. Yet we re-use familiar words so that they become overloaded with different concepts, and then fail to pay attention to the problems caused by this overloading. Evolution by mutation pressure, in the classic Haldane-Fisher sense, means something different than what Lynch’s model means, which is something different than what the Yampolsky-Stoltzfus model means. They are different theories with different assumptions and implications.

The path toward greater clarity depends on making distinctions, e.g,. the distinction between origin pressure (across infinitely many loci) and classical mutation pressure (across infinitely many copies of an allele in a population). The reason to distinguish these, again, is that they behave differently, so that the rules for reasoning about one kind of force are different from the rules for reasoning about the other.

Likewise, one must bear in mind that biological processes are not the same as the operators in models or mathematical formalisms, which capture only some of implications of biological processes for evolution. The classic conception of forces in population genetics includes a thing with the label “mutation” (and another thing with the label “selection”), but this thing does not have all the same implications as the biological process with the label “mutation.”

Sources that fail to make such distinctions will mislead readers with the impression that every reference to mutation is a reference to exactly the same evolutionary theory, when this clearly is not the case.


  • Fisher RA. 1930. The Genetical Theory of Natural Selection. London: Oxford University Press.
  • Gould SJ. 2002. The Structure of Evolutionary Theory. Cambridge, Massachusetts: Harvard University Press.
  • Haldane JBS. 1927. A mathematical theory of natural and artificial selection. V. Selection and mutation. Proc. Cam. Phil. Soc. 26:220-230.
  • Haldane JBS. 1932. The Causes of Evolution. New York: Longmans, Green and Co.
  • Haldane JBS. 1933. The part played by recurrent mutation in evolution. Am. Nat. 67:5-19.
  • Kimura M. 1980. Average time until fixation of a mutant allele in a finite population under continued mutation pressure: Studies by analytical, numerical, and pseudo-sampling methods. Proc Natl Acad Sci U S A 77:522-526.
  • Lynch M. 2007. The frailty of adaptive hypotheses for the origins of organismal complexity. Proc Natl Acad Sci U S A 104 Suppl 1:8597-8604.
  • Provine WB. 1978. The role of mathematical population geneticists in the evolutionary synthesis of the 1930s and 1940s. Stud Hist Biol. 2:167-192.
  • Shull AF. 1936. Evolution. New York: McGraw-Hill.
  • Stoltzfus A. 2006. Mutationism and the Dual Causation of Evolutionary Change. Evol Dev 8:304-317.
  • Yampolsky LY, Stoltzfus A. 2001. Bias in the introduction of variation as an orienting factor in evolution. Evol Dev 3:73-83.

Bad takes #4. Attacking the phrase “mutation-driven.”

(This is part of a series of posts focusing on bad takes on the topic of biases in the introduction of variation, covering both the theory and the evidence. For more bad takes, see the links at the bottom.)

In regard to reports of mutational biases influencing the changes involved in molecular adaptation, Svensson and Berger (2019) write

Despite the importance of mutations in these two studies, we emphasize that selection ultimately drove these adaptive allele frequency changes, rather than evolution being ‘mutation-driven’ as some might claim [1,7,8,13].

Actually the “mutation-driven” language is advocated in reference #1 (Nei’s book), but not in the other 3 sources cited.

The authors object that, whereas the term “drive” refers to a cause that drives an allele to fixation, the changes implicated in the cited studies reflect selective fixation rather than fixation by mutation. The implication is that sources 1, 7, 8 and 13 advocate a theory of population transformation, not by reproductive replacement (via selection or drift), but by mutation pressure, i.e., the cumulative effect of many events of mutational conversion, which is generally a bad idea for reasons pointed out by Kimura (1980), although there are rare cases where it makes sense, e.g., loss of a complex character (for a more thorough explanation of evolution by mutation pressure, see Bad take #2).

But of course, fixation by mutation pressure is not the theory advocated in Nei’s 2013 book Mutation-Driven Evolution, nor the other sources cited, nor sources such as:

Sackman AM, McGee LW, Morrison AJ, Pierce J, Anisman J, Hamilton H, Sanderbeck S, Newman C, Rokyta DR. 2017. Mutation-Driven Parallel Evolution During Viral Adaptation. Mol Biol Evol. 34:3243-3253

One must remember that the piece by Svensson and Berger (2019) is not to be taken seriously, but represents a parody of bad Synthesis apologetics — a Sokal’s hoax for evolutionary biology. Here, the authors are parodying a bad-faith argument that does not address any genuine issue of scientific dispute, but is simply a way to score points with the kind of guileless reader who thinks Masatoshi Nei needs a lesson in basic population genetics from the authors.

If we take away the false pretense that Nei and others are advocating evolution by mutation pressure, the remaining issue is semantic: should we (1) restrict “mutation-driven” only to the case in which mutation is a cause of allele fixation, i.e., the mutation pressure theory of evolution, or (2) allow the meaning of “mutation-driven” intended by Nei and others, which is more explanatory, i.e., evolution is mutation-driven to the extent that the explanation for the character and timing of evolutionary change refers to the character and the probability of the underlying mutations.

Which semantic position is justified? The issue is readily resolved by examining how “drive” is used in evolutionary discourse. Does the literature of evolutionary biology include a meaning of “driven” that would justify the use of “mutation-driven”?

In fact, a generic explanatory meaning for “drive” is well established, e.g., here is just a tiny sample of recent uses from the technical literature:

Population size is clearly a condition, not a change-making causal process. Therefore, whenever we hear our colleagues talking about population size “driving” something, this indicates an explanatory meaning of “drive.” The non-causal nature is unmistakable in the first example above, because what is being “driven” by population size is model choice, which does not physically exist in the realm of biology, but represents an abstraction in the realm of modeling. A cause X and its direct effect Y must occur in the same place, the locale of causation.

Note that this meaning of “drive” can be used — and often is used — with the concept of selection, i.e., we can talk about selection driving a thing, without that thing being an allele frequency, e.g.,

More generally, in a purely statistical analysis of patterns, scientists may refer to the predominant explanatory factor as the factor that “drives” the pattern. In this kind of claim, the implied chain of causation may be absent or unclear. As argued by Green and Jones (2016) in regard to “constraints,” scientists sometimes prefer a non-mechanistic or even non-causal language, because this allows them to discuss formal relations applicable to some system, without having to commit to a (potentially problematic) hypothesis for a mechanistic cause.

Again, real scientists doing real, important scientific work sometimes depict formal relations using the language of factors, constraints, drivers, and so on, without implicating a clear causal theory. One of our responsibilities as scientists is to be clear about causation, but sometimes the way to be clear about causes is to say “I’m not sure what are the causes, but here are some rules that the system seems to be following.”

This does not mean that all uses of “drive” are equally welcome. When some authors above write that “These properties — and not function — seem to be the forces driving much of protein evolution” they are literally saying that properties are forces, which is certainly not a clear and careful use of language. I find many of these uses of “drive” to be unhelpful. I would encourage authors to consider using less colorful but more precise language specifying what is being shaped or influenced by a factor, and to what degree.

To summarize, Svensson and Berger, in their satirical exposé of Synthesis sophistry, have crafted a misrepresentation sandwich for us to consume. The meat is a weak semantic argument to the effect that the word “drive” must refer to population-genetic cause in the classic sense, a mass-action pressure that might cause allele fixation. Examples from the research literature demonstrate conclusively that, as much as one wishes for clearer language among evolutionary biologists, the word “drive” simply does not have this restriction. This nutrient-poor semantic filling is sandwiched between two misrepresentations of the cited sources: (1) that they advocate the “mutation-driven” language (this is false for 3 of the 4 sources cited), and (2) that they advocate evolution by mutation pressure (this is false for all 4 sources).

Finally, note that we are having this discussion about language precisely because our customary causal language needs revision. The legacy of neo-Darwinism is that selection is the paradigm of a cause, and any other factor is judged to be causal or not depending on how much it acts like selection. In the shifting-gene-frequencies theory of the Modern Synthesis, evolutionary causes are mass-action pressures (per statistical physics) that may cause allele fixations, e.g., selection and drift are seen as causes because they are potential causes of fixation. When Haldane (1927) and Fisher (1930) addressed the potential for mutation-induced trends, they treated mutation as a cause of fixation and dismissed it as unimportant. Because the introduction process acts nothing like selection, scientists trained in the Darwinian tradition experience great difficulty in comprehending it or accepting it as a causal process in evolution.

The discovery that biases in the introduction process have important effects in evolution prompts the search for precise causal language to describe this cause-effect relationship. In the absence of a widely accepted action language, scientists today are struggling with the issue: this is why they tend to use explanatory language, indirect language, or weak verbs, e.g., we wrote a paper that used weak language to assert (in the title) that mutation biases “influence” adaptation.

Any attempt to introduce causal or even explanatory language with strong active verbs is certain to provoke opposition from the reactionary elements parodied by Svensson and Berger (2019). As I have written elsewhere, this reactionary tendency is cultural, not scientific: it is motivated by allegiance, not to any specific scientific theory, but to tradition and to traditional authorities. The reactionaries will accept saltations (non-infinitesimal changes) and orthogenesis (tendencies due to internal biases) if the evidence demands it, but they will never say the words “saltation,” “internal biases” or “orthogenesis,” because this would reveal a heretical departure from tradition; likewise, they will allow mutation-biased adaptation due to biases in the introduction process, but they will describe such findings using old words while referencing dead authorities, in order to hide the novelty and link the new concepts to tradition (see also Bad Takes #5).

More bad takes on this topic


Kimura M. 1980. Average time until fixation of a mutant allele in a finite population under continued mutation pressure: Studies by analytical, numerical, and pseudo-sampling methods. Proc Natl Acad Sci U S A 77:522-526.

Bad takes #5. It’s just contingency

(This post is part of a series focusing on bad takes on the topic of biases in the introduction of variation, covering both the theory and the evidence. For more bad takes, see the links at the bottom.)

A common “stages of truth” meme holds that successful disruptive ideas are first (1) dismissed as absurd, then (2) resisted— the idea is declared unlikely and the evidence is strenuously disputed—, and finally (3) regarded as trivial and attributed to long tradition. Haldane’s version is that “The process of acceptance will pass through the usual four stages: (i) this is worthless nonsense; (ii) this is an interesting, but perverse, point of view; (iii) this is true, but quite unimportant; (iv) I always said so.” The QuoteInvestigator piece on the stages-of-truth meme has this version:

For it is ever so with any great truth. It must first be opposed, then ridiculed, after a while accepted, and then comes the time to prove that it is not new, and that the credit of it belongs to some one else

In their ruthless parody of Bad Synthesis Apologetics a la Futuyma, Svensson and Berger (2019) model all the stages of truth in the same paper: first they misrepresent the notion of mutation-biased adaptation as an absurdity contrary to basic principles (see Bad Takes #3 and Bad Takes #4), then they present the actual theory but insist that the evidence is inconclusive and that the phenomenon is unlikely for technical reasons of population genetics, and finally, implicitly admitting that the phenomenon is real and that the theory is correct, they describe it as trivial and familiar:

These studies therefore only exemplify how historical contingency and mutational history interact with selection during adaptation to novel environments [31, 38, 52], entirely in line with standard evolutionary theory and the uncontroversial insight that different genomic regions contribute differentially to adaptation driven by selection, with mutations merely providing the genetic input [53].

In this way, the reader is guided through the stages of truth from heresy to textbook wisdom.

However, our focus here is only on the end-point of this progression, in which Svensson and Berger (2019) give the impression that the new work on mutation-biased adaptation represents familiar textbook wisdom, so that the results induce no changes in evolutionary reasoning, raise no new questions, and suggest no new priorities for research. The specific implication of the passage above is that these findings are merely a matter of “contingency” and present nothing original or new relative to the contents of references 31, 38 and 52.

Yet contingency is not a mechanistic theory: it is an explanatory concept indicating that a system is non-equilibrium, so that the state of the system cannot be predicted without knowing the initial conditions and detailed dynamics. The notion of contingency, by itself, does not provide a theory of the dynamics. If we try to answer the odd question, “what does contingency predict about how the mutation spectrum shapes the spectrum of adaptive substitutions?” then we will get nowhere without a theory for the dynamics, and this theory will not be about contingency (an empty explanatory concept), but about the dynamical issue of how the details of mutation rates influence the spectrum of adaptive substitutions.

References 31 and 38 are from the field of quantitative genetics, and simply do not provide any such dynamical theory, e.g., here is the abstract to reference 31:

The introduction and rapid spread of Drosophila subobscura in the New World two decades ago provide an opportunity to determine the predictability and rate of evolution of a geographic cline. In ancestral Old World populations, wing length increases clinally with latitude. In North American populations, no wing length cline was detected one decade after the introduction. After two decades, however, a cline has evolved and largely converged on the ancestral cline. The rate of morphological evolution on a continental scale is very fast, relative even to rates measured within local populations. Nevertheless, different wing sections dominate the New versus Old World clines. Thus, the evolution of geographic variation in wing length has been predictable, but the means by which the cline is achieved is contingent.

Reference 52 is Good, et al (2017), a deep sequencing study of samples from Lenski’s LTEE (long-term evolution experiment). This is mainly an empirical analysis of allele trajectories and clonal interference and so on. There are no explicit claims for an effect of mutation bias on the spectrum of adaptive substitutions (mutation bias is mentioned only in relation to mutators, but they generate a lot of hitch-hikers so this does not establish an effect of mutation bias on adaptation). Indeed, the presentation of results indicates in various places (e.g., the comments on parallelism) that the authors are not paying attention to the issue of how mutation bias influences probabilities of beneficial changes.

What is going on here? For the naive reader, the richness of the satire by Svensson and Berger (2019) may obscure their aims. The reader will surely lose track of all the different ways that they avoid the real issues, and that is the point: they are illustrating all the different ways of not addressing the novelty of (1) a formal pop-gen theory that focuses on the introduction process, and which makes novel predictions about evolution based on tendencies of variation (addressing aspects of trends, GP maps, findability, etc), in a way that directly contradicts the classic Haldane-Fisher “mutation pressure” argument, and (2) empirical results confirming a distinctive prediction of this theory, namely effects of mutation biases on adaptation (not requiring neutrality or high mutation rates), contradicting a long neo-Darwinian tradition of dismissing internal biases in evolution.

One way to avoid these key issues is to engage in whataboutery, i.e., responding to an issue by demanding attention to a second issue. What about other research? What about selection? Whataboutery provides the writer an opportunity to engage the reader on some related topic, e.g., for purposes of name-dropping. Apropos, rather than expanding the reader’s knowledge by offering insightful and detailed explanations of new and poorly known studies on the topic of mutation bias and molecular adaptation, Svensson and Berger instead lavish their attention on older and much better known work on related topics by eminent scientists, e.g., the LTEE from Lenski and colleagues, lizard stuff from Jonathan Losos, the famous stickleback Pitx1 example, or David Houle’s work on fly wings.

More generally, the approach is to identify new work that is significant for specific reasons, and then, rather than mapping the new work onto the relevant issues (i.e., the ones that make it significant), it is mapped to other issues that make it seem ordinary. Clearly Erik and David had a lot of fun playing this game!

To understand how the game works, consider a completely unrelated claim of novelty, e.g., the invention of a telephone 150 years ago. The critic of novelty may object as follows: You say there is something new here? No, nothing new at all! This is merely a device, and humans have been making devices for centuries! I could show you 15 devices from just the past few years that are more impressive than this one, with more parts. I could build an identical device in an afternoon for $20. There is no new fundamental technology here, merely pieces of wood and metal and wire! There are no new basic principles at work, merely electrical currents and vibrations controlled by magnets. It looks like other devices I have seen. I could break it easily with a hammer. I doubt that it can fly like an airplane.

The problem is not that these objections are false statements when considered in isolation. The problem is that they fail to address the crucial issue: the telephone prototype instantiates a generalizable technology to support remote voice communication through electrical wires.

Likewise, when Svensson and Berger (2019) argue that the new line of work on mutation-biased adaptation is just another example of contingency, this represents a deliberate choice — all in jest, of course — to describe the work in an irrelevant way, like objecting that the telephone is not new because it looks like other devices, or because it has no fundamentally new parts.

What is the true significance, in a nutshell? The essence of neo-Darwinism is a dichotomy of variation and selection, in which variation merely provides raw materials (substance, not form), and selection is the source of order, shape, and direction. Theories of internal biases directly contradict neo-Darwinism. The argument of Haldane and Fisher that such theories are incompatible with population genetics (see Bad takes #2) was eagerly adopted by the architects of modern neo-Darwinism, yet (1) this classic conclusion is unwarranted theoretically and (2) its implications are refuted empirically. These two provocative claims are established by the line of work on mutation-biased adaptation; they are not part of textbook knowledge; they are not established in well known studies cited by Svensson and Berger to illustrate scientific name-dropping.

For more bad takes on this topic


Good BH, McDonald MJ, Barrick JE, Lenski RE, Desai MM. 2017. The dynamics of molecular evolution over 60,000 generations. Nature 551:45-50.

Bad takes #3. Mutation bias as an independent cause of adaptation.

To aid in discussion of mutation-biased adaptation, Svensson and Berger (2019) have compiled a highly entertaining list of bad takes on this topic. Their parody of bad Synthesis apologetics begins with a multifarious attack on the strawman theory that mutation bias is “adaptive in its own right” or “an independent force” or something that “can explain the origin of adaptations independently of, or in addition to, natural selection.” They enthusiastically invoke versions of this theory in 5 different places, just on the first page (yellow highlights)!

They associate this theory with the line of argument on mutation bias and adaptation developed in work from my group (e.g., Yampolsky and Stoltzfus, 2001; Stoltzfus, 2006a, 2006b, 2012, 2019), and continued in studies such as:

Of course, none of these sources promote or assume a theory of mutation bias as an independent cause of adaptation, or a theory of mutation being adaptive in its own right. In the original twin-peaks model of Yampolsky and Stoltzfus (2001), the peak favored by the higher selection coefficient is accessible only via a lower mutation rate, and vice versa. Stoltzfus and Norris (2015) worked very hard to establish that transitions and transversions that change amino acids hardly differ in their fitness effects. That is, we typically assume, or try to establish, that the mutational biases are orthogonal to fitness.

Svensson and Berger (2019) use irony to make this point, by first (1) attacking us for assuming that the mutation biases align with what is beneficial (above), then (2) objecting to our actual interpretation (orthogonal effects) by arguing that the mutation biases align with what is beneficial:

transitions could be favored over transversions owing to selection on genomic base composition. Selectively beneficial transitions and selectively beneficial transversions could also have different distributions of fitness effects

Clearly, Erik and David have studied their history, because they are calling on a classic strawman that has worked like catnip on Darwin’s followers for over a century. Repeatedly, internalist critics of neo-Darwinian logic have suggested that the observed tendencies or directions of evolutionary change are not all external in origin, i.e., due to selection, but may arise internally from some aspect of mutation or development. In response, the advocates of neo-Darwinism — who have a tendency to equate evolution with adaptation, and thus to equate direction with adaptive direction — have accused these critics of proposing some form of directed mutation or adaptive mutation, or of engaging in mysticism or teleology.

Because this argument has been used by Darwin’s followers for over a century, we know how the advocates of internalist theories respond:

I take exception here only to the implication that a definite variation tendency must be considered to be teleological because it is not ‘orderless.’ I venture to assert that variation is sometimes orderly and at other times rather disorderly, and that the one is just as free from teleology as the other. In our aversion to the old teleology, so effectually banished from science by Darwin, we should not forget that the world is full of order . . . If a designer sets limits to variation in order to reach a definite end, the direction of events is teleological; but if organization and the laws of development exclude some lines of variation and favor others, there is certainly nothing supernatural in this” (Whitman, 1919: see p. 385 of Gould, 2002)

In general, when we find that false arguments persist for generations, this is because they are being used, not to resolve difficult questions, but to maintain conformity within a closed ideological system, i.e., neo-Darwinians use these arguments to help other neo-Darwinians to avoid thinking any uncomfortable thoughts.

Of course, we must not confuse theories and people, e.g., a theory supported by bad arguments does not become a bad theory for this reason. The theory and its apologetics are two different things. We can define neo-Darwinism clearly in terms of the dichotomy of the potter (selection) and the clay (variation), and this concept stands by itself. Separate from this, there is a culture or a set of rhetorical practices associated with neo-Darwinian apologetics. It is this neo-Darwinian culture or thought-collective that has a sociological aspect and a self-protective urge that gives rise to the same pathologies as any cult or identity-group.

The false accusations of teleology or directed mutation are part of the conceptual immune system of the neo-Darwinian thought-collective (described in a separate post). This kind of strawman is used in two ways. The first line of defense against new ways of thinking is to claim that they are inherently flawed or patently absurd: they do not represent scientific theories to be considered, but errors to be rejected. This is what neo-Darwinians are taught when they are young: the neo-Darwinian view is simply the rational evidence-based approach to evolution, whereas critics behave irrationally and hold views with obvious flaws.

Eventually, however, some of them grow up and see a broader slice of the world, and can no longer be shielded from the plausibility of alternative ideas. In this case, the priests of the religion must offer a more sophisticated argument to keep the faithful from straying. In this second line of defense, the alternative is granted as a theoretical possibility, but (1) its importance is minimized, and (2) it is described in different language and grounded in the Darwinian faith tradition itself, anchored by reference to the sacred texts. That is, the doubting Darwinian is shown that the apostles and disciples of olden times, and even the great Lord Darwin himself, also experienced moments of doubt, posed difficult questions, and considered alternative views. The initiate now has a more sophisticated understanding of the faith, which does not demand inner purity, but merely outward piety.

Svensson and Berger (2019) illustrate both strategies brilliantly. First they attack claims of mutation-biased adaptation by attacking the straw-man of “independent cause of adaptation,” then they present a more reasonable idea based on population genetics (i.e., the theory we proposed), insisting that this version of the idea is already part of the Modern Synthesis, though of course they cannot identify any classic Synthesis sources, because the theory was not formally proposed until 2001. The easter egg in their derivation in Box 1 is that, although they name Haldane, Kimura, and Fisher — giving readers the impression that famous dead people developed the theory —, the crucial mathematical equation (representing mutation-biased adaptation) is introduced with a citation number in brackets that quietly points to the actual source of the theory, a 2001 paper by non-dead, non-famous authors.

For more bad takes on this topic

This is part of a series of posts focusing on bad takes on the topic of biases in the introduction of variation, covering both the theory and the evidence.


Gould SJ. 2002. The Structure of Evolutionary Theory. Cambridge, Massachusetts: Harvard University Press.

Bad takes #1. We have long known.

An anonymous reviewer responded to the manuscript of Stoltzfus and Yampolsky (2009) with the claim that “we have long known that mutation is important in evolution,” citing the following passage from Haldane (1932).

A selector of sufficient knowledge and power might perhaps obtain from the genes at present available in the human species a race combining an average intellect equal to that of Shakespeare with the stature of Carnera. But he could not produce a race of angels. For the moral character or for the wings, he would have to await or produce suitable mutations

Actually, this passage demonstrates the opposite of what the reviewer implies, and so we included it in the final version of the paper. What is Haldane suggesting?

I can’t resist a good story, so let’s begin with this 1930s photo of Italian boxer Primo Carnera, his friend and fellow heavyweight champ Max Baer, and Hollywood actress Myrna Loy. Baer dated Loy in real life. They made a movie together, the three of them (thus the staged publicity photo). Baer, one of the greatest punchers of all time, became a hero to a generation of Jewish sports fans when he (being half-Jewish) demolished Max Schmeling, Hitler’s champion (after that, Hitler outlawed boxing with Jews). He literally killed one of his opponents, and repeatedly sent Carnera to the floor during their single fight.

Primo Carnera, Myrna Loy, and Max Baer in a publicity photo from the 1930s

But the point of this picture is that, although Baer was a formidable man, Carnera makes him look small. Other fighters were afraid to get in the ring with him. Furthermore, although Carnera was huge — 30 cm taller and 50 kg heavy than the average Italian of his generation —, he was not the aberrant product of a hormonal imbalance. This photo shows a huge man who is stocky but well proportioned, muscular, and surprisingly lean. Again, he was not a misshapen monster, but a man at the far extremes of normal human stature, which is precisely Haldane’s point.

Selective breeding to the quantitative extremes of known human ability, Haldane proposes, could produce a race combining the extreme of Carnera’s magnificent stature with Shakespeare’s magnificent verbal ability.

Haldane contrasts this with a different mode of evolution dependent on new mutations, which might produce a race of angels, if one could wait long enough for the mutations to happen. That is, Haldane is contrasting (1) a mode of evolution that could combine the known extremes of human ability with (2) a mode of evolution that could generate imaginary fictitious not-at-all-real creatures. Both Haldane and Fisher argued that a mode of change dependent on new mutations would be too slow to account for the observed facts of evolution. They argued instead that evolution must take place on the basis of abundant standing variation.

That is, in the passage above, Haldane is not endorsing a mode of mutation-dependent evolution, but gently mocking it, in contrast to a mode of evolution that, based on quantitative standing variation, could produce a race of magnificently eloquent champions.

Thus, the reviewer’s comment was a bad take on Haldane, misrepresenting his intention.

In addition, the “we have always known” comment represents a more general category of bad take that substitutes, in place of a specific target of criticism, a much broader, fuzzier, or more generic claim.

Of course, the reviewer is correct that scientists in the mainstream Modern Synthesis tradition have always known that mutation is important in evolution. More precisely, the importance assigned to mutation was that it is ultimately necessary, because without mutations, evolution would grind to a halt. Haldane, Fisher, Ford, Huxley, Dobzhansky, and others said this explicitly.

However, they did not say that mutation is important as a dispositional factor. Instead, they argued explicitly against this idea, e.g., Haldane (1927) is the original source of the “mutation pressure is a weak force” argument (see Bad takes #2).

The theory of biases in the introduction process, by contrast, says that mutation is important in evolution as a dispositional cause, a cause that makes some outcomes more likely than others, and that this importance is achieved (mechanistically) by way of biases in the introduction process.

So, the reviewer is making an implicit bait-and-switch argument. The theory of biases in the introduction of variation is a specific population-genetic theory with specific conditions and implications, and the reviewer is responding to this by saying “we have always known that mutation is important,” but this is not the same thing: the traditional importance assigned to mutation is not “dispositional cause that makes some outcomes more likely than others” but “ultimate source of raw materials without which evolution would grind to a halt.”

Finally, this bad take is part of a family of bad takes in which the novelty of a claim X is rejected on the grounds that X sounds vaguely like X’, or that X can be categorized as a member of some larger and fuzzier class of claims (see Bad Takes #5: Contingency). This is often the case with “we have long known” arguments. If the theory was in fact old, the reviewer would not have made a vague “we have long known” argument, but would have cited the original source of the theory, e.g., “Of course the theory of biases in the introduction process is not new, because Haldane proposed exactly the same theory 70 years ago and worked out its implications!” In fact, no such antecedent exists, which is why, to defend tradition, the reviewer must resort to a bait-and-switch argument.

For more bad takes on this topic

This is part of a series of posts focusing on bad takes on the topic of biases in the introduction of variation, covering both the theory and the evidence.


Haldane JBS. 1932. The Causes of Evolution. New York: Longmans, Green and Co.

Stoltzfus A, Yampolsky LY. 2009. Climbing mount probable: mutation as a cause of nonrandomness in evolution. J Hered 100:637-647.