The shift to mutationism is documented in our language
Last year Sahotra Sarkar published a paper that got me thinking. His piece entitled “The Genomic Challenge to Adaptationism” focused on the writings of Lynch & Koonin, arguing that molecular studies continue to present a major challenge to the received view of evolution, by suggesting that “non-adaptive processes dominate genome architecture evolution”.
The idea that molecular studies are bringing about a gradual but profound shift in how we understand evolution is something I’ve considered for a long time. It reminds me of the urban myth about boiling a frog, to the effect that the frog will not notice the change if you bring it on slowly enough. Molecular results on evolution have been emerging slowly and steadily since the late 1950s. Initially these results were shunted into a separate stream of “molecular evolution” (with its own journals and conferences), but over time, they have been merged into the mainstream, leading to the impression that molecular results can’t possibly have any revolutionary implications.
But maybe the frog is dead already. I would argue that molecular studies have shifted the way we understand the role of mutation in evolution, to the point that many of us are now aligned with the mutationists of a century ago, and against the original Modern Synthesis (OMS). The shift is apparent in statements like these:
Adaptation proceeds through the selection of mutations” (Jacquier, et al 2013)
Mutation rates are central to evolution, as the rate of evolution is determined by the rate at which mutations are introduced into the population” (Acevedo, et al, 2014, citing Orr, 2000 [rate of adaptation in asexuals] and Kimura, 1983)
The rate of germ line mutation is the ultimate parameter governing the amount of genetic diversity within populations and the divergence between species. (Mugal and Ellegren, 2011)
Amnesia alert: what we used to think (really)
One’s first reaction to such statements might be “So what? That’s textbook knowledge. We’ve always known that!”.
Actually, no, we haven’t always known that. Instead, “we” used to know that the above statements are incorrect or wildly misleading. Here is what our leading authorities said throughout the latter half of the 20th century (for sources, see ):
“The large number of variants arising in each generation by mutation represents only a small fraction of the total amount of genetic variability present in natural populations. … It follows that rates of evolution are not likely to be closely correlated with rates of mutation . . . Even if mutation rates would increase by a factor of 10, newly induced mutations would represent only a very small fraction of the variation present at any one time in populations of outcrossing, sexually reproducing organisms.” (Dobzhansky, et al., 1977, p. 72)
“mutations are rarely if ever the direct source of variation upon which evolutionary change is based. Instead, they replenish the supply of variability in the gene pool which is constantly being reduced by selective elimination of unfavorable variants. Because in any one generation the amount of variation contributed to a population by mutation is tiny compared to that brought about by recombination of pre-existing genetic differences, even a doubling or trebling of the mutation rate will have very little effect upon the amount of genetic variability available to the action of natural selection. Consequently, we should not expect to find any relationship between rate of mutation and rate of evolution. There is no evidence that such a relationship exists.” (my emphasis) (Stebbins, 1966, p. 29)
“Those authors who thought that mutations alone supplied the variability on which selection can act, often called natural selection a chance theory. They said that evolution had to wait for the lucky accident of a favorable mutation before natural selection could become active. This is now known to be completely wrong. Recombination provides in every generation abundant variation on which the selection of the relatively better adapted members of a population can work.” (Mayr, 1994, p. 38)
“The process of mutation supplies the raw materials of evolution, but the tempo of evolution is determined at the populational levels, by natural selection in conjunction with the ecology and the reproductive biology of the group of organisms” (Dobzhansky, 1955, p. 282)
“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.” (Mayr, 1963, p. 613)
“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.” (Ford, 1971, p. 361)
“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.” (Dobzhansky, et al., 1977, p. 6)
“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)
Not everyone suffers from this amnesia, as I was surprised to find a few years ago when I saw Richard Dawkins’s NYT book review of Behe’s The Edge of Evolution. Behe claims, in effect, that there was not sufficient time for all the mutations needed to account for evolution. Dawkins responds by attacking the premise that evolutionary rates depend on mutation rates, which he says contradicts “the entire corpus of mathematical genetics, from 1930 to today”:
“If correct, Behe’s calculations would at a stroke confound generations of mathematical geneticists, who have repeatedly shown that evolutionary rates are not limited by mutation. Single-handedly, Behe is taking on Ronald Fisher, Sewall Wright, J.B.S. Haldane, Theodosius Dobzhansky, Richard Lewontin, John Maynard Smith and hundreds of their talented co-workers and intellectual descendants. Notwithstanding the inconvenient existence of dogs, cabbages and pouter pigeons, the entire corpus of mathematical genetics, from 1930 to today, is flat wrong. Michael Behe, the disowned biochemist of Lehigh University, is the only one who has done his sums right. You think? The best way to find out is for Behe to submit a mathematical paper to The Journal of Theoretical Biology, say, or The American Naturalist, whose editors would send it to qualified referees.”
With his signature over-the-top rhetoric, Dawkins insists that “mathematical genetics” has proven that evolutionary rates are not limited by mutation. Allowing for some exaggeration, this is an accurate representation of OMS orthodoxy ca. 1959, the approximate vintage of Dawkins’s views.
Actually, population-genetics theory did not prove any such thing (see Maynard Smith, 1976 for an inconclusive treatment of this issue from long after the OMS was proposed). The arguments for the “gene pool” view were mainly hand-waving arguments. Fisher, Haldane and Wright did not even develop a coherent theory for a mutation-driven view, much less reject it. Today the most familiar theoretical version of mutation-limited dynamics is the origin-fixation formalism (referenced in some of the quotations above), as in the familiar equation K = 4Nus. This posits a direct relation between the rate of evolution and the rate of mutation. However, such models originated only in 1969 (McCandlish & Stoltzfus, 2014). They were not part of the foundational work by Fisher, Haldane and Wright. They literally were not part of the OMS, because the OMS defines evolution as shifting the frequencies of pre-existing alleles in an abundant gene pool, not as a process directly dependent on new mutations.
In brief, it goes like this. Early in the 20th century, Darwin’s followers fought against any important role for mutations and Mendelian inheritance in evolution, holding on to Darwin’s view of smooth shifts via the bulk selection and blending inheritance of subtle environmental fluctuations, which Darwin mistakenly believed to be heritable. Johannsen’s “pure line” selection experiments killed this theory. The conceptual foundations of a Mendelian evolutionary view were laid, not by Darwinians, but by early geneticists such as Bateson, Johannsen, Punnett, Locke, and others (see my blog about The Forgotten Synthesis). These pioneers considered the possibility of evolution by rare mutations, and also of evolution based on pre-existing variation; they considered beneficial changes as well as neutral ones; they allowed large changes and small ones; they imagined that non-uniformities in mutation might lead to trends or parallelisms. Their view was eclectic and excluded only teleology and Lamarckism.
By 1930, a much narrower view— a new version of Darwinism— had begun to assert itself. The new Darwinians accepted Mendelian genetics and agreed that, without mutations, evolution would grind to a halt. But they also conjured up a special version of Mendelian evolutionary genetics tailored to revive the Victorian look-and-feel of Darwin’s theory, in which the great work of history is done by hordes of anonymous, indistinct fluctuations, guided slowly, quietly and ineffably by the hands of time, towards progress.
In this view, the fluctuations do not “determine”, “govern” or “control” anything at all, which is why any statement saying that mutation “determines”, “governs” or “controls” would be out of place. The governing force, selection, operates at a higher level. Mutation is a mere source of “raw materials” with no tendencies that could influence evolution.
In reality, evolution by fixation of rare or distinctive mutations clearly was possible. Indeed, it was what the mutationists often invoked. But it just didn’t fit with the whole Darwinian way of looking at things, so it was rejected by the architects of the OMS. They simply asserted that, in nature, evolution never happens that way. Instead, they claimed, evolution happens when (in response to an environmental change) selection shifts the frequencies of genes already present in the “gene pool”, which is kept abundantly full of variation at all times (this is the meaning of the final obscure comment by Stebbins above).
The champions of this view are the same people that everyone knows as the architects of the Modern Synthesis. They are praised as the founders of modern evolutionary thinking because they convinced the English-speaking world that the above view had restored Darwinism and triumphed over all rivals.
What we think now
Over the past year, I’ve been reading quite a few papers about mutations and mutational effects. The authors of these papers often start out with a very powerful statement about the importance of mutation, which may be described as a “driving force” or “engine”, or something that “governs” or “determines” rates or directions of evolution. Here is a sample of them (for sources, see ). Some generally emphasize mutation
“Adaptation proceeds through the selection of mutations” (Jacquier et al. 2013)
“Mutation is one of the most fundamental processes in biology. It is the ultimate source of genetic variation and one of the driving forces of evolution.” (Schaibley et al. 2013)
“Mutation is the engine that drives evolution and adaptation forward in that it generates the variation on which natural selection acts “(Hershberg and Petrov 2010)
“Mutations are the main sources of evolutionary novelty, and as such constitute a key driving force in evolution” (Franke, et al. 2011)
Others emphasize mutation as a determinant of evolutionary rate:
“actual sequence evolution is governed by the rates at which mutations arise and the selection that subsequently acts on them (Halpern and Bruno 1998; Thorne et al. 2007)” (Bloom 2014)
“mutation rates are a key determinant of the rate of evolution” (Lang and Murray 2008)
“Mutation rates are central to evolution, as the rate of evolution is determined by the rate at which mutations are introduced into the population” (citing Orr, 2000 [rate of adapt in asexuals] and Kimura, 1983) (Acevedo et al. 2014)
Perhaps the most interesting quotations are the ones that refer explicitly to the dichotomy between a traditional view based on “standing variation” and one based on “new mutations” (“mutation-limited”). As the quotations above indicate, the architects of the Modern Synthesis considered this a closed issue. They thought they knew how evolution works: selection never waits for a new mutation, but proceeds on the basis of abundant variation already present in the “gene pool” (the genesis of this view is discussed in Provine (1971), and the arguments used to support it are reviewed partly by McCandlish & Stoltzfus (2014)).
By contrast, contemporary statements typically treat the relative importance of these two regimes of population genetics as an open issue. For instance, in one statement below, Houle refers to the classical view as merely “a popular model.” In other statements quoted below, the authors present the “new mutations” view as the “traditional” view or “ruling paradigm”, and claim that the classical view has been neglected! 
“On the one hand, a popular model of adaptation assumes that the standing variance in a population is the principal source of the response to selection (e.g., Lande 1979).” (Houle et al. 1996)
“We have little information about the relative importance of these two sources of beneficial alleles after a change of environment” (Barrett and Schluter 2008) [referring to the two different modes of evolution from standing variation or from new mutations]
“Historically, population geneticists have focused attention on the hard-sweep model of adaptation in which a de novo beneficial mutation arises and rapidly fixes in a population. Recently more attention has been given to soft-sweep models, in which alleles that were previously neutral, or nearly so, drift until such a time as the environment shifts and their selection coefficient changes to become beneficial. It remains an active and difficult problem, however, to tease apart the telltale signatures of hard vs. soft sweeps in genomic polymorphism data. ” (Schrider, et al. , 2015)
“On the other hand, in the molecular literature on the adaptive process and on selective sweeps adaptation from a single new mutation is clearly the ruling paradigm (e.g., Maynard Smith and Haigh 1974; Kaplan et al 1989; Barton 1998; Kim and Stephan 2002). In conspicuous neglect of the quantitative genetic view, the standing genetic variation as a source for adaptive substitutions is generally ignored, with only few recent exceptions (Orr and Betancourt 2001; Innan and Kim 2004).” (Hermisson and Pennings 2005)
“Most of the current theory on the genetics of adaptations [citing Orr’s work] assumes that adaptation occurs exclusively from new mutations rather than from standing variation” (Barrett and Schluter 2008)
“Models of adaptive evolution have traditionally assumed adaptation from de novo mutations” (Radwan and Babik 2012), citing Orr’s work
The larger point is that mutationist thinking, heretical for Mayr and Dobzhansky, is now so familiar that people project it backwards on the OMS. Sometimes they even project it backwards on Darwin, as when Dean (2012) refers to “random mutation” and “the sieve of natural selection” as “basic Darwinian principles”.
Why it matters
That all sounds rather historical. Why should you care about history? Why should anyone care what “Darwinism” or “The Modern Synthesis” meant? So long as we are getting the science right, why does it matter if we are ignorant, or wrong, about the history of science?
I agree completely with that sentiment: if we were getting the science right, if the community were confronting the scientific issues in a productive way, the history would be irrelevant. I’m a scientist. I’m not trying to give people a history lesson just for the sake of history.
But my view is that we are not confronting the issues raised by mutationism in a healthy or productive way. For instance, we can draw a distinction— superficial in some ways, but useful— between two distinct regimes of population genetics that I describe in The Buffet and the Sushi Conveyor. The difference between them is not trivial. They have different implications about what controls the rate and direction of evolution, and thus, different implications about what kinds of things are important for evolutionary biologists to study. Statements made about one regime can be false in the other regime. One regime aligns well with neo-Darwinism, and the other aligns with the non-Darwinian views of Bateson, Punnett, Morgan, et al., and with what Masatoshi Nei means by “mutation-driven evolution”.
Given that the OMS was committed to the buffet view, and that this was what distinguished it from Mendelian-mutationism (see Provine or Stoltzfus & Cable, 2014), shouldn’t this issue be front and center in debate about the status of evolutionary theory? Why isn’t this thing as big as the neutralist-selection debate, or the kerfuffle over directed mutations, or group selection?
Another issue that just doesn’t get attention is the role of mutation as a source of direction in evolution. You would think, given that orthogenesis used to be a heresy, that this would be a big deal. But it isn’t.
One of the key reasons for this lack of critical attention is a lack of historical knowledge. Discussions about evolutionary issues often fail to get off the ground due to potential reformers getting shouted down by people who insist that there is nothing new under the sun, and we are all working in Darwin’s goldmine, as Patrick Forterre puts it in a slavish metaphor. Leading evolutionary thinkers today are divided: conservatives believe that contemporary thinking is subsumed by the OMS, and a growing minority of reformers believe that contemporary thinking extends the OMS. Both positions are wrong, because evolutionary biologists have abandoned key commitments of the OMS.
Looking at this the next day, a couple of things occur to me. First, it would have been helpful to define “mutationism”, and in particular, to avoid leaving any impression that mutationism means origin-fixation models. Historic views or theories like Darwinism or mutationism are not defined in terms of detailed mechanisms (or there could be no “Darwinism” today), but in terms of the explanatory roles assigned to various factors or processes, particularly selection and variation. These verbal theories tell us what kinds of verbs and metaphors we can use. Darwinism says that variation is merely a source of raw material, while mutationism entails recognizing a role for mutation as a source of initiative, discontinuity, direction, and creativity in evolution. Mutationist thinking arose with the Mendelian recognition that new alleles created by mutation are inherited perfectly, and that, because of this (they assumed), the timing and character of mutations must in some sense determine the timing and character of evolutionary changes. The mutationists not only accepted this on a theoretical level, they actually sought out and proposed mutational explanations for aspects of the dynamics and directions of evolution. This position is automatically in opposition to certain aspects of Darwinism: it means that one is not a pan-adaptationist, one does not view mutation merely as “raw materials”, and one does not accept (at least, not fully) the creativity-of-selection doctrine central to Darwinism (see Why size matters: Saltation, Creactivity, and the Reign of the DiNOs).
Second, it would have been more fun (and, alas, more work) to gather some quotations to illustrate what the early geneticists believed (the best source is Stoltzfus & Cable, 2014; many of the books cited therein are out of copyright and can be accessed in online facsimile editions for free, so it is relatively easy to check the primary literature). For instance, Morgan’s (1916, p. 194) statement
evolution has taken place by the incorporation into the race of those mutations that are beneficial to the life and reproduction of the organism
is rather like the one from Jacquier, et al 2013 above, and seems harmless, but this way of directly linking adaptation and beneficial mutations is what the architects of the Modern Synthesis ridiculed as the “lucky mutant” view. The following statements suggest that the mutationists understood differences in mutation rates as factors that would affect the outcome of evolution:
“Probably the most effective aid in establishing new genes lies in their repeated production by independent mutations. A gene produced twice by mutation has twice as good a chance to survive as if produced only once.” Shull (1936, p. 140)
“There is another result, clearly established by the genetic work on Drosophila, that is favorable to the final establishment of a new type of character if it is beneficial. Most, perhaps all, of the mutations appear more than once. This improves their chances of becoming incorporated in the species, and if the mutation produces a character that favors survival the chance of its becoming established is still further increased.” (Morgan, 1925, p. 142).
Shull (above) is essentially proposing a rule regarding a precise causal relationship, in which the chance of being established is 2-fold higher for a mutant that arises twice as often, other things being equal. This rule is correct at least for the extreme case of origin-fixation models.
Third, I wish I had noted the fact that early geneticists and also the architects of the Modern Synthesis referred to the 2-step origin-fixation view as “pre-adaptation” (when applied to beneficial changes). The idea that a new feature would appear, then by chance find appropriate circumstances to live, was so far from the Darwinian concept of adaptation as a smooth environment-induced response, that they did not feel comfortable naming it with the same term. For some examples, see When “Darwinian Adaptation” is Neither.
Finally, the question from Bjørn Østman — are we not now confronting these issues in a productive way?— suggests it would have been good to outline precisely what, in my view, needs re-thinking in light of the breakdown of the OMS view. Here are some things that come to mind:
- the realism of origin-fixation models, which seems to be taken for granted (see McCandlish & Stoltzfus, 2014)
- the view that evolutionary theory is a theory of forces (see Why the “four fundamental forces” view is mistaken)
- the creativity implied whenever a complex or simple feature is attributed to selection (see Why Size Matters)
- the mapping of an origin-fixation mechanism to the concept formerly known as “adaptation” (see When “Darwinian Adaptation” is Neither)
- the idea that mutation supplies “raw materials” to selection (see Why Size Matters)
- the “mutation is random” doctrine (“mutation is random”, in my view, is misinterpreted as an ontological claim about the nature of mutation, but as such has no valid justification: it is better understood as a paradigm-defining heuristic to the effect that mutation is unimportant, and therefore need not be studied, as per Ch. 1 of Fisher, 1930)
- all this nonsense about the “Modern Synthesis” being the foundation of evolutionary thinking
And to that list of scientific issues I would add the meta-scientific issues of how we are going to re-assign credit based on identifying the actual OMS, rejecting it as a master theory, and recognizing the vital contributions of Johannsen, Bateson, Morgan, Punnett, Locke and so on. Contemporary authors in evolutionary genetics, for instance, just don’t understand that when they attribute Kimura’s lucky mutant view of evolution to Fisher, this is an abomination comparable to attributing Kimura’s neutral theory to Fisher. The return of mutationist thinking clearly was initiated by biochemists such as Anfinsen, Dayhoff, Zuckerkandl, Jukes, and others in the 1950s and 1960s, and we ought to recognize all of them as progenitors.
And then there is the extra-scientific issue of history. The way that Ernst Mayr and his credulous followers have promulgated an utterly distorted view of scientific history, turning so many vital scientific progenitors into villains and unpersons, would have earned the admiration of Soviet historians (see an earlier blog). We need a different telling of history, e.g. one that addresses the rise, fall and return of mutationism; one that makes sense of what happened with “molecular evolution”; one that explains when the OMS stopped being a master theory.
 The sources of those Modern Synthesis quotations spanning 40 years are:
- Dobzhansky T. 1955. Genetics and the Origin of Species. New York: Wiley & Sons, Inc.
- Dobzhansky T, Ayala FJ, Stebbins GL and Valentine JW. 1977. Evolution: W.H. Freeman.
- Ford EB. 1971. Ecological Genetics. London: Chapman & Hall.
- Mayr E. 1963. Animal Species and Evolution. Cambridge, Massachusetts: Harvard University Press.
- Mayr E. 1994. The Resistance to Darwinism and the Misconceptions on which it was Based. In: Campbell JH, Schopf JW, editors. Creative Evolution?! London: Jones & Bartlett, Inc. p. 35-46.
- Stebbins GL. 1966. Processes of Organic Evolution. Englewood Cliffs, NJ: Prentice Hall.
- Stebbins GL. 1982. Darwin to DNA, Molecules to Humanity. San Francisco: W.H. Freeman and Company.
 The sources of those contemporary mutationist quotations are:
- Acevedo A, Brodsky L and Andino R. 2014. Mutational and fitness landscapes of an RNA virus revealed through population sequencing. Nature 505: 686-690. doi: 10.1038/nature12861
- Barrett RD and Schluter D. 2008. Adaptation from standing genetic variation. Trends Ecol Evol 23: 38-44.
- Bloom JD. 2014. An experimentally determined evolutionary model dramatically improves phylogenetic fit. Mol Biol Evol 31: 1956-1978. doi: 10.1093/molbev/msu173
- Franke J, Klozer A, de Visser JA, Krug J. 2011. Evolutionary accessibility of mutational pathways. PLoS computational biology 7:e1002134.
- Hermisson J and Pennings PS. 2005. Soft sweeps: molecular population genetics of adaptation from standing genetic variation. Genetics 169: 2335-2352.
- Hershberg R and Petrov DA. 2010. Evidence that mutation is universally biased towards AT in bacteria. PLoS genetics 6: e1001115. doi: 10.1371/journal.pgen.1001115
- Houle D, Morikawa B and Lynch M. 1996. Comparing mutational variabilities. Genetics 143: 1467-1483.
- Jacquier H, Birgy A, Le Nagard H, et al. 2013. Capturing the mutational landscape of the beta-lactamase TEM-1. Proc Natl Acad Sci U S A 110: 13067-13072. doi: 10.1073/pnas.1215206110
- Lang GI and Murray AW. 2008. Estimating the per-base-pair mutation rate in the yeast Saccharomyces cerevisiae. Genetics 178: 67-82. doi: 10.1534/genetics.107.071506
- Radwan J and Babik W. 2012. The genomics of adaptation. Proceedings Biological sciences / The Royal Society 279: 5024-5028. doi: 10.1098/rspb.2012.2322
- Schaibley VM, Zawistowski M, Wegmann D, et al. 2013. The influence of genomic context on mutation patterns in the human genome inferred from rare variants. Genome Res 23: 1974-1984. doi: 10.1101/gr.154971.113
- Schrider, et al. “Soft and Partial Selective Sweeps Result from Linked Hard Sweeps”
 I won’t defend the final statement by Radwan and Babik, which is simply wrong. The other 3 statements that seem to get things wrong are not as far off as they might seem. Bear in mind that we (scientists) typically are speaking from a narrow perspective as specialists, and framing our work to maximize impact relative to work in the very recent past. “Traditionally” or “classically” in this context can mean “what the hot papers were saying 10 years ago”. I would agree with H & P at least in the sense that, in my experience, most molecular evolutionists habitually think of adaptation as a 2-step mutation-fixation process. For B & S, “current theory” means “what’s currently hot”, so they are just complaining that new-mutations models are getting undue attention, even as innovative work continues to be done within the older paradigm.