Grounding internalism in the introduction process: from pop-gen to evo-devo

(work in progress: emerging manuscript, currently in the form of a persuasive essay)


(This abstract is aspirational. The actual manuscript delivers the argument in a different way.)

Historical debates on evolution featured internalist ideas that were considered together with, or in opposition to, an externalist focus on natural selection. The mid-20th-century “Modern Synthesis” put an end to this kind of talk: internalist ideas were formally rejected, either for being incompatible with Mendelian population genetics, or merely for being unnecessary. Though internalist lines of thought re-emerged in the form of neo-structuralism and evo-devo, they are widely understood to evoke or require an alternative form of causation separate from population genetics. Here I explain why this impasse exists and how to remove it. First, I argue that an impasse on causation is genuine, and that it reflects how the received view of causation emerged from the distinctive boundary conditions and change-laws of a shifting-gene-frequencies paradigm in which the alleles relevant to evolution are already present in the initial gene pool, and causation is assigned (by an analogy with statistical physics) only to mass-action forces that shift their frequencies. Second, I describe a body of post-Synthesis theory that departs from this paradigm by representing the introduction of new alleles as a change-making process that is not a mass-action force. I show how an explicit treatment of the introduction of novelty by mutation-and-altered-development leads to direct contradictions with classic reasoning, most importantly the Haldane-Fisher “opposing pressures” argument that appeared to rule out evolutionary tendencies due to internal variational biases. Mutation-biased adaptation is a distinctive prediction of this theory, confirmed by recent empirical work. Third, I explain how this seemingly small modification to our understanding of causation represents a major innovation that allows us to specify a formal population-genetic grounding for the key internalist themes of (1) the evolutionary emergence of intrinsically likely forms, (2) internal taxon-specific dispositions that contribute to recurrent evolution; and (3) directional evolutionary trends that are internal in origin. Finally, I outline some of the initial successes and open challenges of a research program focused on the evolutionary impact of mutational, developmental, and systemic biases in the introduction of variation.


An internalist-externalist distinction appears in many contexts. In the context of evolutionary thinking, externalist approaches focus on explaining the outcomes or products of evolution by reference to external conditions, so that, for instance, explanations for changes in some feature would make a linkage with changes in external conditions. Internalist approaches focus on explaining outcomes or products of evolution by reference to internal features so that, for instance, explanations for the emergence of some novel structure would be linked to intrinsic material or dynamic propensities of the evolving system. Internalists and externalists tend to differ not just in how they explain things, but in what they hope to explain: they typically are not just offering contrasting explanations for precisely the same things.

Contemporary internalism is manifested in neo-structuralist arguments about self-organization or findability in the manner of Kauffman (1993); in approaches to molecular evolution that feature mutational explanations (Cano, et al.); in the evolvability research front (Nuño de la Rosa), with its focus on how internal developmental-genetic organization facilitates evolution; and in evo-devo generally. Some of the classic internalist themes that persist into the contemporary literature are (1) the predominance (among the products of evolution) of forms or structures that are intrinsically or structurally likely, (2) taxon-specific evolutionary propensities or dispositions that contribute to recurrent evolution; (3) directional trends that are internal in origin.

For the present purposes, I will simplify this issue of internalism in the following way. Assume that evolution is fundamentally and essentially the result of combining a process of varigenesis, i.e., the generation of variation, and a process of reproductive sorting (resulting in selection and drift), and we are concerned only with the immediate or first-order implications of this combination. The internal factor in evolution is then primarily a matter of the genesis of variation, and the issue of internalism is primarily to understand the role of varigenesis in evolution, with a focus on how to combine variation and reproductive sorting. A key issue is whether varigenesis has a dispositional role, predictably favoring some types of changes or directions, and if so, how this dispositional influence operates, and how strongly it shapes evolution.

Before proceeding further, I want to note that this is a non-trivial simplification both conceptually and historically. For instance, the classic advocates of orthogenesis put their focus on how the genesis of variation influences evolution, but they were not strict internalists, e.g., some considered the environment as an important influence on the genesis of variation (see Ulett, 2014). Likewise, to equate internalism with the first-order effect of variation is to exclude higher-order ideas that figure importantly in internalist discussions, e.g., concepts of feedback through which evolvability evolves. My aim here is not to reduce all of evolution to one theory, nor even to cover all of the themes of internalism, but rather to provide a rigorous grounding for certain classic themes. To get to this point, I need to put some limits on the topic. Stated differently, this is an attempt at reduction or mechanistic justification— specifically an attempt to map certain pre-existing high-level themes to implications of a causal theory— and such reductive arguments typically shift the boundaries of things rather than perfectly mapping old themes to new mechanisms.

For my purposes here, “neo-Darwinism” refers to a view that posits specific and contrasting roles for selection and variation: selection is the potter and variation is the clay. In Darwin’s original theory, the process of indefinite variability (the noise-like environmental variation that Darwin relied on, later called fluctuation) merely supplies the raw materials that selection shapes into adaptations. Darwin said that variation follows immutable laws, but that these laws “bear no relation” to the structures built by natural selection. In this conception, variation is not dispositional. Selection is creative and imposes shape and direction, while variation merely supplies raw materials. In this view, “the ultimate source of explanation in biology is the principle of natural selection” (Ayala, 1970).

Although the neo-Darwinian combination of variation and selection— an unequal marriage in which one partner makes all the decisions and gets all the credit— has dominated evolutionary thinking, alternative views posit other roles for the process of variation, assigning it some leverage in influencing the course of evolution. A concise list of notional theories of the role of variation that have been most important in evolutionary discourse would look something like this, in chronological order:

  1. Variations emerge adaptively by effort, and are preserved, as per Lamarck
  2. Variation supplies in each generation the indefinite raw materials that selection shapes into adaptations, as per Darwin.
  3. The constrained generation of variation sets limits on the choices available to selection, as per Eimer (1898) or Oster and Alberch (1982)
  4. Mutation pressure drives alleles to prominence (against the opposing pressure of selection) under neutrality or high mutation rates, per Haldane (1927)
  5. New quantitative variation (M) contributes to standing variation (G) which, together with selection differentials (β), jointly determines (as ) the short-term rate and direction of multivariate change in quantitative characters (Lande and Arnold, 1983; see note 5)

The first 3 theories are essentially folk theories, whereas the latter 2 are formalized. Theories of “orthogenesis” (perpetually mischaracterized by Darwin’s followers) from Eimer, Cope and others fall into the 3rd category, focusing on how the generation of variation influences evolution, and advocates of this kind of thinking considered both internal and external influences on the origin of variation (see Ulett, 2014).

The mutation pressure theory is explained below.

The formalization of evolutionary quantitative genetics (EQG) per Lande and Arnold (1983) is clearly an outgrowth of neo-Darwinian thinking, but the behavior of this formalism diverges significantly from selection and variation as the potter and the clay. The meaning of the master equation Δz = Gβ is that the trajectories of change for all variable traits are linked together (in a somewhat springy way) by their variational correlation structure, where G is the structured factor that represents the correlations in standing variation. However, G is standing variation, not varigenesis (M). Therefore the relation of selection and varigenesis in this theory is complex and indirect. See note 5 for more explanation.

Given how I have defined the problem of internalism in terms of the role of varigenesis, the issue of grounding internalism in causal theories is a matter of having a complete causal theory that specifies the kind of dispositional role of variation that makes sense of internalist themes.

In contemporary evolutionary discourse, there is clearly a discordance between the kinds of claims that internalist thinkers would like to support, and the kinds of claims with a vera causa status recognized by evolutionary geneticists. This discordance is reflected in (1) skepticism and dismissal from evolutionary geneticists, e.g., the way that Lynch (2007) dismisses basically all of evo-devo and the evolvability research front as speculation and loose talk, or the way that Wray, et al. (2014) refer to a “lack of evidence” for developmental bias, and likewise the way that Houle, et al (2017) take an attitude of extreme skepticism, denying that an influence of mutational variability on adaptation has been demonstrated in a way that fits with any known causal theory; and (2) the longstanding complaint from developmentalists about being left out of the “Synthesis,” which leads to the causal completeness argument (Amundson, 2005) and lineage explanation (Calcott, 2009), and to various calls for reform that emphasize the supposed limitations of population genetics.

Here I argue that we can specify a much broader and more complete grounding for internalism by adding (to the list above) a 6th theory about variation that is new and has not yet played a meaningful role in evolutionary discourse:

  • Mutational and developmental biases in the introduction of variation impose kinetic biases on evolution by a first come, first served logic, without requiring neutrality or high mutation rates (Yampolsky and Stoltzfus, 2001)

To understand how to use this theory to specify a broad causal grounding for internalist concerns, we must remove a series of obstacles, beginning with a major historic error in the use of population-genetic reasoning — an error whose effects reverberate today — concerning a possible causal link between internal tendencies of variation and tendencies of evolution.

The Haldane-Fisher argument and the SGFT

Futuyma (1988) attributes 3 remarkable accomplishments to an “Evolutionary Synthesis” of the 20th century: re-establishing neo-Darwinism on a Mendelian basis, sweeping away all rival theories, and providing a common framework for scientists in various disciplines to address evolution.

How were rival theories rejected? In an argument repeatedly cited by leading thinkers, Haldane (1927) and later Fisher (1930) concluded that mutation is a weak force unable to overcome the opposing pressure of selection, important only when selection is absent or when mutation rates are abnormally high (for more detail, see here). The argument was understood to mean that, given the observed smallness of mutation rates (and the equally well recognized pervasiveness of selection on visible traits), internalist theories relating tendencies of evolution to tendencies of variation are incompatible with population genetics, e.g., Gould (2002) writes as follows, citing Fisher (1930):

“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)

Gould (2002)

This is a formal argument with a clearly recognizable logic, the effect of which is to reject an entire class of internalist theories, with no need for difficult experiments or time-consuming analyses of data! Accordingly, Provine (1978), in “The role of mathematical population geneticists in the evolutionary synthesis of the 1930s and 1940s,” identifies this argument as a key theoretical claim (see also Stoltzfus, 2017, 2019).

“For mutations to dominate the trend of evolution it is thus necessary to postulate mutation rates immensely greater than those which are known to occur.” “The whole group of theories which ascribe to hypothetical physiological mechanisms, controlling the occurrence of mutations, a power of directing the course of evolution, must be set aside, once the blending theory of inheritance is abandoned. The sole surviving theory is that of Natural Selection” (Fisher, 1930)

“For no rate of hereditary change hitherto observed in nature would have any evolutionary effect in the teeth of even the slightest degree of adverse selection. Either mutation-rates many times higher than any as yet detected must be sometimes operative, or else the observed results can be far better accounted for by selection.” (p. 56 of Huxley, 1942)

“If ever it could have been thought that mutation is important in the control of evolution, it is impossible to think so now, for not only do we observe it to be so rare that it cannot compete with the forces of selection but we know this must inevitably be so.” (p. 361 of Ford, 1971)

[Figure legend: Some leading thinkers who invoked the Haldane-Fisher opposing pressures argument (clockwise from left: Haldane, Fisher, Huxley, Mayr, Simpson, Ford, Wright). ]

But the argument is wrong.

An evolutionary process that depends on events of mutation that introduce new alleles is subject to biases in mutational introduction, by a first come, first served dynamic that Haldane and Fisher did not address in their arguments about mutation pressure (see note 8).

The flaw in the Haldane-Fisher argument arises from the assumption that evolution can be treated as a process of shifting the frequencies of alleles in an initial “gene pool,” without events of mutation that introduce new alleles. New mutations have to be involved somewhere in evolution, of course, but they don’t have to be directly involved: if all the relevant mutations happened in the past, and the corresponding variant alleles are present in the gene pool at frequencies resistant to random loss, then we don’t need to address new mutations to understand evolutionary dynamics, which would follow merely from shifting gene frequencies.

In this way, the shifting-gene-frequencies theory (SGFT) posits that evolution can be understood as a shift from an initial multi-locus distribution of allele frequencies, to a final distribution of frequencies for the same alleles. This is what “evolution is shifting gene frequencies” meant for modeling, in practice.

Note that this is a Newtonian framework for theorizing about dynamics. There is an initial state (a set of alleles with their initial frequencies), a set of boundary conditions (the frequencies may range between 0 and 1), and a set of change-laws that govern the dynamics, specifying how frequencies are shifted by mutation, selection, drift, migration and (in the multilocus context) recombination. Although the change-laws were often treated deterministically, stochastic versions also emerged.

Were the classic works of theoretical population genetics really built on thisnarrow foundation? Why isn’t this problem discussed more broadly? I’m not sure why this issue is not a primary focus of reformists, but certainly the issue has been noticed and remarked upon, and not just by non-conformists like myself or Nei (2014). Below are 3 independent sources authored by eminent evolutionary geneticists that note precisely this same restriction in classical theoretical population genetics:

“The process of adaptation occurs on two timescales. In the short term, natural selection merely sorts the variation already present in a population, whereas in the longer term genotypes quite different from any that were initially present evolve through the cumulation of new mutations. The first process is described by the mathematical theory of population genetics. However, this theory begins by defining a fixed set of genotypes and cannot provide a satisfactory analysis of the second process because it does not permit any genuinely new type to arise. ” (Yedid and Bell, 2002)

“Almost every theoretical model in population genetics can be classified into one of two major types.  In one type of model, mutations with stipulated selective effects are assumed to be present in the population as an initial condition . . . The second major type of models [the origin-fixation type] does allow mutations to occur at random intervals of time, but the mutations are assumed to be selectively neutral or nearly neutral.” (Hartl and Taubes, 1998)

“We call short-term evolution the process by which natural selection, combined with reproduction . . ., changes the relative frequencies among a fixed set of genotypes, resulting in a stable equilibrium, a cycle, or even chaotic behavior. Long-term evolution is the process of trial and error whereby the mutations that occur are tested, and if successful, invade the population, renewing the process of short-term evolution toward a new stable equilibrium, cycle, or state of chaos.” (p. 182). “Since the time of Fisher, an implicit working assumption in the quantitative study of evolutionary dynamics is that qualitative laws governing long-term evolution can be extrapolated from results obtained for the short-term process. We maintain that this extrapolation is not accurate.  The two processes are qualitatively different from each other.” (Eshel and Feldman, 2001, p. 163)

All three quotations suggest the same two things: (1) the SGFT was a limiting paradigm in mainstream 20th-century theoretical population-genetics, and (2) as the 20th century closed, this limiting paradigm was breaking down.

The breakdown started, perhaps, with origin-fixation models in 1969 (see McCandlish and Stoltzfus, 2014). For many years, these models were used primarily with neutral or slightly deleterious mutations: this explains the distinctive second category of Hartl and Taubes above. Eventually, SSWM models of adaptation (which overlap in meaning with origin-fixation models) emerged from Gillespie, and became the basis of the minor renaissance in modeling adaptation by Orr and others in the 1990s. That is, theoreticians have moved beyond the SGFT and embraced models of what is sometimes called the “lucky mutant” view or “mutation-driven” evolution, to such a degree that these models now represent a major branch of theory with diverse applications (see McCandlish and Stoltzfus, 2014; Tenaillon, 2014) (see note 9).

But the SGFT was influential in the past, and remains cryptically influential today. Michod (1981) identifies a shifting-gene-frequencies paradigm as the “hard core” of a research program per Lakatos:

(a) The Hard Core

The basic elements of Lakatos’s model are all clearly identifiable within the population genetics research programme. For the population geneticist, the common denominator of all evolutionary forces is their effects on gene frequencies. In other words, gene frequency changes are evolution. This proposition, the hard core of population genetics, is best summarised by Sewall Wright in the conclusion to volume II of his treatise (Wright [1969], p. 472): 

“. . the species is thought of as located at a point in gene frequency space. Evolution consists of movement in this space.”

 This point of view is the basis of the population genetics approach to evolution. This is as true today as it was during the synthesis of the 1920s and 30s.

Michod is correct to identify this as a paradigm, because of the way it defines a broad and powerful perspective on how to think about the problems of evolution, answering basic questions that otherwise might be very hard to answer, and which might be answered quite differently by scientists working on evolution from different perspectives:

  • What is evolution? How do I know if it has happened?
  • Where does evolution take place? What is the causal locale?
  • How do I model evolution? What is the field or state-space?
  • What are the causes of evolution? How do I quantify them and weigh their importance in evolution?
  • How do I study evolutionary causes?

Certainly there were no agreed-upon answers to these questions prior to the Synthesis era. The distinctive answers suggested by the shifting-gene-frequencies paradigm shaped the Synthesis movement:

What is evolution? How do I know if it has happened? Evolution is shifting gene frequencies. Evolution has happened if there has been a shift in gene frequencies at the population level. A single event of birth or death is not evolution, and likewise, an event of mutation or recombination is not evolution. Instead, evolution has happened if there has been some significant shift in allele frequencies. We can argument ad nauseam about what “significant” means in this context, but this “how much X is enough?” question is trivial compared to the primary decision that X— the thing whose size we are going to argue about— is a shift in frequencies and not something else.

Where does evolution take place? Evolution takes place in populations because populations are cohesive entities with allele frequencies. Individuals do not have allele frequencies. Species have allele frequencies, but only because they exist as populations (one or more) with allele frequencies.

How do I model evolution? What is the field or state-space? As Wright (above) suggests, “the species is thought of as located at a point in gene frequency space. Evolution consists of movement in this space.” A model of evolution represents the evolving thing, the population, as a point moving in its state-space of allele frequencies under the action of the forces [10].

What are the causes of evolution? How do I quantify them and weigh their importance? The causes of evolution are the processes that cause shifts in allele frequencies, in units of frequency change over time. The forces that cause larger shifts are, by definition, stronger forces.

How do I study evolutionary causes? The only direct way to study evolutionary causes is to adopt the approach of population genetics, i.e., focusing on populations undergoing changes in allele frequencies, to assess what is causing those changes.

Some of the guidance provided by this paradigm turned into explicit dogma (e.g., the causes of evolution are forces that shift frequencies), and some of it was established more in the form of hidden assumptions or soft prejudices.

Considered more as a falsifiable claim than as a paradigm, the shifting-gene-frequencies theory asserts that we can understand evolution in nature adequately as a shift from one frequency distribution to another, so that any time-course of evolution can be represented as a trajectory in a continuous allele-frequency space.

[Figure legend: The shifting gene frequencies theory (SGFT). In the SGFT, adaptation — understood as a smooth shift in trait distributions (left) — is attributed to simultaneous shifts in the frequencies of alleles at multiple loci (middle), each with a small phenotypic effect. Formally, the population is a point in the topological interior of an allele-frequency space, i.e., the space of non-zero frequencies, and evolution is movement in this interior space (right). Thus, the forces of evolution are processes that can shift the population in this interior space. By contrast, the introduction process jumps a population from a surface into the interior where reproductive sorting processes (selection and drift) operate.]

Within the SGFT, the forces of evolution are the biological processes that move the system in its state-space, i.e., the processes that shift frequencies. The ability to shift frequencies is obviously the measure of strength for a force: a biological process that causes larger shifts is necessarily a stronger force. Selection, being the strongest force, tends to dominate the process of shifting gene frequencies, i.e., it dominates the course of evolution.

What is the role of mutation in this theory?

In the process of shifting from an old to a new multi-locus frequency distribution, mutation pressure merely shifts the relative frequencies of pre-existing alleles. Because mutation rates are so small, these shifts are tiny in comparison to effects of selection and (typically) drift. Thus, the argument of Haldane and Fisher makes perfect sense within the SGFT.

That is, the Haldane-Fisher argument is both a fallacy (in a broader context) and, at the same time, the correctly derived implication of the SGFT: if evolution can be adequately understood merely as shifting gene frequencies, then mutation is indeed a weak force, unimportant unless selection is absent (neutral characters) or the rate of mutation is unusually large.

[Figure legend: The conclusion of Haldane (1927). ]

That is, mutation is a “weak force” in classical population-genetic thinking because the SGFT does not cover the novelty-introducing aspect of mutation. In effect, this aspect of mutation is treated as a background condition, rather than as a change-making causal process with explicit dynamics (see note 1). When a “gene pool” with pre-existing variation is assumed, the effect is that the novelty-introducing role of mutation is absorbed into this assumption as a background condition: the introduction process is literally is not part of “evolution” (shifting gene frequencies), but happens implicitly, before “evolution” gets started.

This theory makes mutation pressure largely irrelevant to modeling evolutionary change. This is why Lewontin (1974) says “There is virtually no qualitative or gross quantitative conclusion about the genetic structure of populations in deterministic theory that is sensitive to small values of migration, or any that depends on mutation rates.” The treatment of theoretical population genetics by Edwards (1977), shown in the image below, has hundreds of equations, but no terms for mutation. The word “mutation” appears only once in the entire book, on page 3, where the author says “All genes will be assumed stable, and mutation will not be taken into account.”

Note that the SGFT does not imply or suggest that new mutations never happen. Haldane, Dobzhansky and others stated explicitly that evolution ultimately would grind to a halt without new mutations. Instead, the verbal theory of the SGFT says that, even though mutations are ultimately necessary, they are not immediately necessary, i.e., they are not directly involved, because the “gene pool” acts as a dynamic buffer, maintaining variation so that there is always abundant material for selection to respond to a change in conditions.

The popularity of the SGFT was driven partly by the sense that adaptation would be too slow if it involved waiting for the right mutation, instead of beginning with an abundant gene pool (e.g., this is particularly emphasized in Wright’s 1932 paper). Before about 1940, when the age of the earth was established at 4000 MY instead of 20 MY or 200 MY, evolutionary biologists were particularly motivated by the need to establish that the process of evolutionary adaptation was fast enough to explain observed levels of adaptation and diversity. We don’t think like this anymore, but a century ago, a theory of evolution that made adaptation fast was considered to be ex posteriori a better theory.

In addition, the SGFT was experimentally validated, a known mechanism. The experimental touchstone for the SGFT was Castle’s famous experiment with hooded rats (see Provine, 1971). Johannsen had already proven that selection is effective in sorting out true-breeding Mendelian types, but Castle and his colleagues showed something quite different. They started with a population of mottled black-and-white rats, and bred nearly all white, and nearly all black populations by selection in just 20 generations, not enough time for new mutations to play any appreciable role. This proved that selection could create “new types” (Provine) or “wholly new grades” (Castle) without the involvement of mutation, simply by shifting gene frequencies.

Finally, the SGFT provided a rhetorical foundation for Darwin’s followers to reject mutationism in the sense of “mutation proposes, selection disposes” (decides), a non-Darwinian theory distinct from their gradualist conception of evolution by the shifting and blending of abundant infinitesimals. The mutationist conception of evolution as a 2-step mutation-fixation process — the “lucky mutant” theory formalized in 1969 in origin-fixation models — is common today (see The shift to mutationism is documented in our language). However, the architects of the Modern Synthesis called on the SGFT to argue against the lucky mutant view (for more detail, see When Darwinian Adaptation is neither). That is, even though the SGFT was a speculative theory of unknown realism, the architects of the Modern Synthesis convinced themselves that the theory was firmly established, and they conveyed this attitude of certainty to their readers, e.g.,

 “Novelty does not arise because of unique mutations or other genetic changes that appear spontaneously and randomly in populations, regardless of their environment. Selection pressure for it is generated by the appearance of novel challenges presented by the environment and by the ability of certain populations to meet such challenges.” (Stebbins, 1982, p. 160)

“It is most important to clear up first some misconceptions still held by a few, not familiar with modern genetics:  (1) Evolution is not primarily a genetic event.  Mutation merely supplies the gene  pool with genetic variation; it is selection that induces evolutionary change.” (p. 613 of Mayr, 1963)

This commitment continued to echo for decades in the notion that evolution does not depend on new mutations, a doctrine repeated in textbooks, e.g.,

“In practically all populations, however, the role of new mutations is not of immediate significance” (p. 464)

Strickberger MW. 1990. Evolution. Boston: Jones and Bartlett Publishers.

Thus, the SGFT was not merely a modeling convention — it was not just a technique used by mathematicians to make the equations easy to solve. Instead, the formal models and the conception of forces as mass-action pressures came together with a verbal theory about how evolution actually works in nature, and this integrated theory provided a basis to reject, not just orthogenesis, but mutationism in the sense of evolution via new mutations, i.e., mutation proposes, selection disposes (decides).

Even more broadly, the SGFT underlies the grand Synthesis claims noted earlier (Futuyma, 1988): restoring neo-Darwinism, sweeping away all rivals, and providing a unified framework for scientists in various disciplines to address evolution.

Yet, evolution in nature does not have to follow the SGFT. As stated earlier, an evolutionary process that depends on events of introduction — events of mutation that introduce a new allele, or events of mutation-and-altered-development that introduce a new phenotype — is subject to biases in the introduction process, by a simple “first come, first served” logic.

The logic of this theory was demonstrated by Yampolsky and Stoltzfus (2001) using a population-genetic model with 2 loci and 2 alleles. From the starting ab population, mutations with rates u1 and u2 introduce the beneficial genotypes Ab or aB, with a mutation bias favoring aB with magnitude B = u2 / u1 and with a greater fitness advantage (here, 2-fold) favoring Ab. The lines in the plot below all go up from left to right, indicating that the bias in outcomes (frequency of evolving aB relative to Ab) increases with the bias in mutation. The smaller populations show the degree of bias expected under origin-fixation dynamics (dashed line).

A distinctive prediction of this theory is that the influence of mutation biases does not require neutrality or high mutation rates (contra Haldane 1927), but will emerge (under the right conditions) from biases in ordinary types of nucleotide mutations, e.g., transition-transversion bias. This effect has been demonstrated conclusively in the past few years in both laboratory adaptation and in cases of natural adaptation (in diverse taxa) traced to the molecular level (for review, see Gomez, et al. 2020 or Stoltzfus, 2019).

[Figure legend: The observed transition-transversion ratio among parallel adaptive changes is significantly higher than the null 1:2 ratio (Stoltzfus and McCandlish, 2017). This pattern is consistent with the theory of biases in the introduction process, but not with the mutation pressure theory of Haldane and Fisher.]

Thus, a causal link between tendencies of variation and tendencies of evolution is theoretically possible and is actually observed. This result refutes a key argument from the mid-20th-century orthodoxy: internalist theories that attempt to link evolutionary tendencies to internal tendencies of variation are not inherently incompatible with Mendelian population genetics, but only with the SGFT (see note 2).


So far, we have established that the Haldane-Fisher argument is unsound theoretically, and that its conclusion is contradicted empirically. Haldane’s (1927) conclusion, even when considered narrowly, does not provide correct guidance for reasoning about evolution, e.g., when we see mutational patterns in molecular evolution, we cannot assume that this must reflect high mutation rates or neutral evolution. And the broad application of the Haldane-Fisher argument as a cudgel against internalism is crazy wrong.

Yet, in regard to the structure of evolutionary thought, much intellectual work will be required to reverse the damage done by this influential fallacy. Evolutionary discourse has proceeded through a century of theory development and exploratory thinking subject to the constraints that (1) a workable theory of biases in the introduction process was unknown to its major participants, and (2) the Haldane-Fisher argument placed a large “Do Not Enter” sign on the door leading to internalist thinking. This is a disturbing thought.

Do Not Enter Traffic Signs | Seton

This limitation was not known, for instance, in the 1980s, when the Modern Synthesis was being challenged on various fronts (molecular evolution, macroevolution, evo-devo), and reformers were exploring new ways of thinking. Gould and Lewontin did not know it in 1979, when they wrote their famous critique of adaptationist thinking. Maynard Smith, et al. did not know it in 1985 when they wrote about “developmental constraints.” Kauffman did not know it in 1993 when, in The Origins of Order, he invoked “self-organization” to explain the findability of structures that are common in genetic state-spaces.

Yet all 3 sources are widely cited and have been influential — evidence of widespread hunger for internalist or structuralist alternatives to neo-Darwinism.

What happened, and what didn’t happen, because of this “do not enter” sign?

In the “spandrels” paper, Gould and Lewontin (1979) eviscerated the adaptationist research program, but their arguments for alternatives to natural selection were unconvincing. Twenty years later, at the close of his career, Gould (2002) cited the Haldane-Fisher argument and wrote (as quoted above) that “empirical data on low mutation rates sound the death-knell of internalism” (p. 510).  What if Gould had known all along that this argument is mistaken?

Maynard Smith, et al. (1985), in their seminal piece on “developmental constraints,” noted explicitly that the Haldane-Fisher argument posed a barrier to the proposed efficacy of developmental biases in variation. If a theory of biases in the introduction process had existed in 1985, Maynard Smith, et al. could have used it to refute the Haldane-Fisher argument, and to justify their claims regarding developmental effects, yet their foundational statement offers no general answer to the crucial problem of lacking a valid population-genetic basis (in the highlighted passage, they go on to suggest neutral evolution, obviously not an adequate foundation to address evo-devo concerns).

Accordingly, Reeve and Sherman (1993), in their subsequent defense of the adaptationist program, cited Gould and Lewontin as well as Maynard Smith, et al. (1985) and complained that the advocates of developmental constraint had offered no evolutionary mechanism. They called on the logic of the Haldane-Fisher argument when they ask, rhetorically, “why couldn’t selection suppress an ‘easily generated physicochemical process’ if the latter were disfavored?” Decades later, the notion of developmental constraint remains a flexible explanatory concept not tied to a specific evolutionary mechanism (see Green and Jones, 2016).

In the discourse of developmentalists, the lack of a population-genetic mechanism for this effect has led to an exploration of alternative views of causation. That is, developmentalist-structuralist thinkers ignored the “do not enter” sign and continued to assume that internal factors actually matter in evolution. Yet, because classical population genetics did not seem to provide a causal basis for this intuition, they concluded that population genetics has some kind of metaphysical limitation that makes it inadequate as the basis for complete causal theories.

That is, due to the influence of the SGF paradigm, population genetics is widely accepted as the language of causation in evolution, e.g., Dobzhansky (1937) declared that “Since evolution is a change in the genetic composition of populations, the mechanisms of evolution constitute problems of population genetics.”   Yet, by the Haldane-Fisher argument, population-genetics rules out a dispositional role for internal variational factors. This has led internalist thinkers to suspect that something about population genetics makes it inadequate to construct complete accounts of evolutionary change.

“intellectually respectable evolutionary theorizing must be based on population genetics theory, which forms the substantive core of the relevant evolutionary theory.”

Sarkar (2014)

The causal completeness argument (Amundson, 2001, 2005) is a formalization of this complaint against population genetics. Because phenotypes exist and they are the stuff of evolution, an account of evolutionary causation that refers only to population genetics cannot be complete: development must fit in, somewhere, in a causal role. One way to integrate this role is to suggest that a full account of evolution must combine (1) the usual dry population-genetic account of causation by forces with (2) an alternative narrative of wet biological changes in development (e.g., Wilkins, 1998). This completes the causal account of evolution by supplementing standard forces with a kind of “lineage explanation” per Calcott (2009). In lineage explanation, the focus is on constructing a developmental-genetically plausible narrative for changes in a lineage over evolutionary time, as opposed to a focus on individual development over a lifetime, or on population genetics over evolutionary time.

The problem of a missing causal foundation manifests differently in the (completely separate) literature of molecular evolvability or self-organization following on Kauffman (1993). Kauffman sought to explain why certain features or forms emerge commonly by evolutionary processes, even without being selected.

A possible causal explanation emerges from the fact that the structures that are more common in genetic state-space, e.g., RNA folds that have more possible sequences, necessarily have more mutational arrows pointed at them, including from other parts of state-space.

We might be tempted to suggest that this fact alone explains the findability of common structures, but this only tells us that a mutational bias exists — how such a bias influences evolution is a separate issue that requires a population-genetic theory linking tendencies of mutation to tendencies of evolution.

To grasp this point more clearly, think of Sober’s (1984) distinction of “source laws” and “consequence laws” of selection. Population genetics tells us how to compute what will happen in a population if A and B differ in fitness by some amount such as 2 %, given some background conditions including a scheme of heredity. That is, population genetics covers the consequence laws of selection. But it doesn’t tell where the differences in fitness come from, i.e., how they emerge biologically. For that, we need the source laws of selection, which come from physiology and ecology and so on.

Likewise, a complete causal theory for a variational influence would require both source laws that address how the variational tendencies emerge, and consequence laws that address their impact on evolution. As noted above, Maynard Smith, et al. (1985) drew attention to the source laws for developmental tendencies of variation, but failed to supply a consequence law linking those to measurable evolutionary effects.

More generally, in the evo-devo literature, the focus is on developmental source laws, and the issue of consequence laws is often not identifiable (e.g., Salazar-Ciudad, 2021), so that the assumption that tendencies of variation must somehow cause evolutionary tendencies is wholly implicit.

By contrast, for more traditionally minded evolutionary geneticists, the issue raised by evo-devo is precisely this alleged causal link between developmental biases and evolutionary ones, a link that is considered problematic and unlikely. For instance, in “Mutation predicts 40 million years of fly wing evolution,” Houle, et al. (2017) have done perhaps the finest and most rigorous work to date showing a detailed quantitative correlation between (1) measured tendencies of varigenesis, i.e., new phenotypic variation M, and (2) measured patterns of evolutionary divergence R. This seemed to resolve 40 years of debate over the evo-devo claim that developmental biases influence evolution, an argument that was always based far too much on developmental models of variation, instead of actual measurements of mutational variability. But the authors themselves take an attitude of utmost skepticism and deny that their results demonstrate a causal link from M to R.

When we are considering discrete traits, the Haldane-Fisher argument provides the consequence laws for biases in variation under the SGFT. Mutation is a weak force because mutation rates are small. Therefore, tendencies of mutation cannot be difference-makers in evolution, except in the case of neutral characters or unusually high mutation rates (Haldane, 1927).

Today, however, we can reject the SGFT and the Haldane-Fisher argument, and instead invoke the mutationist dynamics of origin-fixation models (for instance) to propose that the joint probability of origin-and-fixation of common structures (i.e., common in abstract genotype-spaces) is higher because their probability of mutational origin is higher. In this way, we can specify a complete chain of causation linking (1) a source law specifying that common structures have more mutational arrows pointed at them, with (2) a consequence law specifying that biases in the mutational introduction of alternative structures impose a bias on evolution (dependent on population-genetic conditions). Note that the consequence law comes from population genetics but the source law does not: it comes from a model for how RNAs develop a phenotype (i.e., how they fold into a shape), and then mapping the phenotypes (shapes) to genotype space.

But this kind of reasoning did not exist in 1993, and few scientists know about it today. Thus, proponents of effects of findability describe it in other ways, e.g., Kauffman invoked “self-organization.” The general response of evolutionary geneticists to Kauffman’s work was that he clearly had some fascinating results, but it was not clear how relevant they were (given the abstractness of the models), or what they said about evolutionary causes. Kauffman repeatedly said that selection and “self-organization” worked together, in a partnership. But Kauffman was not calling on the usual list of evolutionary forces that shift allele frequencies to give a mechanistic account of self-organization, so we had no way to evaluate the causal status of this partnership. One reviewer called his references to self-organization “almost magical” (Fox, 1993).

In other parts of the contemporary literature on molecular evolvability, the effects of proximity and cardinality (of connected phenotype networks in genotype-space) that, in the above interpretation, are mediated by biases in the introduction process, are described as an effect of background conditions, as “constraints” emerging from properties of fitness landscapes (e.g., here), rather than being described in terms of causal forces.

[Figure legend: Frequency vs. rank for the most common types of RNA folds of 100-nt sequences (from Dingle, et al, 2021). The circled folds are the ones found in nature. Thus, natural evolutionary processes discover the folds that are most common in sequence space. ]

In this way, the findability phenomenon is presented as something related to the complexity of the space in which evolution happens, i.e., patterns emerge, not due to any particular evolutionary force, but due to the unavoidable geography of the state-space for evolution. Yet the dependence of findability on the way that this state-space is sampled by mutation, leading to biases in the introduction process (Stoltzfus, 2012), is shown by Schaaper and Louis (2014). They refer to this effect as the “arrival of the frequent” or as “phenotype bias.” Likewise, Dingle, et al (2020) show that the findability effect disappears when sampling compensates for the differing cardinality of structures in sequence space.

A causal grounding for internalism

“What the world most needs, then, is not a good five-cent cigar, but a workable — and correct — theory of orthogenesis.”

(Shull, 1935)

Thus, the central barrier to establishing a causal grounding for internalist thinking in evolutionary biology is that the prevailing theory of causal forces is grounded specifically in a limited conception of evolutionary genetics (the SGF paradigm), rather than in a more general conception that implicates events of introduction. A more general conception of causation would include causes that are not formally population-genetic forces.

What are the classical forces? In the conception of causation grounded in the SGFT, a causal force is a mass-action pressure modeled after the pressures of statistical physics, i.e., a pressure is a pressure on allele frequencies, and it results from aggregating over the effects of innumerable events among the individual member organisms of a population (see Sober, 1984). Selection and drift result from the aggregate effects of innumerable births and deaths. The force of mutation is mutation pressure, the aggregate effect of innumerable events of mutational conversion in different individuals.

Note that, just as statistical physics is not a reductionist theory, the SGFT is simply not a reductionist theory, in the sense of pushing the fundamental basis of reality or causation down to the lowest possible level. The SGFT clearly posits an emergent population “level”, and the architects of the Modern Synthesis argued explicitly that the forces of evolution are emergent at the population level, and do not exist at the more reduced level of individual organisms. For instance, in their textbook, Dobzhansky, et al (1977) write

Each unitary random variation is therefore of little consequence, and may be compared to random movements of molecules within a gas or liquid.  Directional movements of air or water can be produced only by forces that act at a much broader level than the movements of individual molecules, e.g., differences in air pressure, which produce wind, or differences in slope, which produce stream currents.  In an analogous fashion, the directional force of evolution, natural selection, acts on the basis of conditions existing at the broad level of the environment as it affects populations. (p. 6)

The correct association of the concept of reduction, in regard to the role of population genetics in the Modern Synthesis, has to do with theory reduction. The Modern Synthesis clearly takes a set of recognized high-level phenomena of evolution, primarily the phenomenon of adaptation, and attributes them to the consequences of a set of underlying causal processes. The phenomenology is reduced to the operation of causes in this way.

The particular conception of an emergent population force (in the SGFT) means that an individual event of mutation that introduces a new allele does not satisfy the definition of an evolutionary cause. It is a proximate cause, in the language of Mayr. Likewise, the development of an individual is a proximate cause.

A casual way to state the consequences of this limitation is that the prevailing theory of causal forces used in evolutionary reasoning works well for causes of fixation but not for causes of origination, yet a full account of evolutionary causation requires that both origination and fixation are treated as change-making causal processes with explicit dynamics.

Thus, the flaw in the forces theory is exactly the same thing as the flaw in the SGFT. The sufficiency of the SGFT depends on evolution remaining in the topological interior of the relevant allele-frequency space, where all frequencies are non-zero. In this topological interior, all of the classical forces are identical in the sense that each force can change a frequency f to f + δ, where δ is an infinitesimal. A change from f = 0.5000 to 0.5001 can happen by any force, although a shift of 1 part in 5,000 is a large shift for mutation because mutation rates are so small. A process that causes larger shifts is a stronger force. Mutation is a very weak force.

In this way, the scheme of “forces” achieves generality by a common currency of causation, infinitesimal mass-action shifts in frequency. In the interior of the state-space for evolution (in the SGFT), any infinitesimal change, anywhere in the space, can happen by any force. This means that we can chain together any series of infinitesimal changes into a trajectory, and this trajectory can (in principle) be caused by any force, or by any combination of forces.

But the logic of forces falls apart if we consider movement from the surface (edge) of an allele-frequency space into the interior. In the left figure below, we have a small shift from the center of a 2-dimensional allele-frequency space (0.5000, 0.5000) to (0.5002, 0.5004). This could be caused by selection, drift or mutation, or by any combination of them, although again, a shift this large is enormous for mutation alone, and would not normally happen in one or a few generations. In the right figure, this same change in frequencies is moved down to the horizontal axis, i.e., the shift is now from (0.5000, 0) to (0.5002, 0.0005). This is the same shift mathematically, but not evolutionarily, because mutation is absolutely required to cause a shift upward from 0.

The logic of forces breaks down because the impact of the biological process of mutation is weaker than every other force in the interior of an allele-frequency space, but infinitely stronger than every other force at the surfaces, where it acts by discrete events, not continuous shifts. This is qualitatively different causal behavior. When an evolutionary process includes discrete events of introduction that jump an evolving system off of the surface of an allele-frequency space into the interior (where the forces of selection and drift operate), mass-action pressures are not a sufficient guide to causation.

This argument might sound very abstract, thus not relevant to practical evolutionary reasoning. Yet, anyone who saw how the evo-devo challenge played out in the 1980s and 1990s knows that abstract arguments about what qualifies as a true evolutionary cause (i.e, not development) have been deployed with great effect against claims of novelty from evo-devo. For instance, Wallace (1986) asks whether embryologists can contribute to understanding evolutionary mechanisms, and then answers negatively, arguing that “problems concerned with the orderly development of the individual are unrelated to those of the evolution of organisms through time.”

“If we are to understand evolution, we must remember that it is a process which occurs in populations, not in individuals.  Individual animals may dig, swim, climb or gallop, and they also develop, but they do not evolve.  To attempt an explanation of evolution in terms of the development of individuals is to commit precisely that error of misplaced reductionism of which geneticists are sometimes accused” (Maynard Smith, 1983, p. 45).

“I must have read in the last two years, four or five papers and one book on development and evolution.  Now development, the decoding of the genetic program, is clearly a matter of proximate causations.  Evolution, equally clearly, is a matter of evolutionary causations.  And yet, in all these papers and that book, the two kinds of causations were hopelessly mixed up.” (Mayr, 1994) 

“No principle of population genetics has been overturned by an observation in molecular, cellular, or developmental biology, nor has any novel mechanism of evolution been revealed by such fields.” (Lynch, 2007)

To escape this kind of smack-down from powerful scientists whose judgments continue to guide the field, presumptive causal arguments from evo-devo, or from any other sub-field in evolutionary biology, must refer to the forces of population genetics, because the statistical forces theory is the only accepted theory for what constitutes a genuine evolutionary cause.

But if events of introduction are evolutionary causes, and biases in the introduction process are causes of evolutionary bias, then

  • events of mutation can be evolutionary causes,
  • events of mutation-and-altered-development that introduce new phenotypes can be evolutionary causes, and
  • mutational and developmental biases in the generation of variation can be evolutionary causes.

In particular, when the introduction process is recognized as causal, this allows us to specify a formal locale of causation in which to recast the plausibility arguments in lineage explanation into arguments about the developmental factors that induce biases in the introduction process.

That is, this kind of causal grounding for internalist thinking does not repudiate the familiar elements of population genetics or supplement them with a parallel plane of developmental causation, but instead is based on (1) pointing to the part of mathematical theory covering the introduction process, which already exists and is currently in active development, (2) taking into account what we now know about the powerful influence of this qualitatively distinct process on the observed course of evolution, and the theoretically expected course, and finally (3) insisting that we must locate a cause in this part of population genetics, i.e., we must declare that the introduction (origination) process is a genuine cause, a change-making causal process with propensities that must be treated explicitly (again, see note 2).

To be perfectly clear, the necessity of doing this, justifying the use of “must” in the previous paragraph, is that the evidence (see Payne, et al 2022, Gomez, et al. 2020 or Stoltzfus, 2019) compels us to recognize that the dynamics of mutational introduction are profoundly consequential, and our theorizing suggests that a far broader role is inevitable. The notion that we can treat evolution as shifting gene frequencies, without directly involving the dynamics of introduction, is untenable, and the required correction to our conception of causation is to recognize the introduction process (mutational or otherwise) as something that must be treated explicitly as a cause in order to get evolution right.

To the extent that the term “population genetics” is associated with the SGF paradigm of the population as a cohesive emergent entity subject to causal displacement only via the classical mass-action forces, this expanded framework to account for evolutionary change is not population genetics because it breaks the SGF paradigm, i.e., we could choose to avoid the term “population genetics” and use a broader term like “evolutionary genetics.” However, this is just a question of labels. What is important to understand is that, regardless of the labels, we are breaking historical precedent and departing from the SGF paradigm in a way that induces new rules: integrating the introduction process induces qualitatively different behavior that explicitly contradicts the implications of population-genetic causation as it was understood (for instance) by Haldane and Fisher.

[The last 3 paragraphs are worth re-reading. ]

From the beginning, critics of Darwin’s thinking have objected that selection does not create anything new, and that the theory is therefore missing something fundamental. Darwin’s followers developed several well known responses to this objection, justifying the creativity of selection (see Ch. 6 of Stoltzfus, 2021). One of them is essentially that there is infinitesimal variation in every trait, and selection can leverage that diversity to create novelty solely by quantitative shifts. In a world consisting of a fixed set of continuous quantities (e.g., quantitative genetics), this is abstractly true. Another response is that selection is creative in the sense of bringing together rare combinations out of the diversity of the gene pool. This is also true, in a sense that depends on presuming mechanisms of recombination. Another argument is that selection can accrue effects in a particular direction, consistently, over long periods of time. This, too, is clearly true.

And yet, these hand-waving arguments that focus on justifying the creativity of selection do not suffice to address the issue of initiative or dynamics that arises if we attempt to give a dynamically sufficient account of evolution, i.e., if we address evolution explicitly as a process of change. The fundamental problem is that we cannot get the dynamics of evolution right without representing discrete events of the introduction of novelty by mutation-and-altered-development. We must recognize the introduction process as a genuine evolutionary cause.

Once we have added this vital piece of conceptual infrastructure, it then becomes possible to build a larger framework for causal theories. By appealing directly to the introduction process as an alternative type of causation, we can specify complete chains of causation from internal features that determine mutational and developmental propensities of variation, to quantifiable evolutionary behavior, via the population-genetic consequences of biases in the introduction process.

Let us briefly consider how to utilize the concept of biases in the introduction process (as a genuine cause of evolutionary orientation or direction) to specify a causal grounding for 3 historic themes of internalist thinking:

  • Taxon-specific propensities
  • Intrinsically likely forms
  • Directional trends

The first step is to make the transition from mutation biases and nucleotide-level effects to phenotypes. Let varigenesis cover all of the processes involved in the generation of new variation, from mutation to altered phenotypic development, subject to any applicable conditions. In quantitative genetics, varigenesis is represented by the M matrix of variances and covariances for new phenotypic variation (see note 5). For a discrete phenotype-space, we may consider a vector of rates U, with one rate for each alternative phenotype.

In the original Yampolsky-Stoltzfus model, the mutation bias B is a ratio of two mutation rates u1 and u2 , and these are specific mutation rates from one genotype to another.

But when we turn our focus to phenotypes, we can simply redefine u1  and u2 in terms of alternative phenotypes. For instance, consider an example in the figure below, based on the genetic code, which is the genotype-phenotype (GP) map relating codon genotypes to amino acid phenotypes. The rate u1 represents Asp-to-Val and the rate u2 represents Asp-to-Glu, which implicates 2 different mutational paths. Therefore, even if all mutation rates are the same (no mutation bias), the GP map induces a 2-fold phenotypic bias favoring Asp-to-Glu.

To the extent that fitnesses depend only on the phenotype, the two mutational paths from Asp to Glu are identical and will behave as if this were 1 path with a 2-fold higher rate. In this way, all the same conclusions that apply to a B-fold bias in the Yampolsky-Stoltzfus model will also apply to a B-fold phenotypic bias in varigenesis. That is, a GP map such as the genetic code induces asymmetries in the introduction of alternative phenotypes.

The figure above right represents a precisely analogous idea that is common in the evo-devo literature, which is that some alternative phenotypes may be more likely (in varigenesis) because they implicate a larger number of mutationally accessible genotypes, i.e., genotypic neighbors in the GP map. Here, the 1-mutant neighborhood of a genotype encoding phenotype P0 includes 5 genotypes with phenotype P2, and only 1 with genotype P1. In this case, without any mutation bias per se, there is still a 5-fold phenotypic bias in varigenesis toward P2.

In general, the form of the above argument is to use the neighboring phenotypes implicated by a GP map to define equivalence classes of genotypes, so that we can aggregate mutation rates by equivalence class, with the result that the differential mutational accessibility of alternative phenotypes will emerge due to asymmetries in the GP map, even if all mutation rates are the same. That is, for a given starting genotype, a mutation spectrum at the genotypic level, together with a GP map, induces a description of potentialities or dispositions of phenotypic change in a developmental-genetic system, i.e., a description of varigenesis.

This provides a rigorous justification for the notion that each taxon, having a distinctive genotype and GP map, has an intrinsic evolutionary potential or inherited predisposition, due to propensities of varigenesis.

[Note: reactions at a phil-bio-circle presentation of this piece convince me that the above argument, in order to capture an essential aspect of evo-devo, needs to distinguish arbitrary encodings from other sources of asymmetry in the accessibility of neighboring phenotypes. The example based on the genetic code (above, left) illustrates asymmetries in accessibility that are induced by an abstract and arbitrary digital encoding of biology in the genetics of sequences. That is, the genetic code is a largely arbitrary mapping of triplet genotypes to amino acid phenotypes, and it induces a set of neighbor relationships that are arbitrarily different in degree of mutational connectivity. Why should Asp-to-Val be less connected than Asp-to-Glu? There is no direct biological explanation, e.g., this relationship does not emerge due to Asp and Val sharing biosynthesis pathways. I am well aware of the hypothesis that the genetic code is adaptively organized (see Stoltzfus and Yampolsky, 2009), but this is an indirect effect— calling on an evolutionary process of code changes over vast scales of time— and the effect-size is very small.

This asymmetry due to an arbitrary encoding does not smell right as a rationalization of evo-devo arguments, e.g., in structuralist evo-devo arguments per Newman, the propensities that are attributed to developmental systems reflect the emergent dynamic properties of materials such as cell layers, and not merely the details of an arbitrary encoding.

Nevertheless, the differences in these dynamic properties of materials induced by a change in genotype can be mapped to the discrete space of genotypes, and this mapping will induce asymmetries in accessibility that are subject to the same consequence laws as the asymmetries induced by an arbitrary encoding. Thus the example on the right above, with P1 and P2, is a better match to evo-devo if the relatively higher accessibility of P2 is an effect of development, e.g., the phenocopy effect, and not an effect of arbitrary genetic encoding. From the way the example is given above, we can’t really tell. However, the problem is resolved in the following section, to the extent that the RNA folding example below is precisely the right kind of example: the structure of a GP map, and the propinquity of phenotypes in genotype-space, reflects the self-organizing properties of RNAs, i.e., the folding propensities that arise as emergent properties of each specific RNA sequence. ]

Next, let’s consider the tradition of structuralist arguments to the effect that certain familiar structures or features commonly emerge in nature because they are, in some sense, intrinsically likely, i.e., because they are the most natural or easily generated states of the materials in question.

We already addressed the contemporary form of this argument per Kauffman, which has been made in regard to RNA folds, protein folds, regulatory network structures, and some features of tissue layers: the forms that are intrinsically likely are understood to be the forms that are common in genetic possibility-spaces, and the question of evolutionary causation is what evolutionary cause makes intrinsically likely forms evolutionarily likely.

In regard to RNA folds, the folds with the most sequences occupy the greatest volume in genotype space, thus they have the largest number of mutational arrows pointed at them, including the arrows pointed at them from other regions of genotype space (which is actually a function of surface area rather than volume or cardinality). This means they are more likely to be proposed, thus more likely to be proposed-and-accepted, by an evolutionary process that explores sequence space via mutation.

[Figure legend: Two effects of mutational phenotype accessibility emerge from the way that phenotype networks map to genetic state-spaces (in the figure, mutation only samples adjacent vertices and each network represents genotypes with the same phenotype or fold). The shorter-term effect of mutational accessibility is that, from P0, P2 is more accessible than P1. The longer-term effect is that P0, with more genotypes, has a larger contour length (or more generally, surface area), thus it has more mutational arrows pointed at it from other regions of state-space.]

Thus, it is possible to specify a rigorous causal grounding for the kind of structuralist argument that explains what is evolutionarily likely by referring to what is common in abstract possibility-spaces.

Next, consider the idea of long-term directional trends due to internal biases in variation. Classical thinking says that such trends are impossible, and that (except under the case of neutral evolution) selection is the sole source of direction in evolution. However, models of adaptive walks with protein-coding genes subject to GC or AT biases in mutation show that compositional trends are the predictable result of biases in the introduction process.

[Figure legend: Mean trajectories of simulated adaptive walks on a protein NK landscape (Stoltzfus 2006), where evolution is subject to AT:GC mutation bias of 1:10 (blue), 1:3 (brown), 1:1 (green), 3:1 (orange) or 10:1 (red). Proteins adapting under AT bias become enriched for amino acids with AT rich codons (FYMINK), and those adapting under GC bias become enriched for amino acids with GC-rich codons (GARP).]

Note that when we collapse evolutionary change down to 1 dimension, the result is that internal and external factors, if they do not coincide in direction, must clash in direction. This way of combining the two types of causes leads to a consideration of which force is stronger, and (given the “pressure” conception of forces) selection is assumed to be the winner of this zero-sum game. But for an evolutionary process operating in a high-dimensional space such as a protein fitness landscape, there are typically many ways to go up, i.e., many directions toward increased fitness, some of them more favored by mutation, and some less favored. As a result, the trajectory of adaptive evolution in a high-dimensional space may have components of direction that are due to fitness effects, and other components of direction that are due to internal variational biases.

Thus, it is possible to specify a rigorous causal grounding for the notion of trends due to internal biases, and we can use this theoretical foundation to rebut the false intuition, widespread in the literature, that strong selection must necessarily suppress the effect of internal tendencies of variation. The source of this intuition is unclear. Does it arise from conceptualizing selection as a governing agent? Is it based on treating evolution as some kind of zero-sum game in which any deviation from a selective ideal is considered a loss? Modeling tells us that, regardless of the source of this intuition, it is mistaken: the same mutation bias will make adaptation easier in some cases and harder in others, depending on circumstances, a point that is illustrated by Cano and Payne (2020) using empirical fitness landscapes.

To summarize, the paragraphs above outline a causal grounding for the classic internalist-structuralist themes of (1) taxon-specific propensities, (2) intrinsically likely forms and (3) directional trends. This is a broad argument but it is not infinitely broad, e.g., it does not propose a new “Synthesis” or try to capture every complaint of every reformer. To suggest this causal grounding does not mean that all past internalist statements are true or even that they are all theoretically possible. Many of these past claims could be stupid. What it means is that, for each of the three classic types of claims identified above, we can map the form of the claim onto a causal model that validates its logic. If we can map a specific internalist claim to a causal model of this form, then it becomes a substantive falsifiable hypothesis about internal causes that can be tested using whatever tools are available to test hypotheses.

“Adaptation has a known mechanism: natural selection acting on the genetics of populations … Thus we have a choice between a concrete factor with a known mechanism and the vagueness of inherent tendencies, vital urges, or cosmic goals, without known mechanism.” (Simpson, 1967, p. 159)

This means that we are in a different place than in 1967 when Simpson wrote the above passage dismissing the notion of internal trends. Simpson’s argument is invalid, and this is not because we have discovered vital urges or cosmic goals, but because we have reconsidered evolutionary genetics both in theory and in fact, and we have concluded that internal biases are a real possibility grounded in the theoretically and empirically demonstrated effects of biases in the introduction process. The influence of such biases is now in the “known mechanism” category, available to be applied in all areas of evolutionary research.

Distinguishing other theories and paradigms

Which theories are (or were) actually used in reasoning about the role of variation in evolution? What roles for variation have been considered explicitly in accounts of evolution? What kinds of reasoning do these theories support, as documented by recurrent and explicit claims in the evolutionary literature? Here are some:

  1. Variations emerged adaptively by effort, and were preserved, as per Lamarck
  2. Variation supplied indefinite raw materials that selection shaped into adaptations, as per Darwin.
  3. The mechanisms of development (and in some versions, the influence of conditions) imposed constraints on variation, setting limits on what is possible, as per Eimer (1898) or Oster and Alberch (1982)
  4. Mutation pressure drove allele frequencies under neutrality or high mutation rates, per Haldane (1927)
  5. New quantitative variation (M) contributed to standing variation (G) which, together with selection differentials (β), jointly determined (as ) the short-term rate and direction of multivariate change in quantitative characters (Lande and Arnold, 1983; see note 5).

Relative to these ideas, the theory of the efficacy of biases in the introduction process (as a cause of orientation or direction) is distinctive, i.e., it represents a 6th theory with distinctive and testable implications. The logic of the theory generates various outputs that are otherwise not known to be part of evolutionary reasoning. Indeed, one way to explore this distinctiveness is to use the rhetorical approach of crafting statements that the theory distinctively enables. Such statements can refer, not only to expected evolutionary behavior, but also to other theories, and to informal claims in the literature that may be supported or contradicted, like these:

  • Biases in the introduction of variation can impose biases on the course of evolution without requiring neutrality, high mutation rates, or absolute constraints
    • Thus, variational biases on the course of adaptation are possible.
    • The common assumption in the molecular evolution literature that mutational effects on evolution require or imply neutrality is mistaken
    • The Haldane-Fisher argument as expressed by Haldane (1927) or Fisher (1930), and as employed by authors such as Huxley, Ford, Gould, Maynard Smith, et al, does not provide correct reasoning about the potential impact of biases in varigenesis because it fails to cover biases in origination.
    • The joint dependence (that emerges under some conditions) of adaptive changes on fixation probability and chance of mutational introduction invites previously unimagined considerations of Berkson’s paradox
  • For moderate values of B, there are conditions (e.g., in the origin-fixation regime) under which a B-fold bias in the introduction of variants results in a B-fold bias in evolutionary change
  • Biases in mutational accessibility of alternative phenotypes represent a kind of developmental bias, and conditions exist under which this kind of developmental bias may influence evolution in the same way, i.e., by the same kind of population-genetic mechanism, as a mutational bias of the same magnitude
    • This result invalidates the historically important argument (by Mayr, Wallace and others) attempting to undermine causal claims of evo-devo on the grounds that development cannot be construed as an evolutionary cause.
  • Adaptive traverses of high-dimensional spaces can exhibit, simultaneously, components of direction that reflect fitness effects mediated by selection, and components that reflect biases in varigenesis mediated by the introduction process
    • This result invalidates a kind of informal logic (of selection as a governing force) suggesting that internal biases must come at an adaptive cost or that they somehow work against or impede selection
  • Systematic biases in the mutational introduction of phenotypic forms (due to their differing surface area in genotype-space) provide a possible population-genetic mechanism for the findability aspect of “self-organization” reported by Kauffman (1993) or the “phenotype bias” reported by Dingle, et al (2021).

The grounding for internalism that emerges from this theory does not map in a simple way to the current reformist literature in evolutionary biology, with its complaints about reductionism, calls for the “return of the organism,” and exploration of the diffuse EES-SET axis of dispute. I don’t see this as a problem: I see it as inevitable. Einstein said that “We can’t solve problems by using the same kind of thinking we used when we created them.” If we accept this logic, then it would be very unlikely for the solution to a long-standing conundrum to map in a neat and clear way to the terms and concepts people have been using all along. The argument here evokes a conflict with a specific aspect of classic thinking, a specific conception of causal forces as mass-action pressures that interferes with productive thinking about the role of generative processes in evolution.

Relative to the classic conception of evolutionary causes as population-level pressures on allele frequencies, the introduction process conflicts with the statistical pressure criterion, but not necessarily the population-level emergence criterion. The introduction process is arguably emergent at the population level: if a specific individual in state A1 mutates to state A2, this is clearly an event of mutation, but we cannot determine whether it is an event of introduction without examining the population of which the individual is a member, i.e., we can’t diagnose an introduction event except at the population level. Again, mutational introduction and mutational conversion are distinct: introduction is emergent at the population level (see note 7).

However, the introduction process is different from classical forces because it is not a deterministic mass-action pressure aggregating over the behavior of countless individual members of a population (see note 3). To characterize the introduction process as a cause is to put the focus on a probability distribution for events that reflect generative processes acting inside organisms. These processes are studied by mutation researchers and developmental biologists.

The main distinction from the “constraints” literature of evo-devo is the concern to specify complete chains of causation from internal features that determine propensities of variation, to quantifiable evolutionary behavior, via population genetics. As explained above, the typical approach in the evo-devo literature, following Maynard Smith, et al (1985), leaves a gap in this chain of causation, where the missing theory would explain how developmental propensities of varigenesis become evolutionary propensities. [Note that Maynard Smith et al did not ignore this issue, but they published a review without filling this gap, and then this review was cited by thousands of other sources.] In the evo-devo literature, efforts to reform thinking about causation typically focus on supplementing population-genetic causation with lineage explanation (Calcott, 2009), rather than rethinking population-genetic causation.

A crucial distinction from the “evolvability” literature and the more recent literature of “developmental bias” in the EES context is that the causal grounding for internalist thinking offered here does not, in any way whatsoever, presume or imply that variation is facilitated, contrary to the fatuous treatment by Svensson and Berger (2019). The literature has been (to my way of thinking) relentlessly confusing on the extent to which the distinctiveness of evo-devo, or the distinctiveness of evolvability claims, is presumed to rest on facilitated variation.

By contrast, the focus here is on consequence laws— consequence laws that apply whether or not any source laws exist that specify facilitated variation. For instance, it is not necessary to assume that the molecular bias for transition over transversion mutations is in some way beneficial (see Stoltzfus and Norris, 2015). The theory predicts an influence of transition bias on adaptation even when the mutation bias is perfectly orthogonal to fitness effects. The issue of whether varigenesis is dispositional in its effect on evolution can be adjudicated entirely separately from whether varigenesis is facilitated or whether organisms are surprisingly evolvable.

Of course, non-orthogonality is inevitable in a high-dimensional world. In the case of any real-world landscape, a mutational bias toward transitions (1) will tend to align the overall process of evolutionary exploration better (quantitatively) with beneficial trajectories, or (2) will tend to align it worse. The modeling study by Cano and Payne (2020) demonstrates this point using empirical fitness landscapes for binding sites.

Perhaps this will seem disappointing for those familiar with the literature of evolvability or the EES Front, where the idea that variation is facilitated, and that living systems are surprisingly “innovable,” is deeply entrenched. Where is the mojo of internalism if internal variational propensities are merely arbitrary and not an expression of the superior evolvability of naturally evolved systems?

Relative to this way of thinking, the proposal here is about learning to walk before trying to run: it emphasizes an issue that is logically prior. Perhaps variation is facilitated, but a dispositional evolutionary role for varigenesis is both the premise and the promise of this claim. It is the zero-order effect that necessarily underlies all possible higher-order effects pertaining to intrinsic variability.

In fact, the notion of taxon-specific propensities of variation that are merely dispositional without being facilitated is historically part of evo-devo, e.g., it was the explicit position of Maynard Smith, et al (1985) that developmental biases are arbitrary. Similarly, the primary argument of Alberch and Gale (1985) is that two different taxa (salamanders and frogs) tend to lose digits differently in evolution (pre- or post-axially) for internal reasons, i.e., they tend to be lost differently when development is perturbed: Alberch and Gale were not arguing that each taxon evolved a better way to lose digits, but merely a different way.


The notion that evolution may have tendencies that reflect internal tendencies of variation is an old idea (see note 4). Yet, evolutionary discourse has proceeded without any rigorous grounding for internalist thinking. In particular, the Haldane-Fisher argument appeared to undermine this kind of theory.

Nevertheless, a rigorous grounding for internalist thinking is possible, based on the theory of biases in the introduction process. The logic of this theory has been validated by mathematical and computer modeling. Empirical studies have shown a strong effect of ordinary mutation biases on the changes involved in adaptation, an effect that is expected under the theory but which is not possible under the mutation pressure theory of Haldane and Fisher.

The kinds of variational tendencies covered by the theory include (1) mutation biases such as transition-transversion bias, (2) local asymmetries induced by the properties of genotype-phenotype (GP) maps, which reflect both arbitrary encoding and the propensities of developmental systems, and (3) differences in findability and connectivity of phenotypic forms induced by broad features of the architecture of genetic spaces.

When this previously missing causal link is considered in the broader context of contemporary internalist arguments, it provides a way to specify complete chains of causation from internal tendencies of variation to quantifiable tendencies of evolution, integrated with the evolutionary genetics of populations, rationalizing key themes of internalist thinking: taxon-specific dispositions, directional trends, and intrinsically likely structures.

This argument is not infinitely broad. It does not purport to cover everything. However, it offers a broad alternative to neo-Darwinism, i.e., we can specify an alternative to neo-Darwinism that can be used to generate hypotheses that provide a causal grounding for common internalist themes— a complete grounding that extends from internal properties to quantifiable evolutionary tendencies, by way of the evolutionary genetics of populations. Because the theory is quantitative, it will be possible, ultimately, to make statements that compare the relative importance of internal factors influencing varigenesis with the importance of selection.


I thank Tobias Uller and members of the phil-bio-circle discussion group (particularly Stuart Newman, Alan Love and Sahotra Sarkar) for comments. NIST disclaimer. Charles R. Darwin, who is often credited with ghost-writing contemporary evolutionary work, did not plan, write, review, or contribute in any meaningful way to this manuscript.


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1. Classical population genetics does not ignore mutation or treat it solely as a background condition. In particular, classic work pays loads of attention to deleterious mutation pressure. That is, in the case of deleterious mutation pressure, mutation is often treated as a change-making causal process characterized by explicit dynamics. But we are not concerned here with deleterious mutation pressure. We are concerned with the novelty-introducing role of mutation, in situations where this role may lead to changes that are actually incorporated in long-term evolution.

2. We should not be surprised by the lack of generality of the Modern Synthesis, which was never intended to be a general framework, but was constructed deliberately to exclude certain broad classes of ideas. That is, the SGFT and the ideas of causation that emerged mid-century were constructed deliberately to rationalize a neo-Darwinian view and to make alternatives appear unreasonable or impossible, particularly the “mutationist” views of the early geneticists. To some extent, the position developed by Mayr and his cohort of influencers was less like an ordinary scientific theory — driven by the challenge of accounting for empirical patterns — and more like a rhetorical battleship with its guns aimed squarely at alternatives to neo-Darwinism.

In the contemporary literature, the “Synthesis” remains more of a rhetorical strategy than a scientific theory, but now the focus is purely defensive, aimed at developing a flexible rhetorical strategy to fight off calls for reform by shifting the goal-posts, rather than a strategy to vanquish rivals and establish pre-eminence. That is, contemporary defenses of the Synthesis represent a rhetorical posture of defending the fullness and authority of tradition against the claims of reformers, by anchoring all new developments in tradition. The common theme is still the TINA doctrine (There Is No Alternative) yet, whereas this originally meant that one closed and restrictive theory claimed victory and excluded all the others, now it means that one open and flexible tradition appropriates all valuable ideas and claims ownership of them. Unlike the case for an ordinary theory, no risk is allowed in the Synthesis portfolio, i.e., it is alleged to include only well founded claims and positions that are immune to falsification.

By contrast, Provine, in his 2001 re-issue of The Origins of Theoretical Population Genetics, said that the Modern Synthesis “came unraveled” in the 1980s. Because Provine construed the Synthesis orthodoxy mainly as a position on population genetics, he is most concerned with the breakdown of the SGFT and the rise of neutralism. That is, Provine is not associating the demise of the Synthesis with the paleontology challenge (1970s to 1980s) or the evo-devo challenge (1980s onward), but instead with a changing understanding of population genetics primarily due to the challenge from molecular evolution.

3. Note that the conception and use of forces is typically deterministic, e.g., Sober (1984) says that “In evolutionary theory, mutation and selection are treated as deterministic forces of evolution” whereas drift is treated stochastically.  Importantly, one may aggregate the effects of the introduction process over infinitely many loci, e.g., all the sites in a genome, and this makes it possible to speak in a technically correct way about a mass-action pressure, but it is a pressure of introduction. Many, many claims in the molecular evolution literature refer to “mutation pressure” (e.g., Lynch 2007) but do not make any sense unless we reinterpret them in terms of introduction pressure. But introduction pressure is a different kind of pressure from the classical forces, operating in a different field: it aggregates over sites or loci in a genome rather than over member organisms in a population. Because it is an entirely different kind of pressure, it has different implications (for more explanation, read this). It would be possible to articulate an alternative theory of forces for evolutionary behavior in a discrete space where the steps are origin-fixation steps (Pablo Razeto-Barry has an unpublished manuscript on this).

4. This old idea is sometimes called “orthogenesis,” but the relentless caricatures by traditional authorities (noted by Ulett, 2009) have given “orthogenesis” such a pejorative connotation that it is not useful to use the term. For a review of historic ideas about constraints or channeling of variation relatively untainted by Darwinian prejudices, see Popov (2009) or Ulett (2014).

5. I’m giving myself a pass to put evolutionary quantitative genetics (EQG) in the background here because foregrounding it would be confusing. The theory is fundamentally phenomenological rather than causal, in the sense that it was not built in a bottom-up way from mechanisms or causes, but specified in a top-down way by the constraint of flexibly capturing the measurable relations of certain important quantities. So, it is always difficult to fathom EQG in a discussion of causes, though clearly the original motivation was tied to a neo-Darwinian view of variation as raw materials, i.e., variation (passive object) as a material cause, not varigenesis (active process) as an agent with dispositional effects. Because raw materials are just raw materials, providing substance only and not form, the only meaningful question to ask about them is some version of “how much do I have?” But if variation is seen as a dynamic process operating in a multidimensional space, then we have lots of questions to ask, or (stated differently) lots of ways to parameterize it.

Apropos, EQG following on the multivariate generalization of Lande and Arnold (1983) is no longer strictly aligned with neo-Darwinism, but became a formalism with the (initially cryptic) potential to support more causally oriented theorizing with varigenesis as a dispositional factor in evolution via M, although quantitative geneticists themselves have no love for this idea, and it has only a limited scope because the entire framework has a limited scope. The framework, by original conception, only applies to quantitative traits with abundant infinitesimal variation, and the typical implementations treat dimensional heterogeneity but not directional bias. That is, varigenesis (M) represents a process that generates different amounts of abundant infinitesimal raw material in different multivariate dimensions. It can generate more variation along some dimension, but biases in one direction (along a dimension) are usually not considered, and when they are considered, they are not found to be important (except Xue, et al 2015 find support for directional trends in a quantitative character, albeit with a non-standard approach).

The ultimate point here is that EQG also provides a specific and rigorous theoretical grounding for internalist thinking, one that is taken very seriously by some leading thinkers (e.g., Thomas Hansen and Günter Wagner), but this grounding is of such limited utility that I’m finding it convenient to set aside for my purposes here, e.g., it doesn’t provide a way to rebut the Haldane-Fisher argument, to account for directional trends or mutation-biased adaptation, or to justify findability claims. However, I am open to being convinced, by someone who knows better, that EQG provides a broader causal grounding for internalism than I have suggested.

6. A folk theory of biases in the introduction process emerged in an odd place: the macroevolution debate of the 1970s and 1980s. The participants in this debate quickly reached a consensus that no new fundamental mechanisms were needed to account for macroevolution, only a hierarchical expansion of existing mechanisms, i.e., an expansion from the traditional level of a population of individuals, to all the levels in a hierarchy of populations (cells, individuals, species, higher taxa).

However, in the process of this expansion, some of the participants creatively misinterpreted traditional thinking. In particular, Vrba and Eldredge (1984) depicted evolution as a dual process of the introduction and reproductive sorting (by selection and drift) of variants, and they emphasized that evolutionary biases could emerge from either introduction or sorting. Based on this formula, they helpfully reinterpreted evo-devo statements (Rachootin and Thompson; Oster and Alberch) to mean that “bias in the introduction of phenotypic variation may be more important to directional phenotypic evolution than sorting by selection.” That is, their elegantly stated verbal theory (1) recognizes, as distinct phases of the evolutionary process, the production or introduction of variation, and the reproductive sorting of variation (by selection and drift), (2) in parallel, distinguishes biases in introduction from biases in sorting as alternative causes of evolutionary bias, and (3) generalizes this theory of dual causation to multiple levels of a hierarchy.

In this way, Vrba and Eldredge (1984) proposed a novel quasi-mutationist theory of evolution as a process of mutation proposes, sorting disposes. However, the theory lacked any model or formalization, so it was not possible to generate quantitative expectations or offer any proofs. Furthermore, participants in the macroevolution debate did not treat this as a radical proposal demanding validation, because it was presented (mistakenly) as merely a restatement of orthodoxy. That is, whereas Maynard Smith et al (1985) recognized the conflict between implicit evo-devo theories and classical population genetics— presumably because the authors included Maynard Smith, Lande and Kauffman (individuals with expertise in formal theory)—, Vrba and Eldredge did not. Their language continues to reverberate in the paleontology literature, but the issues of causation have never been clarified, to my knowledge.

(7) Here and elsewhere I refer to the introduction process in a general way, because it is a generally useful idea that goes beyond mutational origination. Various processes that we do not normally consider as mutation can introduce discrete genetic novelties, e.g., events of lateral transfer, inter-compartmental transfer, recombination, and endosymbiogenesis. Further, large classes of evolutionary processes feature dynamic dependence on events of introduction. In island biogeography, for instance, we can conceptualize a dual process of introduction (a gravid fly is blown to an island) and establishment (an immigrant fly gives rise to a persistent lineage on the island), such that biases in either stage would be effectual. Adaptive dynamics could be seen as a dual proposal-acceptance (introduction-invasion) process, subject to biases in introduction. Cases of cultural evolution such as the evolution of ideas or of language likewise could be treated with origin-fixation dynamics. Per Vrba and Eldredge (1984), the birth of a species is an event of introduction in a hierarchy of levels. I suspect that the origin-fixation formalism typically is not applied in these fields, although I have seen a case of its application to neologisms in language evolution.

In a discrete world, there is always an event that introduces something novel, i.e., an event that makes the step from a frequency of 0 to a frequency of 1/N. However, in the world of modeling, or perhaps in the physical world, there may be cases in which it is useful to define the introduction process as the transient of a continuous value as it departs from 0. Certainly one may foresee, for the case of evolutionary dynamics, conditions under which the dynamics of this departure from 0 are dominated by the contribution of mutation from other alleles even when other processes are operating simultaneously (indeed, there was such a deterministic treatment in Yampolsky and Stoltzfus, 2001).

8. Traditionalists will certainly respond to this kind of claim by quote-mining the canon to find scraps that show Fisher and Haldane paying attention to some aspect of mutation or mutation rates, and objecting on this basis that of course Fisher and Haldane recognized the importance of new mutations or the rates of occurrence of beneficial mutations. However, our focus here is on scientific theories— not on people or vague suggestions—, and particularly on the theories that have shaped evolutionary discourse by being written down, formalized, shared, taught, and applied, i.e., theories and theory-based arguments that actually matter because they drive research, they are used in explanations, and they are used in arguments, e.g., certain Synthesis positions on causation (levels, types, forces) were used in the 1980s and 1990s to make evo-devo reformists sit down and shut up, i.e., these ideas of causation performed real work in evolutionary discourse, making them important. If Haldane secretly recanted his mutation pressure argument from 1927, 1932, and 1933, or if he offered an alternative mutationist theory in a later piece that had no influence, this is irrelevant both to science and (as a first approximation) to scientific history. Perhaps Haldane was secretly a mutationist. Perhaps he also was secretly a Christian and a capitalist. Who cares? Meanwhile, the Haldane-Fisher argument is a genuine argument used repeatedly in evolutionary discourse. It is not in any sense a straw-man argument: it is an argument that matters in a way that can be documented. So long as the canon defining the historical discourse on evolution includes sources like Fisher (1930), Huxley (1942) or Haldane (1932), the Haldane-Fisher argument is part of evolutionary thought, a documented and readily recognizable thread woven into the 20th century discourse on evolution.

A great deal of damage has been done in recent evolutionary discourse by the conflation of arguments about the novel scientific significance of an idea and the primarily cultural arguments that attempt to anchor the idea in tradition. A measure of the genuine scientific novelty of idea X in disciplinary matrix Y is the extent to which practitioners in Y would benefit from integrating X, or the extent to which they are currently reasoning incorrectly due to a lack of awareness of X. This has almost nothing to do with the ability to anchor X in the relevant historical canon, particularly if those who are practicing the art of back-projection have very low standards and are subject to confirmation bias, as is the case in evolutionary discourse. For instance, a press release regarding the demonstration of mutation-biased adaptation by Cano, et al 2022 makes this about “helping to return Darwin’s second scenario [of evolution by new mutations] to its rightful place in evolutionary theory.”

9. Apropos of note 8, the process of historical distortion through back-projection — the projection of contemporary views backwards onto intellectual progenitors — is evident in regard to Fisher’s geometric model, e.g., in Tenaillon (2014). The supplement to Stoltzfus (2017) explains this transmogrification, and Rockman (2012) makes essentially the same point in a footnote. Fisher’s original argument suited a deterministic world in which an allele is chosen by selection if it is beneficial, regardless of the degree of beneficiality, so that the problem of the size distribution of changes in evolution is solved completely by solving for the chance of beneficiality as a function of effect-size. A fully explicit version of Fisher’s argument would go like this:

  1. the population has a set X of alleles with some distribution of effect-sizes, whose presence is logically prior to selection, so that it implicitly reflects a generative process (in Fisher’s version, this is implicitly a random sample of mutation vectors in the geometric space),
  2. within X there is a subset X’ with s > 0,
  3. selection will choose every member of X’ deterministically,
  4. finally, the geometric model gives the chance that an allele is beneficial, i.e., is a member of X’, as a function of effect-size,

That is, the geometric model yields the chance that an allele is a member of the set that is chosen deterministically by selection. Kimura took the explicit part of this argument, the geometric model, and embedded it within a stochastic origin-fixation conception of evolution, so that effect-size of the benefit becomes important. That is, Kimura took proposition (3) and replaced it with “selection will choose from X’ in proportion to the chance of fixation” (e.g., 2s). Not only is this mutationist innovation contrary to Fisher’s thinking, it utterly changes the conclusion of the argument to favor intermediate-sized changes instead of infinitesimal ones. Yet, contemporary authors use “Fisher’s model” to describe Kimura’s model, and imply that Fisher shared Kimura’s mutationist conception of evolution but made a mistake or was confused about how to calculate the result. Again, see Stoltzfus (2017) or Rockman (2012).

10. Wright, in addition to invoking a continuous space of allele frequencies, also depicted a discrete space, a connected network of genotypic nodes. He claimed that the two representations were equivalent, which shows that he did not think this through very carefully. If we imagine a network of the 8 genotypes that form from combinations of alleles at 3 loci (each with 2 alleles), and we imagine the focal system being placed on one of these nodes in the network, we will get a completely different set of expectations about how evolution works than if we imagine the focal system as a point in the 3-dimensional space of allele frequencies. To make evolution in the discrete space act even remotely like evolution in the continuous one, we must instead distribute the probability density of the focal system over the entire discrete network.

Some thoughts on the conceptual immune system of the “Synthesis”

As noted in Bad Takes #3, there is a long tradition of dismissing internalist-structuralist thinking on the false grounds that such ideas are necessarily appeals to teleology or mystical inner urges. If an alternative theory can be dismissed in this manner a priori, as an absurdity, then no further effort is required: no complex theoretical modeling is required, no time-consuming experiments, and no difficult analyses of empirical data. Instead, one simply considers a caricature of the alternative theory, dismisses it as absurd, and goes back to assuming that selection is the ultimate source of meaning and explanation in biology.

Indeed, a key part of the conceptual immune system of the neo-Darwinian thought-collective is a series of facile arguments, each representing some type of excluded-middle or false-dilemma fallacy.

To reject thisArgue against this versionIgnoring this version
SaltationEvolution only takes leaps; new features must arise fully formedEvolution normally includes steps or jumps reflecting distinctive variations
CatastrophismThe emergence of key innovations or higher taxa requires catastrophes (revolutions)Non-normal catastrophes play a disproportionate role in major evolutionary episodes
MutationismEvolution is driven by mutation pressure without selectionThe timing and character of evolutionary change strongly reflects the timing and character of mutation events
OrthogenesisEvolution moves in a pre-determined straight line due to mystical inner urgesThe course of evolution strongly reflects mutational-developmental channeling of variation

In the long history of evolutionary thinking, one can find examples in which authors advocate, or seem to advocate, ideas in both the second and third columns. If our aim is to identify, explore and evaluate theories about how the world really works, we are naturally drawn to the best version of a theory, not the stupid version most easily knocked down by facile arguments, i.e., a genuine approach to scientific inquiry entails a focus on the third column.

However, if we want to understand how a thought-collective perpetuates itself decade after decade, we need to understand propaganda. Within the neo-Darwinian thought-collective, the focus is on arguments against the theories in the second column, used to reject what Dawkins calls the “doomed rivals” of neo-Darwinism. In Synthesis propaganda, these excluded-middle arguments are used to maintain the all-important TINA doctrine: There Is No Alternative.

In a healthy and diverse intellectual environment, excluded-middle fallacies have no power. However, the Synthesis created an intellectual monoculture. Within this monoculture, the labels for alternative views were repeatedly associated with bad ideas and subjected to ridicule, turning the labels into bogeymen (a bogeyman is an imaginary creature invoked by adults to scare children into compliance). Through ridicule and the fear of ridicule, the system inhibits alternative thinking and preserves the appearance, if not the substance, of a neo-Darwinian status quo. The conceptual immune system is working when gatekeepers use these terms to shut down debate, but the system also works via self-censorship: well meaning scientists, fearing they will be ridiculed as extremists— or merely fearing they will be misunderstood—, avoid using historically correct terminology like “saltation” or “mutationism” or “neo-Darwinism”, and avoid making accurate references to historic debates.


Orthogenesis appears to be the most successful bogeyman, e.g., the wikipedia page for Orthogenesis repeatedly misleads readers by suggesting that orthogenesis is intrinsically teleological or non-materialistic, in spite of the fact that the article cites, and even directly quotes, multiple scholarly sources that rebut this tendentious linkage. On the talk page, the main author refers bluntly to “God-directed evolution towards a preplanned final goal, which is what orthogenesis is about.” But this is not what orthogenesis is about. Scholarly sources cited in the article (Levit and Olsson; Ulett; Popov; Gould; Schrepfer) repeatedly identify orthogenesis as a general theory about directions that emerge from tendencies of variation, and indicate that the term has been used with a range of views from mystical and teleological to fully materialistic, with well known scientists like Cope or Eimer representing the more respectable materialistic versions. That is, historical scholars describe a general theory, but wikipedians under the influence of Synthesis culture sense that the reason the world needs a wikipedia article on orthogenesis is to serve the conceptual immune system of neo-Darwinism by documenting the foolishness of alternative views.

Self-censorship is well illustrated by scientists who reject gradualism but distance themselves from terms like “saltation” or “macromutation.” For instance, Arthur (2004), after making clear he is a saltationist, e.g., like Goldschmidt, reassures readers he wants to “make clear I am not a ‘saltationist’ like Goldschmidt” (p. 107). Orr and Coyne (1992) utterly ransacked the historic Synthesis case for gradualism yet they say this:

“We hasten to add, however, that we are not ‘macromutationists’ who believe that adaptations are nearly always based on major genes. The neo-Darwinian view could well be correct. It is almost certainly true, however, that some adaptations involve many genes of small effect and others involve major genes. The question we address is, How often does adaptation involve a major gene?”

But under natura non facit saltum, the answer to how often major-effect mutations contribute to adaptation is “almost never,” which (as Orr and Coyne already know) is incorrect. Note that one of the authors of Orr and Coyne (1992) went on to become the go-to defender of orthodoxy for science reporters (see below), and the other eventually went in the opposite direction, citing Bateson approvingly and dismissing gradualism as “little more than a mathematical convenience” (Orr, 2005). Maybe that is why the paper is at war with itself.

Svensson (2023) is deploying the conceptual immune system in the following passage:

Given the strong experimental and empirical evidence against directed mutations (Lenski and Mittler 1993; Futuyma 2017; Svensson and Berger 2019) and the failure of the early mutationists to appreciate the power of natural selection, it is astonishing that some contemporary evolutionary biologists are pushing for a revival of mutationism or mutation-driven evolution (Stoltzfus 2006; Nei 2013; Stoltzfus and Cable 2014). Mutationism was closely connected to the theory of orthogenesis…

Here Svensson encourages readers to join him in scoffing at scientists by linking them to 3 different bogeymen, none of which features in the cited works by Stoltzfus (2006), Nei 2013 and Stoltzfus and Cable (2014).[1] These authors all treat “mutationism” sympathetically, but none rejects the power of selection, e.g., the title of Stoltzfus (2006) is literally “Mutationism and the dual causation of evolutionary change”. None of these pieces invokes directed mutation or advocates what readers would recognize as orthogenesis (i.e., the excluded extreme): Svensson is simply fabricating links to two more bogeymen to increase the chances of ridicule. The piece by Stoltzfus and Cable (2014) is not science but a lengthy historical analysis that debunks the mutationism myth being employed by Svensson in the same sentence.

Importantly, the main clause in the first sentence above from Svensson does not refer to a scientific theory but to persons “pushing for revival.” That is, Svensson does not say that a scientific position is wrong, nor does Svensson express “astonishment” at an idea, but instead the author expresses astonishment at the behavior of persons, i.e., the grammar of the sentence indicates that this is an overt attempt at personal shaming. The “pushing for revival” rhetoric also misrepresents the 3 cited sources, e.g., here is the final paragraph of Stoltzfus (2006):

Nei clearly conceives of his own thinking as “neo-Mutationism”, i.e., something different from historic mutationism, and his main focus is on explaining new thinking and applying it to molecular evolution rather than engaging in historical debates. Stoltzfus and Cable (2014) argue, based on a scholarly analysis of the views of Morgan, Bateson, de Vries and Punnett, that contemporary thinking is closer to their ecumenical view than to neo-Darwinism, i.e., not pushing for revival but reporting on a retreat from a former orthodoxy, one that is easily documented (see The shift to mutationism is documented in our language).

Though the “pushing for revival” rhetoric is false and unscientific, it represents a skillful use of rhetoric by Svensson: he is directly tapping into the conceptual immune system, relying on the fact that his readers have been trained to respond with aversion to the words “mutationism”, “orthogenesis” and “directed mutation.”

Role in Synthesis tribalism

Sometimes, references to the strawman versions of non-Darwinian theories are not focused on ridiculing outsiders or doubters, but on rallying followers to align with their tribal identity. For instance, consider Futuyma (2015):

The seeming exclusivity of the ES [Evolutionary Synthesis] can be understood (and excused, if deemed necessary) only by appreciating the state of evolutionary discourse in the early twentieth century (see Simpson 1944; Rensch 1959; Bowler 1983; Reif et al. 2000). Darwinism was in “eclipse” (Huxley 1942; Bowler 1983), in that almost no biologists accepted natural selection as a significant agent of evolution. (The exceptions were chiefly some of the naturalists.)… Hugo de Vries and Thomas Hunt Morgan, founders of genetics, instead interpreted mutations as a sufficient cause of evolution… [omitted comments on Lamarckism and orthogenesis]… Those who today disparage the Evolutionary Synthesis as a constrained, dogmatic assertion that evolution consists only of natural selection on random genetic mutations within species must recognize that the authors of the Synthesis were responding to an almost complete repudiation of natural selection, adaptation, and coherent connection of macroevolution to these processes.

As an argument about scientific history, this is a chain of fallacies.[1] The first fallacy is that critics of neo-Darwinism such as de Vries and Morgan denied the agency and importance of selection, or that they accepted mutations as a sufficient basis of evolution. But let us suppose that critics of neo-Darwinism denied selection: how does that justify or explain the architects making selection all-important, the exclusive source of order and direction? Wouldn’t it have been wiser to counter the extremists with a more moderate position? That makes two fallacies. Now, set aside those two fallacies, i.e., suppose that critics denied selection and that this somehow justifies advocacy of an opposing extreme. Where does that leave us today? We now have a choice of two extreme theories, neither of which fits the evidence. The logical choice is to declare both of these dinosaurs extinct, right? Given that “excusing” is something we do for people not for theories, why does Futuyma make this a matter of literally “excusing” dead people? And given that we are called on to forgive, why does Futuyma conclude that we must direct out sympathy to one specific group of extremists rather than both?

Of course, the appeal of Futuyma’s rhetoric is based on tribalism, not logic. Synthesis Historiography tells us that, before the Great Synthesis unified the kingdom, bringing a period of peace and prosperity, there was an era of chaos and darkness called The Eclipse, when the light of Darwin was absent, with constant war between the tribes of Lamarckians, Darwinians, mutationists, orthogenesists and saltationists. In order to unify the kingdom and return the throne to the House of Darwin (the rightful rulers), the knights of the Synthesis had to purge the anti-Darwinians, who behave irrationally and hold views with obvious flaws. That is, the origin story for the Synthesis tribe has a historic battle in which the good guys use reason and evidence to beat the bad guys whose heads are full of nonsense.

In the passage quoted above, Futuyma is calling on the power of these shared cultural tropes, naming The Eclipse and all the classic bogeymen— Lamarckism, saltations, orthogenesis and mutationism— to remind tribal members which side they are on: the good guys fighting against the benighted enemies of Darwin and selection. Thus Futuyma skillfully manipulates in-group readers using a shared mythology, with arguments that will seem bizarrely illogical to an outsider.

Capturing the middle ground for Darwin

In most contexts, the system of false-dilemma arguments suffices to maintain ideological conformity and rally the faithful. However, sometimes there are doubters or rebels or merely ordinary scientists who stumble on an unorthodox result and wonder if there might be something of value in alternatives to neo-Darwinism.

In this case, gatekeepers must offer a more sophisticated argument. One common approach is appropriation: conceding some aspect of the alternative view, but describing it in different language, grounding it in familiar sources and associating it with illustrious ancestors, and insisting that this actually part of the mainstream tradition and is not the same thing as any historical alternative to neo-Darwinism.

For instance, when confronted with evidence that evolution may sometimes reflect developmental channeling of variation, the guardians of orthodoxy may admit that the evidence exists, but insist that it is not very compelling, that this is definitely not orthogenesis, and anyway, that this possibility was foreseen by Darwin’s apostles and disciples, therefore it is already part of tribal culture. Futuyma (2017) makes this type of appropriation argument, citing the following passage from Mayr:

“Every group of animals is ‘predisposed’ to vary in certain of its structures, and to be amazingly stable in others . . . Only part of these differences can be explained by the differences in selection pressures to which the organisms are exposed; the remainder are due to the developmental and evolutionary limitation set by the organisms’ genotype and its epigenetic system . . . the epigenotype sets severe limits to the phenotypic expression of such [random] mutations; it restricts the phenotypic potential. The understanding of this limitation facilitates the understanding of evolutionary parallelism and polyphyletic evolution.”

Mayr (1963) p. 608

A better historic source to cite for this idea would have been Eimer or indeed, dozens of other non-Darwinian scientists who advocated much more forcefully for a role of internal developmental biases. However, to cite Eimer would be to go outside the Synthesis tradition.

Mayr typically was disdainful of internalist theories and evo-devo— he said the developmentalists were “hopelessly confused” because they didn’t understand that development is just a proximate cause—, and he repeatedly invoked the contrary neo-Darwinian position that, because natural populations have infinite variability, when the same thing happens twice in evolution, this must be because it is the uniquely apt solution. In the above passage, Mayr appears to have gone off-script (his meaning is not precisely clear: one could interpret this as a statement about epistatic effects mediated by selection). However, Futuyma, (2017) is happy to accept the above statement as justification to fully appropriate developmental bias on behalf of the Synthesis tradition. He literally writes, “The idea that development can influence the direction of evolution was fully congenial to the architects of the ES.” Note that this is a statement about people and not about scientific theories, i.e., there is no explanation of how developmental bias follows from the shifting gene frequencies theory, or why Mayr was wrong to reject developmentalist arguments in the 1980s and 1990s. He does not even attempt such a theoretical reconciliation (for an attempt, see Amundson 2005 or Scholl and Pigliucci 2010). He quotes some people and declares on this basis that the case is closed. He is not defending any theory of causation, but defending the fullness and authority of tradition.

Even as a claim about tradition, the notion that the architects of the Modern Synthesis were “fully congenial” to the idea of internal dispositions is clearly false. For evo-devo people who fought for respectability against Synthesis gatekeepers, this must feel like gaslighting. Mayr is merely stating an idea in vague terms. He doesn’t actually use the key word “direction” in the cited passage, which is important (for those of us who think about these things) because it leaves open whether he is allowing directionally biased effects (more up than down) or merely dimensional effects (more trait 1 than 2). We can’t tell because this is just hand-waving and Mayr has not provided an explicit theory that would clarify such issues. When scientists are serious about an idea, they typically invest intellectual labor in exploring, applying, and defending an idea, clarifying their own thinking, and making important distinctions (e.g., think of how Simpson or Mayr developed terminology for modes of speciation or evolutionary rates). Did Mayr publish any research on internal dispositions? Did he inspire an evo-devo research program with his forceful advocacy of developmental bias? Did he offer a terminology to recognize different classes of bias? No, none of that. A more accurate description of historical sources would be that some of the architects toyed with orthogenesis-adjacent ideas while (more typically) advocating for the standard neo-Darwinian view that, because variation is abundant in all directions, systematic patterns reflect selection and not variation.

Let’s return to the issue of gradualism vs. saltationism. At one extreme is the position of natura non facit salta, i.e., nature does not take leaps. Thinkers such as Fisher and Darwin thought that, for practical purposes, all evolutionary changes are composed from infinitesimal effects. Darwin said that his theory would “absolutely break down” if any organ could not have been formed by a succession of infinitesimal changes. The intermediate position of historic saltationists such as Bateson and T.H. Huxley is that evolution has some jumps. The contrary extreme from gradualism, in which evolution is (for practical purposes) all large jumps, is found only as a strawman theory.

As explained in Why size matters, the gradualist position is not arbitrary for neo-Darwinism and other views that assume empirical adaptationism. If selection and variation are like the potter and the clay, with variation merely providing raw materials and selection providing shape and direction, then variation has to be composed of fine particles. If all change is small, it is possible to argue that selection governs evolution and can do anything, working from infinitesimal variation in every trait. But if evolutionary change comes in chunks, this immediately takes something out of the control of selection—the character and timing of discrete variations—, and then we need some kind of theory for the character and timing of variations in order to have a workable theory of evolution.

In other words, empirical adaptationism necessarily provokes theories of gradualism (in the sense of infinitesimalism). This is not just a logical conclusion, it is how scholars such as Beatty or Gould have reconstructed the actual development of Darwin’s thinking. Likewise, the empirical conclusion that saltations actually occur in evolution provokes the search for internalist theories that address the generation of non-infinitesimal variations. This is not just a logical conclusion, it is why Bateson cataloged distinctive variations in order to study evolution.

Darwin provided some early examples of the excluded-middle arguments outlined above. In his writings, he nearly always embellishes his case against discrete evolutionary steps by referring to them with dramatic language as “monstrosities”:

I reflected much on the chance of favorable monstrosities (i.e., great and sudden variations) arising. I have, of course, no objection to this, indeed it would be a great aid, but I did not allude [in OOS] to the subject for, after much labor, I could find nothing which satisfied me of the probability of such occurrences. There seems to me in almost every case too much, too complex, and too beautiful adaptation, in every structure, to believe in its sudden production.

Why “great and sudden”? Why not “modest”? Why not “medium-sized and sudden”? Describing saltations in provocative and negative language is a common rhetorical trick, e.g., Wright associates them literally with “miracles”:

“From assisting Prof. Castle, I learned at firsthand the efficacy of mass selection in changing permanently a character subject merely to quantitative variability. Because of this and a distaste for miracles in science, I started with full acceptance of Darwin’s contention that evolution depends mainly on quantitative variability rather than on favorable major mutations. ” (Wright S. 1978. The Relation Of Livestock Breeding To Theories Of Evolution. Journal Of Animal Science 46:1192-200.)

Note that Wright misrepresents Darwin’s position as calling for “mainly” rather than exclusively quantitative variability, i.e., natura non facit saltum.

This reliance on strawman arguments and misdirection sometimes makes it difficult to determine what Darwin’s followers actually believe. Clearly they are against monstrosities, but how large of a non-monstrosity will they tolerate? Clearly Wright is against miracles and for quantitative variability, but what exactly does that mean? When gradualism fails, will he claim that there are no miracles and insist he was right all along?

Today the issue has been turned on its head. Saltationism is now the mainstream view, but “saltationism” is still presented as the straw-man theory that all evolutionary changes are dramatic leaps, or in which major taxon-defining traits must appear in a single step (e.g., Coyne). As we have seen, the contemporary scientists who conclude in favor of saltationism on empirical or theoretical grounds insist that they are not saltationists, and they sincerely hold the erroneous belief that they are aligned with Darwin and historical neo-Darwinism.

This is what happens when people absorb the TINA doctrine, i.e., they learn the lesson that neo-Darwinism is just what is reasonable, and all the alternatives are crazy, without learning neo-Darwinism as a substantive falsifiable position. Scientists are typically agile thinkers, great at making up rationalizations: if you train them to accept that gradualism is right, they will find some way to make it right, based on whatever assumptions and definitions yield the approved conclusion. For instance, note how the issue is framed by researchers cited by Chouard:

Many researchers have welcomed the return to favour of large-effect mutations and have resurrected Goldschmidt’s long reviled idea of the hopeful monster. But they can’t ignore the small-effect mutations. “We need much more data before the issue of large versus small can be settled”, says Coyne. Kingsley, like Coyne favours a middle-ground view, in which neither large- nor small-effect mutations are ruled out. “Our work has too often been portrayed as saying that Darwin was wrong” about big leaps in adaptation, he says. But in fact, none of the traits his group has studied is completely due to the effects of a single gene.

Instead of defending the all-small position of genuine neo-Darwinian gradualism, the traditionalists now defend the not-all-large (i.e., some-small) position that one “can’t ignore the small-effect mutations.”

Likewise, in response to Shapiro’s criticism that molecular saltations speak against Darwinism, Dean (2012) objects thus:

His stance is patently unfair. Thomas Huxley famously criticized Darwin for championing too gradualist a view of phenotypic evolution. Today’s Darwinists accept Huxley’s criticism . . . Horizontal gene transfer, symbiotic genome fusions, massive genome restructuring (to remarkably little phenotypic effect in day lilies and muntjac deer), and dramatic phenotypic changes based on only a few amino acid replacements are just some of the supposedly non-Darwinian phenomena routinely studied by Darwinists.

Notice the charge of being “unfair.” Here the author has gone all the way to a purely cultural position on neo-Darwinism: there is no fixed scientific theory attached to the brand, only a cultural tradition consisting of people (Darwinians) whose beliefs may change at any time. If the right sort of people start studying saltations or invoking them, this makes saltations part of neo-Darwinism.


I could go on, but these examples should be sufficient to make the point about how the conceptual immune system works. Excluded-middle arguments based on ridicule are the first line of defense, but when scientists stumble upon the middle ground, traditionalists will claim it for tradition, even if this involves misrepresenting history and shifting the goal-posts. When apologists for tradition shift from merely rejecting strawmen to appropriating the excluded middle on behalf of tradition, this represents a genuine scientific shift that is masked by conservative rhetoric. Being able to see through the misleading rhetoric is a skill that can be learned. In the current climate of evolutionary discourse, it is a necessary skill.

Another necessary skill is courage. The secret power of the conceptual immune system is that the excluded-middle arguments rely on ridicule delivered by gatekeepers, and the aura of ridicule remains when scientists discover the excluded middle.[2] Scientists want to be respected, not ridiculed, by their peers: this threat is enough to cow most of them into voluntarily making the wrong association, in order to avoid disrespect. If you use terms like “saltation”, “orthogenesis” or “mutationism” positively (or invoke “neo-Darwinism” negatively) even if your usage is historically correct and accurate, this guarantees that you will be subjected to knee-jerk reactions of ridicule, or you will be accused of seeking attention using inflammatory rhetoric. Clearly the past generation of scientists was afraid of saying such words even when they are perfectly apt and reasonable.[3] I hope that current and future generations will not be so fearful.


  • Arthur W. 2004. Biased Embryos and Evolution. Cambridge: Cambridge University Press.
  • Dean (2012) Review of Evolution: a View from the 21st Century. Microbe Magazine (available via the wayback)
  • Gould SJ. 2002. The Structure of Evolutionary Theory. Cambridge, Massachusetts: Harvard University Press.
  • Levit GS, Olsson L. 2006. “Evolution on Rails”: Mechanisms and Levels of Orthogenesis. Annals for the History and Philosophy of Biology 11: 97-136.
  • Mayr E. 1963. Animal Species and Evolution. Cambridge, Massachusetts: Harvard University Press.
  • Orr HA, Coyne JA. 1992. The Genetics of Adaptation: A Reassessment. American Naturalist 140:725-742.
  • Popov I. 2009. The problem of constraints on variation, from Darwin to the present. Ludus Vitalis 17:201-220.
  • Ulett MA. 2014. Making the case for orthogenesis: The popularization of definitely directed evolution (1890–1926). Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences 45:124-132.


[1] For a takedown of this passage from Futuyma, see Stoltzfus (2017). Critics of neo-Darwinism typically objected to its two main vulnerabilities, natura non facit saltum and the dichotomy of roles in which selection is the potter and variation is the clay. In every alternative to neo-Darwinism, the variation-generating process plays a dispositional role. Note that, in attempting to understand what critics of neo-Darwinism believe, one must not mistake skepticism about the quality and rigor of selective explanations for doubts about the (in principle) power of selection. Bateson did not deny selection as a true cause responsible for adaptation, but he was so jaded he thought that selective explanations would always be inaccessible to scientific proof and would remain mere armchair speculation. Nei seems to have a similar position.

[2] Because ridicule is such a strong demotivator, maintaining conformity does not require a large class of aggressive gatekeepers a la Svensson. A little bit goes a long way. As explained in the introductory paragraphs, most people don’t need to be shamed directly to avoid thinking unorthodox thoughts, they will just do it on their own because, again, people want to be respected.

[3] Note that accurately depicting mutationism, neo-Darwinism, or other historic views does not require any special courage for historians or other scholars who are not striving for, and are not dependent on, the approval of mainstream Synthesis culture. Among mainstream evolutionary thinkers, Allen Orr has shown courage in quoting Bateson approvingly and in depicting gradualism correctly as an extreme position. Gould was unafraid to show sympathy to non-Darwinian thinking, but his sympathy seems more like pity when one notices how frequently Gould associates critics of neo-Darwinism (e.g., de Vries, Goldschmidt, Bateson) with behavioral disorders, reinforcing the Synthesis tribal mythology in which only crazy people reject neo-Darwinism.

Bad takes #2. Evolution by “mutation pressure”

Unfamiliar ideas are often mis-identified and mis-characterized. It takes time for a new idea to be sufficiently familiar that it can be debated meaningfully. We look forward to those more meaningful debates. Until then, fending off bad takes is the order of the day! See the Bad Takes Index.

In his equally entertaining and obnoxious piece “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 language suggests a process of population transformation by the mutational conversion of individuals, in contrast to population transformation by reproductive replacement.

That is, in a simplified world of discretely inherited types, we can imagine two general ways to transform a reproducing 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. Selection and drift are often listed as the two main causes of evolution, and they act by 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 (see image for a simulation).

A simulation of evolution by mutation pressure (from the mutation pressure page developed by John McDonald). N = 20 red squares at left represent individuals, with offspring generations going to the right. The reproductive variance is 0, so each individual leaves exactly 1 offspring in the next generation, inheriting the parental state or a mutated state with u = 0.025. By 100 generations, the population is mostly transformed, by mutational conversion alone, without reproductive differences.

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 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.

Evolution by mutation pressure according to Haldane and Fisher

In the broader context of evolutionary theorizing, the mutation pressure theory appears most prominently as a strawman rejected by Haldane (1927, 1932) and Fisher (1930). That is, Haldane and Fisher did not advocate the notion 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 might call “constraints” today. That is, the mutation pressure theory began as a dubious 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)

To understand what Haldane is doing, one must bear in mind that, in the neo-Darwinian tradition, selection is the model of an evolutionary cause: other factors or processes are considered to be causal only to the extent that they look like selection. What selection does is to shift frequencies (and ultimately drive alleles to fixation), so Darwin’s modern followers define evolution as shifting frequencies and they define causal forces as pressures that might cause fixation. In effect, Haldane equates the importance of mutation with the potential for mutation pressure to drive allele frequencies. In this way of thinking, if mutation-biased evolution is happening, this is because mutation is driving alleles to high frequency against the opposing pressure of selection, which leads to Haldane’s conclusion that either (1) the mutation rate has to be abnormally high, or (2) selection has to be practically absent (i.e., neutrality). Fisher’s (1930) reasoning was similar. 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 one would conclude from Haldane (1927), patterns of mutation bias in evolution generally do not indicate evolution by mutation pressure via high mutation rates, or via neutral characters. 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 for its role in an influential fallacy: generations of evolutionary thinkers believed wrongly that the mutation pressure theory proves mathematically that internalist theories are incompatible with population genetics.

Other theories

Now, with this background, we may return to Lynch’s bad take, associating various authors with mutation pressure as a driving force. 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 is not a model of evolution by mutation pressure in the classic sense of Haldane and Fisher and IMHO does not correspond to what any of the cited authors are trying to say.

To understand what the model tells us, we must analyze it in 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 (note how the classical mutation-selection balance of Haldane and Fisher is closely related to their argument about evolution by mutation pressure).

Lynch appears to reach a different solution 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. However, this result actually does not represent the equilibrium frequency of A1 in a population of individuals, as for Haldane-Fisher: instead, it refers to 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 relative genomic frequency of two synonymous codons like CAT and CAC encoding histidine, where one of the codons (let’s assume CAC) is slightly more favored by selection.

The two cases, classic and Lynch, correspond to the large-population and small-population approximations for the ratio of favored to disfavored codons in Bulmer’s (1991) mutation-selection-drift model. In a large deterministic population, each histidine codon is fixed for the favored synonym (CAC), yet the disfavored codon (CAT) is maintained at low frequency in mutation-selection balance per Haldane-Fisher. In the small population, each histidine codon is fixed for either the favored codon (CAC) or the disfavored codon (CAT), and the frequency distribution of fixed states for loci is determined by the balance of two origin-fixation rates. So, in either case, if the disfavored codon is expected a fraction f of the time, then f is also the expected frequency of that codon over an infinite genomic set of histidine sites.

Thus, 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 (sites). This origination pressure 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 this model ensures the presence of deleterious states for small values of S, but it is not clear what justifies Lynch’s framing of 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, Lynch ought to point the finger at drift (not mutation) as the reason for non-optimality.

In fact, this is all utterly misleading when taken in context. After telling the reader that the idea of evolution by mutation pressure is not new, Lynch continues as follows

The notion that mutation pressure can be a driving force in evolution is not new (6, 24–31), and the conditions that must be fulfilled if mutation is to alter the direction of evolution relative to adaptive expectations are readily derived.

This is a sweeping claim about mutation and directionality! Yet, what follows is not a general model of effects of mutation on the direction of evolutionary change, but Bulmer’s model featuring fixations of deleterious alleles! That is, Lynch refers generally to mutational effects altering the “direction” of evolution, yet apparently, given his Manichean worldview, “direction” is just a matter of down vs up in fitness. And we just established that drift, not mutation, is the cause of deleterious fixations, which will happen even if there is no mutation bias (e.g., the disfavored codon will sometimes be fixed, even without any mutation bias). In the end, Lynch has presented correct mathematical results, but framed these results in an incorrect way that can only lead to confusion.

Accordingly, Svensson (here or here) has repeatedly claimed, citing Lynch’s paper, that an effect of mutation bias on adaptation would require “drift in small populations.” This error arises from a literal reading of Lynch, who (1) conflates diverse ideas (including ours) under the heading of evolution by mutation pressure, and then (2) makes a sweeping reference to mutational effects on “direction.” However, as explained, the effect requiring small populations in Lynch’s model is the fixation of a slightly deleterious allele by drift in small populations, whereas arguments about mutation-biased adaptation do not involve fixations of deleterious alleles at all, e.g., the behavior of the Yampolsky-Stoltzfus model does not rely in any sense on the fixation of deleterious alleles by drift.

What is the cause of so much misapprehension? The molecular revolution induced profound changes in thinking that have not been properly processed. Instead, we have attempted to squeeze a new understanding into the same old vocabulary— using old words for new concepts. In some cases, the result is verbal violence, as in the way that “Darwinian adaptation” is now used for the lucky mutant view previously known as a non-Darwinian theory of pre-adaptation. Familiar words are now overloaded with different concepts, and we have not paid 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. The forces theory is inadequate, and leads scientists to incorrect conclusions, e.g., the assumption that mutation-biased evolution requires neutrality, which is pervasive in the literature.

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

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.


Biased gene conversion is a newly recognized population-genetic force, non-identical with mutation, selection, or recombination. BGC is a conversion mechanism, not a replacement mechanism, but the formula for BGC is A1 + A2 –> A2 + A2, whereas the mutation formula is A1 –> A2. Similarly, the crossing-over formula is A1B1 + A2B2 –> A1B2 + A2B1. Thus, although the molecular operation of gene conversion is associated with cross-overs and with the machinery for recombination, the genetic operation of BGC is not the same thing as recombination.

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

Unfamiliar ideas are often mis-identified and mis-characterized. It takes time for a new idea to be sufficiently familiar that it can be debated meaningfully. We look forward to those more meaningful debates. Until then, fending off bad takes is the order of the day! See the Bad Takes Index.

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, which are Yampolsky and Stoltzfus ( 2001), Stoltzfus (2006) and Stoltzfus and Cable (2014).

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 cases where it makes sense, e.g., loss of a complex character (for a more thorough explanation, 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 this (note the title):

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

Nor is this what Pennings, et al. (2022) mean when they clarify that “our study is focused on the dynamics of adaptation and reversal in the context of point mutation-driven, stepwise evolution, rather than evolution through horizontal gene transfer or plasmid conjugation”. Nor is this what Tenaillon (2014) means when he writes

“In particular, the long-term evolution of 12 replicate populations of Escherichia coli by R.E. Lenski unraveled a succession of mutation fixations that reached up to 10 % fitness effect (Lenski & Travisano 1994). Large effect mutations appeared therefore to be the drivers of adaptation.”

Furthermore, Svensson and Berger (2019) surely know that authors such as ourselves or Masatoshi Nei, a famous population geneticist, are not advocating fixation by mutation pressure rather than by selection (or drift). For instance, the equation from Yampolsky and Stoltzfus that they recreate in Box 1 is based explicitly on the probability of fixation for a beneficial allele given by Haldane (1927).

That is, Svensson and Berger are making what is called a “bad-faith argument”, an argument that they know is wrong but which they use anyway, trusting that the argument gain favor with naive readers.

One must remember that the piece by Svensson and Berger (2019) is not a serious scholarly analysis, but a parody of Bad Synthesis Apologetics, a Sokal’s hoax exposing that— when the topic is either post-modernist cultural analysis or the status of evolutionary theory— it is possible to “publish an article liberally salted with nonsense if (a) it sounded good and (b) it flattered the editors’ ideological preconceptions.”

With their cheeky “mutation-driven” objection, the authors are parodying the kind of bad-faith argument that does not address any genuine issue of 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 Svensson and Berger. It is a long-standing part of Synthesis culture to believe that critics of orthodoxy behave irrationally and hold views with obvious flaws.

If we take away this false pretense, the remaining issue is semantic: (1) does “mutation-driven” refer distinctively to the case in which mutation is a cause of allele fixation, i.e., the mutation pressure theory of evolution, or (2) does an additional meaning of “driving” exist that is more explanatory, justifying the use of “mutation-driven” for the case in which character and timing of evolutionary change depends on the character and the timing of mutations.

The issue is readily resolved by examining the usage of “drive” in evolutionary discourse. Does the literature of evolutionary biology restrict the “drive” language to causation only? The answer is clearly negative. Here is a tiny sample of recent uses from the technical literature:

Population size is clearly a condition, not a change-making causal process. Therefore, when our colleagues refer to population size “driving” something, this indicates an explanatory and not causal-mechanistic 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, based on a purely descriptive analysis of patterns, e.g., a statistical analysis, 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 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.

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 gibberish. I find many of these uses of “drive” to be unhelpful, especially when results could be described more clearly using causal language (but see below).

To summarize, in their parody of Synthesis sophistry, Erik and David cover the “mutation-driven” issue with a delightfully empty misrepresentation sandwich, layered with bogus arguments. 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 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 invoke mutation pressure as a cause of fixation (this is false for all 4 sources).

Finally, note that we are having this discussion about language precisely because our customary causal language is insufficient. 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. This theory of causes makes no distinction between shifts of a frequency from 0 to 1/N (or 1/(2N)) vs shifts among non-zero frequencies. When Haldane (1927) and Fisher (1930) addressed the potential for mutation-induced trends, they treated mutation as a cause of mass shifting and dismissed it as unimportant.

We have no other recognized causal language than statistical “forces” (“pressures”) at the population level. In particular, we have no recognized causal language for the effects of the introduction process: such effects are most often mis-described in terms of mutation pressure, or they are described indirectly or passively, as a matter of background conditions, or using the explanatory language of constraints or chance. 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. Because the introduction process is not like selection at all, it has not been recognized as a causal process.

Attempts to describe the role of mutation actively rather than passively, with strong verbs, are certain to provoke opposition from the reactionary elements parodied by Svensson and Berger (2019). As I have written elsewhere, this position is cultural, not scientific: the reactionaries are culturally rigid but scientifically flexible. They will accept saltations (non-infinitesimal changes, major-effect alleles) and orthogenesis (tendencies due to internal biases) if the evidence demands it, but they will never endorse the terms “saltation,” “internal biases in evolution” or “orthogenesis,” because this would reveal a heretical departure from tradition. They will not reject mutation-biased adaptation due to biases in the introduction process, but they will describe it with old words while referencing dead authorities, in order to anchor new concepts in traditional sources (see also Bad Takes #5).


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

Unfamiliar ideas are often mis-identified and mis-characterized. It takes time for a new idea to be sufficiently familiar that it can be debated meaningfully. We look forward to those more meaningful debates. Until then, fending off bad takes is the order of the day! See the Bad Takes Index.

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

Svensson and Berger (2019)— in an article that reads like a Sokal’s hoax of Bad Synthesis Apologetics— model all the stages of truth in the same paper: (1) they dismiss strawman versions (e.g., mutation as an independent cause of adaptation) as absurd (see Bad Takes #3 and Bad Takes #4), (2) they present a clumsy version of the theory but dispute the evidence and declare it implausible based on a list of fake theoretical restrictions, and (3) finally, implicitly admitting that the phenomenon is real and that the theory we proposed 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 patent absurdity to yesterday’s news.

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 ordinary textbook knowledge, so that these new 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.

[figure legend: A recent exploration of “contingency” by Wong (2019), revealing the lack of a precise meaning other than something vaguely to do with chanciness.]

Yet contingency is not a causal 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 have no need for a concept of contingency (an explanatory concept, not a cause of anything), but will directly addresses how the details of mutation rates influence the spectrum of adaptive substitutions.

Svensson and Berger have a bad habit of misrepresenting cited works. What do refs 31, 38 and 52 say? 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 mutators generate a lot of hitch-hikers in this experiment, so that the influence of mutators on the set of adaptive changes is not clearly established). Indeed, the presentation of results indicates in various places (e.g., the comments on parallelism) that Good et al are not paying attention to the issue of how mutation bias influences probabilities of beneficial changes.

What is going on here? Svensson and Berger (2019) seem intent on illustrating how to avoid 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 parallelism, 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. Rather than taking the opportunity to educate readers on the details of a new and exciting — but poorly known — body of work on mutation bias and molecular adaptation, i.e., the ostensible topic of their commentary, 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, Svensson and Berger (2019) illustrate how Synthesis apologists do not contemplate the practice of science in terms of falsifiable theories, precise reasoning, or the prospect of striking future discoveries, but are mainly concerned with crafting a narrative of tradition that integrates important people and flexible themes. They trivialize new work by assigning it to familiar and vague categories that make it seem ordinary, rather than mapping it to the specific issues that motivate it, make it significant, and raise unanswered questions for the future.

Model of Bell’s first telephone from 1875

To understand how this game works, consider a completely unrelated example, namely the invention of a telephone 150 years ago (image). The novelty-hating curmudgeon may object as follows: You say there is something new here? How arrogant to make such a claim! There is nothing new here at all! This is merely an engineered device, and inventors have been crafting 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. You have done nothing to acknowledge this past work. Have you no respect? There is no fundamentally new technology here, merely pieces of wood and metal and wire! I could build something like this in an afternoon for $25. There are no new electrical or mechanical 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. They could all be true. The problem is that they fail to address the crucial issue: the telephone prototype instantiates a generalizable technology to support remote voice communication through wires, thus over long distances.

Svensson and Berger have done an excellent job of illustrating how to play the irrelevant-objections-to-novelty game. When they argue that new work on mutation-biased adaptation is just another example of contingency, this represents the strategy of describing new work in a trivially general way, like saying that the first telephone is just a device. When they claim that the theory we proposed is already part of the Modern Synthesis, on the grounds that it can be broken down into familiar parts, this is like objecting that the telephone is made of familiar parts and therefore does not represent something new but is merely part of a familiar tradition of constructing devices.

Of course, the significance of a new device— or a new theory— is not in the list of parts, but in what the assembled whole accomplishes.

What is the actual significance of recent work on mutation-biased adaptation? 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 evolution subject to internal biases directly contradict neo-Darwinism and were considered heretical. 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 recent 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.


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.

Unfamiliar ideas are often mis-identified and mis-characterized. It takes time for a new idea to be sufficiently familiar that it can be debated meaningfully. We look forward to those more meaningful debates. Until then, fending off bad takes is the order of the day! See the Bad Takes Index.

Svensson and Berger (2019) begin their commentary on “The role of mutation bias in adaptive evolution” with a multi-threaded attack on the 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.” Just on the first page, they invoke versions of this theory in 5 different places (figure). Clearly, the main purpose of Svensson and Berger (2019) is to debunk this theory of mutation bias as an independent cause of adaptation.

The authors 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 extended by studies such as:

However, 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. For instance, 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— contrary to lore— transitions and transversions that change amino acids hardly differ in their distributions of fitness effects, a result used explicitly by Stoltzfus and McCandlish (2017) as the basis to treat transition bias as something orthogonal to selection.

Clearly, the main purpose of Svensson and Berger (2019) is to debunk this theory of mutation bias as an independent cause of adaptation.

Whereas some other authors have promoted the idea of adaptive mutation (e.g., Cairns, Caporale, Rosenberg), “natural genetic engineering” (Shapiro) or merely some statistical correlations between mutational patterns and fitness effects (Monroe, et al. 2022), the above sources do none of those things.

That is, the theory targeted by Svensson and Berger (2019) is not in the sources listed above, but exemplifies the concept of a strawman argument: misleading readers by presenting a false representation of an alternative view, one that is easy to knock down.

A strawman argument. Svensson and Berger (2019) illustrate the hypothesis of mutation as an “independent cause of adaptation” by a thick arrow with a question mark (the other parts of the figure are intended to represent conventional thinking). In the caption, they falsely attribute this idea to Nei (2013) and Stoltzfus and Yampolsky (2009).

The form of this strawman argument has a long history. Repeatedly, critics of neo-Darwinism have suggested that observed tendencies or directions of evolutionary change are not explained solely by selection, but reflect internal aspects of mutation or development, and advocates of neo-Darwinism have responded by dismissing these ideas as appeals to directed mutation or adaptive mutation, often implying an association with mysticism or teleology (e.g., Simpson, 1967).

Is this simply a case of intellectual dishonesty? Perhaps, but it also arises naturally from narrow thinking that equates evolution with adaptation, or that treats adaptation as a zero-sum game. When internalist critics invoke intrinsically favored directions in phenotype-space, evolutionary biologists trained in the neo-Darwinian school of thought tend to respond to this as an appeal to intrinsically adaptive directions, because they have not been taught any other way of thinking about directions.

Because Darwin’s followers have used this strawman argument 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)

Here Whitman is literally explaining that orderly tendencies may arise from strictly physical processes with no requirement for supernatural influences. But for Simpson (1967), this idea refers to “the vagueness of inherent tendencies, vital urges, or cosmic goals, without known mechanism.”

In general, when deceptive arguments against alternative views are maintained and nurtured for generations, this is because they are being used, not to resolve substantive scientific questions, but to maintain conformity within a closed ideological system, i.e., advocates of neo-Darwinism use these arguments to reinforce their prior beliefs and shut out new ideas that might alienate them from colleagues or create cognitive dissonance. Gatekeepers like Svensson and Berger discourage new thinking by presenting it as bad science or sensationalism, relying on the same fatuous strawman used in a century of prior gate-keeping.

Of course, we must not confuse theories and people, e.g., a theory supported by legions of trolls making 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 kinds of 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). The system is based on excluded middle arguments in which alternatives like saltationism, orthogenesis, and mutationism are presented only as crazy extremes. The system is used in two ways. The first line of defense is to present alternative views as being inherently flawed or absurd: they represent mental errors that can be dismissed a priori, without any difficult research or analysis. In the version of history that neo-Darwinians teach, critics of neo-Darwinism behave irrationally and hold views with obvious flaws (see Stoltzfus, 2017).

Eventually, however, some of the more intellectually rigorous thinkers begin to sense that scientific theories are supposed to stand for something substantive and risky, and they begin to consider the plausibility of alternatives to neo-Darwinism. In this case, the guarantors of tradition must offer a more sophisticated argument. In this second line of defense, the previously excluded middle is transformed, minimized, and appropriated for tradition. That is, the alternative is granted as a theoretical possibility, but its importance is minimized, it is presented in a modest or disguised form using different language, and it is grounded in a tradition that is associated with neo-Darwinism, by reference to obscure passages in the sacred texts. The defense shifts from a specific falsifiable theory to a flexible tradition or thought-collective. The thought-collective is defended by using ambiguity to shift the focus of discussion away from radical thoughts, and toward vague suggestions emanating from the pantheon of heroes.[1]

Svensson and Berger (2019) illustrate both strategies. First they attack the straw-man of “independent cause of adaptation,” then they present a more reasonable idea based on population genetics— a butchered version of the theory proposed by Yampolsky and Stoltzfus (2001)—, and present this as conventional wisdom (although practically unimportant). They do this in multiple ways. First they state that the theory is part of the neutral theory— which in their curious conception of history was somehow swallowed up post hoc by the Modern Synthesis— but they cite no source for this, e.g., if Kimura actually said this in his 1983 book or his hundreds of papers, they could have cited Kimura, but they don’t. Then they imply that Dobzhansky understood the theory, citing a vague and indirect comment about similarities of “germ plasm” (in a pre-Synthesis source that refers explicitly to Vavilov’s mutationist theory of parallelism!). Then they present a derivation of a key equation for effects of arrival bias in Box 1. This box gives a short series of mathematical results and names Haldane, Kimura, and Fisher without naming Yampolsky and Stoltzfus, subtly guiding the reader to assign the credit to famous dead people rather than to the living authors who actually proposed the theory and derived the equation.

However, at the same time that they appropriate the theory on behalf of Fisher, Dobzhansky, Kimura and others, they also purport to undermine it by dismissing the empirical evidence and claiming that the theory depends on unusual conditions including sign epistasis and drift in small populations, even though the model they depict in Box 1 has no clear dependence on either of these conditions (indeed, these are not actual requirements, but fabrications debunked by Couce, et al).

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. For more bad takes, see the index to bad takes.


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

Simpson GG. 1967. The Meaning of Evolution. New Haven, Conn.: Yale University Press. The quoted passage appears on p. 159.

[1] This passage really needs more concrete examples but I’ve written about this elsewhere. Futuyma’s Synthesis apologetics are a rich source of appropriation arguments (for examples, see this blog), e.g., Mayr is called on to appropriate developmental bias as part of the Synthesis, and Fisher, of all people, is called on to appropriate saltations.

Bad takes #1. We have long known

Unfamiliar ideas are often mis-identified and mis-characterized. It takes time for a new idea to be sufficiently familiar that it can be debated meaningfully. We look forward to those more meaningful debates. Until then, fending off bad takes is the order of the day! See the Bad Takes Index.

A reviewer of Stoltzfus and Yampolsky (2009) wrote that “we have long known that mutation is important in evolution,” citing the following passage from Haldane (1932) as if to suggest that the message of our paper (emphasizing the dispositional role of mutation) was old news:

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

We included this in the final version of the paper because, actually, this passage demonstrates the opposite of what the reviewer implies. 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 and half-Jewish, became a hero to a generation of Jewish sports fans when he demolished Max Schmeling, the German champion, prompting Hitler to outlaw 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. Though enormous — 30 cm taller and 50 kg heavy than the average Italian of his generation —, Carnera 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 a healthy human physique, 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 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 pure-hearted, winged angels, if one could wait long enough for the mutations to happen. That is, Haldane is contrasting (1) a mode of evolution that is gradual and combinatorial, bringing together known extremes, with (2) a mode of evolution that could generate imaginary fictitious not-real creatures. Haldane, Wright and Fisher each 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, a former orthodoxy that is largely forgotten today.

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 has missed Haldane’s meaning.

To understand what this reviewer is trying to accomplish via this “we have long known” argument, let’s imagine an alternative universe in which the reviewer says this:

“We have long known about the important role of biases in the introduction process emphasized in this manuscript. Haldane (1932) and Fisher (1930) explored the theoretical implications of such biases (under regimes of origin-fixation and clonal interference); Simpson and many others incorporated a theory of internal variational trends (i.e., orthogenesis) into their interpretations of the fossil record. Therefore, the authors’ implicit claim of novelty is unfounded. The theory is simply not new and not theirs, and they need to cite the proper sources for it.”

Of course, the reviewer does not say this, because nothing like this ever happened. In our universe, Fisher and Haldane failed to explore this theory (origin-fixation models didn’t appear until 1969, and clonal interference was not formally modeled until much later). In our universe, Simpson and others mocked the idea of orthogenesis.

Certainly, the reviewer is correct that scientists in the mainstream Modern Synthesis tradition have always known that mutation is important in evolution. Haldane, Fisher, Ford, Huxley, Dobzhansky, and others said explicitly that mutation is ultimately necessary, because without mutations, evolution would eventually grind to a halt.

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 argument that mutation pressure is a weak force (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 doing a rhetorical feint (aka bait-and-switch argument): the words “we have long known…” encourage the reader to think that he is going to undermine the novelty of the theory, but his actual claim fails to do this. The theory of biases in the introduction of variation is a specific theory, linking certain kinds of inputs with certain kinds of outputs, via a certain kind of population-genetic mechanism. And the reviewer is responding to this theory by saying “we have long known that mutation is important” which is not the same thing. The words “mutation is important” do not by themselves specify this theory— or any theory—, and in fact, the traditional importance assigned to mutation is clearly 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.” These are two utterly different theories about the role of variation, and only one of them is traditional and neo-Darwinian.

Finally, it is important to understand the role of flimsy “we have long known” arguments in evolutionary discourse. The pattern of the argument is that it appears to undermine a claim of novelty by identifying the same claim in traditional sources, but what is actually happening is that a specific target is being swapped out for something else, often a fuzzy or generic claim. The novelty of X is rejected on the grounds that X sounds a lot like old theory Y, or because both X and Y can be categorized as a member of some larger and fuzzier class of claims, e.g., “chance” or “contingency” (see Bad Takes #5: Contingency). This is often the case with “we have long known” arguments emanating from traditionalist pundits.

Again, if a theory X is actually unoriginal, pundits don’t need to make vague “we have long known” arguments, but can simply cite the original source of X per standard scientific practice. It is precisely when X is new that traditionalist pundits must construct vague “we have long known” arguments to rescue tradition from its failures.


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.

NRC Research Associateship: mutation and evolution

The US National Research Council (NRC) offers competitive Research Associateships for post-doctoral and senior scientists to conduct research in participating federal labs. The awards include a generous stipend as well as benefits (health insurance, travel, relocation), as explained on the program web site.

To apply, you must write a brief research proposal that reflects a plan of your own, or a plan that we develop together, involving some computational approach to molecular evolution. Especially welcome are proposals for empirical or theoretical work on biases in the introduction of variation as a dispositional factor in evolution, building on work such as Yampolsky and Stoltzfus (2001), Stoltzfus and McCandlish (2017) or Stoltzfus and Norris (2016).

The upcoming deadline for proposals is February 1, 2021 (there is another deadline August 1). If you are interested, contact me with a brief introduction, and we’ll go from there.

Arlin Stoltzfus (

Research Biologist, NIST (Data Scientist, Office of Data & Informatics)
Fellow, IBBR; Adj. Assoc. Prof., UMCP;
IBBR, 9600 Gudelsky Drive, Rockville, MD, 20850


Stoltzfus A, McCandlish DM. 2017. Mutational biases influence parallel adaptation. Mol Biol Evol 34:2163-2172

Stoltzfus A, Norris RW. 2016. On the Causes of Evolutionary Transition:Transversion Bias. Mol Biol Evol 33:595-602.

Yampolsky LY, Stoltzfus A. 2001. Bias in the introduction of variation as an orienting factor in evolution. Evol Dev 3:73-83.

PoMo, Oh No! A comment on The Logic of Chance

For a long time I was meaning to write a review of Eugene Koonin’s The Logic of Chance: The Nature and Origin of Biological Evolution.  The book has been out for over 6 years now.  In lieu of an actual review, I’d like to discuss Koonin’s characterization of an emerging view of evolution as a “post-modern” alternative to the “Modern” synthesis.  What could that mean?


A very bad theory about theories

In some venues, this is a familiar trope: a creationist asserts that evolution is “just a theory,” and a science advocate responds, explaining that, for scientists, a “theory” is a thoroughly tested, well established explanation.

Yet, for over 200 years, scientists have used “theory” for conjectures that are not well established, even ones whose truth is rejected, e.g., Lamarck’s theory.   What is going on?