Transposon dynamics and the epigenetic switch hypothesis

Abstract

The recent explosion of interest in epigenetics is often portrayed as the dawning of a scientific revolution that promises to transform biomedical science along with developmental and evolutionary biology. Much of this enthusiasm surrounds what we call the epigenetic switch hypothesis, which regards certain examples of epigenetic inheritance as an adaptive organismal response to environmental change. This interpretation overlooks an alternative explanation in terms of coevolutionary dynamics between parasitic transposons and the host genome. This raises a question about whether epigenetics researchers tend to overlook transposon dynamics more generally. To address this question, we surveyed a large sample of scientific publications on the topics of epigenetics and transposons over the past fifty years. We found that enthusiasm for epigenetics is often inversely related to interest in transposon dynamics across the four disciplines we examined. Most surprising was a declining interest in transposons within biomedical science and cellular and molecular biology over the past two decades. Also notable was a delayed and relatively muted enthusiasm for epigenetics within evolutionary biology. An analysis of scientific abstracts from the past twenty-five years further reveals systematic differences among disciplines in their uses of the term epigenetic, especially with respect to heritability commitments and functional interpretations. Taken together, these results paint a nuanced picture of the rise of epigenetics and the possible neglect of transposon dynamics, especially among biomedical scientists.

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Vol.:(0123456789)
Theoretical Medicine and Bioethics (2021) 42:137–154
https://doi.org/10.1007/s11017-021-09548-x
1 3
Transposon dynamics andtheepigenetic switch hypothesis
StefanLinquist1 · BradyFullerton1
Accepted: 15 October 2021 / Published online: 17 December 2021
© The Author(s) 2022, corrected publication 2022
Abstract
The recent explosion of interest in epigenetics is often portrayed as the dawning of a
scientific revolution that promises to transform biomedical science along with devel-
opmental and evolutionary biology. Much of this enthusiasm surrounds what we
call the epigenetic switch hypothesis, which regards certain examples of epigenetic
inheritance as an adaptive organismal response to environmental change. This inter-
pretation overlooks an alternative explanation in terms of coevolutionary dynam-
ics between parasitic transposons and the host genome. This raises a question about
whether epigenetics researchers tend to overlook transposon dynamics more gener-
ally. To address this question, we surveyed a large sample of scientific publications
on the topics of epigenetics and transposons over the past fifty years. We found that
enthusiasm for epigenetics is often inversely related to interest in transposon dynam-
ics across the four disciplines we examined. Most surprising was a declining interest
in transposons within biomedical science and cellular and molecular biology over
the past two decades. Also notable was a delayed and relatively muted enthusiasm
for epigenetics within evolutionary biology. An analysis of scientific abstracts from
the past twenty-five years further reveals systematic differences among disciplines
in their uses of the term epigenetic, especially with respect to heritability commit-
ments and functional interpretations. Taken together, these results paint a nuanced
picture of the rise of epigenetics and the possible neglect of transposon dynamics,
especially among biomedical scientists.
Keywords Epigenetic inheritance· Transposable elements· Function concepts·
Philosophy of genomics
* Stefan Linquist
linquist@uoguelph.ca
1 Department ofPhilosophy, University ofGuelph, Guelph, ON, Canada
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Introduction
It is widely maintained that biology is undergoing an epigenetic revolution.
According to this narrative, the gene is being dethroned from its privileged
explanatory and investigation-guiding roles. In its place, scientists are focusing
on various epigenetic factors—equally significant to genes in their casual and
information-bearing functions, or so it is argued—that have long been neglected
in the study of development and evolution.
The study of human disease is one of the fields that epigenetics is expected to
transform. Biomedical interest in epigenetics traces back to the discovery that wide-
spread loss of DNA methylation is associated with cancer [1]. At the time, it was
a significant discovery that cancer could be triggered not only by mutation in gene
sequence, but also by the removal of methylation marks. During the 2000s, biomedi-
cal work on epigenetics explored the tendency for cells to acquire an elevated vul-
nerability to stress [2]. This phenomenon was associated with alterations to DNA
methylation triggered by environmental factors, such as a reduction in quality of diet
[3], that are potentially transmitted to offspring in utero [4]. More recently, we are
seeing the rise of large-scale research consortia such as the Encyclopedia of DNA
Elements (ENCODE), which seeks to identify all functional elements in the human
genome by focusing in particular on “regions of transcription, transcription factor
association, chromatin structure and histone modification” [5, p. 57]. ENCODE’s
most controversial and widely publicized result states that over 80% of the human
genome is associated with some biochemical function [5]. From a gene-centric per-
spective, this claim would be surprising, since protein-coding regions constitute a
mere 4% of the human genome [6]. Detractors object that ENCODE’s finding relies
on an overly permissive definition of function, that their study used unjustifiably
weak criteria for identifying genetic candidates as functional, and that their frame-
work cannot explain differences among species’ genome sizes [7–10]. In defense of
ENCODE, some authors interpret their controversial statement as an estimate of the
proportion of genomic regions that are of potential biomedical interest [11]. Gener-
ally speaking, it is clear that epigenetics has motivated considerable research within
the biomedical sciences, challenging conventional notions of biological function and
expanding the range of entities thought to be functionally relevant to human disease.
It is tempting to follow authors like Eva Jablonka and Marion Lamb, who
claim that epigenetics involves aparadigm shift in biology [12], or Russell Bon-
duriansky and Troy Day, who suggest that epigenetics constitutes a “new under-
standing of inheritance and evolution” [13]. Thisis a seductive picture, especially
to philosophers. Conceptual change in science is an established field of philo-
sophical research. The study of gene concepts has been one of the most fecund
topics within the philosophy of biology. This work reveals that scientific concep-
tions of the gene and genetic disease are in an ongoing historical dialogue with
technological advances in biology [14–16]. To many philosophers, it would be
unsurprising if further technological developments led to additional modifica-
tions to scientific conceptions of heredity. Gene concepts have proven to be fluid,
the thinking goes. Why should gene centrism itself not be up for grabs?
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Transposon dynamics andtheepigenetic switch hypothesis
Some authors challenge the suggestion that there is an epigenetic revolution afoot. It
is possible to distinguish three general objections. The first takes issue with the claim
that epigenetic insights qualify as revolutionary. Peter Godfrey-Smith notes that over
the course of its historical development, molecular biology has become gradually less
doctrinaire [17]. Theoretical principles that were central to this discipline in its early
stages, such as G.W. Beadle’s one gene–one enzyme hypothesis, have become less
important as molecular details have been filled in. Epigenetic phenomena might have
posed a serious challenge to the principles on which molecular biology was founded.
However, in Godfrey-Smith’s view, these phenomena are less threatening now that
principles have been supplanted with mechanistic details.
A second objection focuses on the various meanings of ‘epigenetic’ [18–20]. Some
instances of epigenetic regulation merely involve the (gene-mediated) influence of an
environmental factor on some phenotype. Gene centrists have always allowed that envi-
ronmental factors influence gene expression. Such examples of epigenetic phenomena
are therefore not unorthodox. At the same time, the term epigenetic sometimes refers
to the open-ended transmission of a phenotypic change that involves no change in gene
sequence. This phenomenon is thought to be rare in eukaryotes [21], but would indeed
call for a radical shift in biological thinking if it were common. Conflating familiar epi-
genetic effects with rarer or more controversial phenomena potentially gives a distorted
impression of what the study of epigenetics is about.
A third objection concerns the functional interpretation of certain epigenetic phe-
nomena. Epigenetic revolutionaries point to examples of phenotypic mutation that are
induced by some environmental change, appear to be adaptive for the organism, and
involve no change in DNA sequence, but are transmitted in sexual lineages across gen-
erations. Such examples are interpreted as evidence for a switch-like mechanism that
rapidly adapts the phenotype to environmental change. This mechanism is allegedly
less visible from a research program focused on genes. Also, if adaptive epigenetic
inheritance is common, this challenges the neo-Darwinian idea thatphenotypic adapta-
tion typically involves random genetic variation and selection.
Our first aim in this paper is to explore an alternative explanation of epigenetic inher-
itance that views it not as an adaptive epigenetic switch, but rather as the byproduct of
transposon dynamics. This explanation has long been available but is rarely considered,
raising the question of whether transposon dynamics generally tend to be neglected in
discussions about epigenetics. Our second aim is to address this question using a quan-
titative analysis of papers sampled from the Web of Science. In this way, we examine
the popularity of epigenetics versus transposons across different disciplines over the
past five decades. Finally, using a qualitative analysis comparing different conceptions
of epigenetics across disciplines over the past twenty-five years, we compare the varied
disciplinary views of epigenetics researchers on the topics of heritability and function.
Epigenetic switches andthesignificance oftransposons
One of the most widely discussed examples of epigenetic inheritance involves the
transmission of coat coloration in lab mice. The agouti gene is expressed in mouse
hair follicles and normally produces a dark brown coat. However, in some mice
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there is a change in the expression of this gene, producing a coat that appears some-
times yellow or on other occasions variegated. All strains of mice share an identical
agouti gene with no variation in nucleotide sequence. Differences in coat color are
instead produced by variation in methylation patterns upstream of the pigment gene.
An interesting feature of this example is that color pattern is maternally inherited for
up to three generations, indicating that parents transmit methylation patterns to their
offspring.
The agouti gene has become a model system for epigenetics. For instance, a study
by Dana Dolinoy etal. exposed female mice to bisphenol A (BPA) and noticed a
shift toward yellow in the coat color distribution of their offspring [22]. Again, vari-
ation in coat color was caused not by a DNA mutation but rather by a change in
methylation. Moreover, the effect was counteracted when female mice were fed a
diet supplemented with methyl donors.
Such examples have been interpreted as evidence for an epigenetic inheritance
mechanism, or switch, that rapidly adapts organisms to their environment. In dis-
cussing agouti gene expression in mice, Jablonka and Lamb propose:
Because it provides an additional source of variation, evolution can occur
through the epigenetic dimension of heredity even if nothing is happening in
the genetic dimension. But it means more than this. Epigenetic variations are
generated at a higher rate than genetic ones, especially in changed environ-
mental conditions, and several epigenetic variations may occur at the same
time. Furthermore, they may not be blind to function, because changes in epi-
genetic marks probably occur preferentially on genes that are induced to be
active by new conditions. [12, p. 144]
Likewise, Bonduriasnki and Day claim that the agouti mouse example “shows
how such epigenetic traits could contribute to adaptive evolution” [13, p. 58]. There
are three basic components to this interpretation. First, there is the proposal that
phenotypic changes are induced by the environment. Second, there is the claim that
those changes involve a modification to methylation or some other epigenetic mark,
but no change in gene sequence. Finally, there is often the suggestion that epigenetic
changes are biased toward adaptive phenotypic responses. The conjunction of these
three propositions is what we refer to as the epigenetic switch hypothesis.
Others have raised doubts about the existence of epigenetic switches because the
relevant effects persist for no more than three generations. To be of evolutionary
interest, it is argued, an epi-mutation would have to persist for much longer. A recent
review by Alfredo Sánchez-Tójar etal. found little evidence for such transgenera-
tional epigenetic effects. However, this remains a topic for further research [21].
Perhaps a more philosophically interesting objection concerns the fact that
the agouti mutation involves the suppression of a transposable element, located
upstream of the agouti gene. Jablonka and Lamb mention in passing that “there was
a small extra bit of DNA (originating from a transposon) in the regulatory region of
a coat color gene” [12, p. 142]; but they overlook the theoretical significance of this
point. As we explain in the next few paragraphs, the fact that epigenetic mutations
are often transacted by transposable elements suggests an alternative to the epige-
netic switch hypothesis.
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Transposon dynamics andtheepigenetic switch hypothesis
Transposable elements (TEs) are mobile strands of DNA capable of jumping into
new chromosomal locations. The act of transposition (jumping) often involves the
creation of additional TE copies. Hence, individual TEs can replicate multiple times
per generation in a process akin to meiotic drive. It is well known that TE inser-
tion can interfere with protein synthesis or cause various sorts of harmful mutation.
Organisms have thus evolved a variety of mechanisms for deactivating, suppressing,
or removing TEs from the genome. These mechanisms, in turn, impose a selection
pressure on TEs to evolve ways to overcome the host organism’s defenses. Over mil-
lions of years, these coevolutionary dynamics have given rise to eukaryotic genomes
replete with TEs—with 40–60% of the nuclear DNA in humans descending from
TEs—most of which are temporarily silenced or permanently deactivated [23].
There are several reasons TEs may appear to have organism-beneficial functions
when they are in fact deleterious. One way for a TE lineage to potentially avoid
deactivation or deletion is by inserting copies very close to a protein-coding gene
[24]. These sites are safe havens, so to speak, because the host cannot easily meth-
ylate TEs at these locations without altering the expression of its own genes. It is
therefore no surprise that many TEs preferentially insert close to protein-coding
genes [25].
It is easy to mistake these stealthy TEs for organism-beneficial insertions [10].
Genomics researchers identify the strands of DNA located adjacent to genes as reg-
ulatory regions because they contain transcription factor binding sites. The occur-
rence of TEs within regulatory regions has led some genomics researchers to impli-
cate them in gene regulation, disregarding the possibility that the TEs might simply
be hiding in a safe location. This interpretation is further supported by the fact that
TEs contain their own binding sites which are normally used to harness the host’s
replication machinery for their own benefit. Hence, TEs are especially effective
mimics of genuine regulatory regions.
Another deceptive feature of TEs is that they are activated by stress. When an
organism is exposed to chemical, thermal, or other forms of stress, there is some-
times a burst of TE activity [25]. Barbara McClintock hasinterpretedTE bursts as
evidence for a switch-like mechanism that facilitates rapid phenotypic adaptation
by elevating mutation rate [26]. Once again, however, the situation looks different
from the perspective of TE–host coevolution. Organisms employ various strategies
to protect genes from TE insertion. Some suppression strategies occur at the level
of the DNA strand, where methyl groups are inserted on top of transposon binding
sites to prevent them from being recognized by the host’s transcription factors and
replicated. In fact, it is now thought that DNA methylation originated as a system for
TE suppression, with gene regulation a secondary (exapted) function [27]. Impor-
tant for our argument is that suppression mechanisms are themselves compromised
by stress. Just as a parasite can get the upper hand on a patient with a compromised
immune system, so can TEs flourish in a genome with weakened suppression. Thus,
what appears to be switch-like behavior in response to environmental change might
in fact be a breakdown in TE suppression machinery.
These considerations cast new light on the agouti mouse example. Recall that
variability in coat color is caused by variable methylation patterns surrounding
TE insertion upstream of the pigment gene. It is quite plausible that different color
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morphs represent different levels of TE suppression, with more heavily methylated
strains being a step ahead in the coevolutionary arms race. Were this TE to degrade
or be removed, the site would presumably cease to become hyper-methylated and
the yellow phenotype would disappear. Moreover, if this example is typical, and epi-
genetic effects typically involve an effort to suppress TEs, then it is unlikely that
epigenetic mutations will have adaptive effects. It is essentially up to the transposon
to determine where it wants to insert. Selection acting among TE lineages (within
the organism) will favor transposons that avoid detection and deletion. This might
involve stealthy insertions close to genes in some cases or in other cases the avoid-
ance of genic regions altogether, but there is no reason to expect an insertion prefer-
ence for regions that will benefit the host.
David Haig argues that it is often in the evolutionary interest of both the organism
and the transposon for TE insertions to be silenced in somatic tissues (as opposed to
the germ line) [28]. This allows the host organism to survive and reproduce, passing
along its complement of TEs to the next generation. Evolutionary interests conflict
more directly in the germ line. If a TE insertion kills the host, then the TE will be
removed from the population. This imposes a downward selection pressure moderat-
ing the rate of TE replication. However, it has long been recognized that in sexual
species it is difficult for selection to entirely purge the genome of determinantal TEs
[29]. Eukaryotic organisms are stuck with these genetic parasites and, again, there
is no reason to expect that TEs will preferentially insert into regions that are likely
to benefit the host. Nor does the methylation of those insertions occur with some
directed beneficial effect on the organism, other than to mitigate the negative effects
of a TE insertion on normal host function. These considerations cast doubt on the
idea that epigenetic responses to environmental change will tend to be adaptive, at
least, not insofar as they are associated with the suppression of TEs.
If epigenetic differences are typically driven by responses to TE insertion, this
also has implications for the persistence of epi-mutations. Organisms are engaged
in a constant effort to detect and suppress TEs. Eventually, active TE insertions will
degrade and no longer attract methylation. As a result, any TE-mediated switch will
have a limited life span because processes within the organism are actively degrad-
ing it.
What about the suggestion that epigenetic switches respond to specific environ-
mental cues? From a coevolutionary perspective, not just any environmental factor
can be “hooked up” to the epigenetic machinery. If the loss of methylation is typ-
ically caused by a breakdown in TE suppression, then only harmful environmen-
tal factors will induce this type of epigenetic change. Relatedly, after the stressful
conditions have subsided, the TE suppression machinery ought to resume its job
of methylating TE insertions. Hence, unless the organism is exposed to a continual
regime of stress, persisting over many generations, one would expect TE-based epi-
genetic mutations to be short lived.
The topic of TE–host dynamics is a fascinating area of research that would take
us beyond the objectives of this paper to describe in detail. We hope to have said
enough to at least raise questions about the ways that examples of epigenetic inherit-
ance are interpreted by some proponents of the epigenetic switch hypothesis. At the
very least, one might expect that considerations about TE dynamics would be raised
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Transposon dynamics andtheepigenetic switch hypothesis
as an alternative explanation for examples such as agouti gene expression in mice.
Instead of being viewed as an epigenetic switch, the environmental induction and
epigenetic transmission of the colored phenotype might simply be the byproduct of
TE suppression. Why has this alternative been largely ignored by authors working
on epigenetic inheritance?
It has been suggested that the fields of molecular biology and genomics are sim-
ply out of touch with recent trends in evolutionary biology [30]. This could be due
to insufficient evolutionary training in those fields. Another potentially relevant fac-
tor is the high prevalence of adaptationist thinking within molecular biology and
genomics. A number of authors have noted that adaptationist hypotheses are unjus-
tifiably popular in these disciplines [7–9, 31, 32]. Another, non-exclusive possibility
concerns the influence of large research consortia like ENCODE and the economic
incentives driving these projects. Garnering large sums of public funding sometimes
involves interpreting results in ways that sound exciting, revolutionary, or relevant
to human disease. Describing examples like the agouti mouse coat coloration as an
epigenetic switch sounds more exciting than the alternative possibility, that this phe-
nomenon is the fleeting, stress-induced byproduct of a genetic parasite.
We have suggested that information about TE–organism coevolution recom-
mends an explanation of certain epigenetic phenomena that rivals the epigenetic
switch hypothesis. This raises the question of whether, given the ballooning popu-
larity of epigenetics research, those coevolutionary dynamics are generally being
overlooked or downplayed. This question can be explored by comparing the relative
popularity of epigenetic versus transposon research over time and across disciplines.
We expect that researchers working in the field of evolution, who are familiar with
genome-level coevolutionary dynamics, are less enthusiastic about epigenetics com-
pared to researchers working in proximal biological sciences, where evolutionary
thinking is less common. Likewise, if the attraction to epigenetics is influenced in
part by large research consortia like ENCODE, then one might expect epigenetics to
be more popular in biomedical biology and genomics compared to other disciplines.
A related set of questions concerns the ways that different disciplines conceptual-
ize epigenetics. It is possible that researchers in biomedical fields rarely embrace the
epigenetic switch hypothesis and use epigenetic to refer to different phenomena than
researchers working in other disciplines, for instance. The remainder of this paper
describes two bibliometric studies attempting to shed light on these questions.
Methods
Topics anddisciplines
Our methods were inspired by Haig’s survey of scientific articles published between
1950 and 2010, which shows a dramatic increase in the proportion of scientific
papers with epigenetics in the title [19]. Using digital tools and databases associated
with the Web of Science, we undertook two bibliometric analyses of scientific arti-
cles. The Web of Science platform allows users to search for papers containing terms
in specific fields (e.g., title, keywords, or associated metadata). We first selected all
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papers in the Web of Science published in English between 1970 and 2019 that con-
tain DNA in their topic field—which subsumes the title, abstract, author, and key-
words fields—and organized them into five-year intervals. To give some sense of
the results, between 1970 and 1974, there were roughly 10,000 papers published
on DNA. By 2015–2019, there were over 315,000 papers on this topic. We then
selected the subset of DNA papers that also contain epigenetic as a root word in
their topic field and repeated this procedure for transposon/TE/transposable element
as a root word. Considering that the Web of Science is a comprehensive citation cat-
alogue, our analyses likely include the majority of scientific papers published on the
subject of DNA. As a result, scientific interest in epigenetics and transposons can be
compared as proportions of the total scientific interest in DNA over time. Although
the absolute number of papers on any topic will tend to increase given the growing
number of scientific articles published each year, the proportion of papers on a topic
will either rise or fall depending on its popularity. Hence, our measure provides an
estimate of the proportional interest in epigenetics and transposons.
Journals in the Web of Science are assigned codes according to subject, known
as the Web of Science Subject Categories, and all papers appearing within a given
journal are allocated to its corresponding category or categories. When searching
epigenetics within DNA, there are hundreds of categories ranging from genetics and
heredity to logic to theatre. However, most papers fall within a small number of cat-
egories. We focused our analysis on what we identify as four disciplines: biomedi-
cine, proximal biology, evolution, and general biology. Biomedicine is a conjunc-
tion of five Web of Science categories: medicine general internal, medicine research
experimental, oncology, pharmacology, and immunology. These were chosen partly
because they are highly represented and partly because they fall under the general
theme of biomedical research. We lumped them into a single variable primarily to
simplify the analysis. However, we performed a consistency check, comparing each
category within the biomedical discipline to check for anomalies in their relative
proportions.
Likewise, proximal biology is a conjunction of four Web of Science categories:
cell biology, developmental biology, genetics heredity, and biochemistry molecular
biology. Again, these categories are highly represented under the topic of DNA, and
they exhibit a number of thematic similarities. We applied the same rationale and
consistency check to these categories.
General biology and evolution are stand-alone categories provided by the Web
of Science. We included general biology in our analysis with the expectation that it
would provide a baseline for comparing other disciplines. Evolution was included
because of its relevance to our focal questions.
Quantitative analyses
We conducted two quantitative analyses to determine relative scientific interest in
epigenetics and transposons across disciplines. The first analysis tracks the propor-
tion of papers on epigenetics in the broader pool of publication on DNA within each
of the four disciplines across all five-year intervals. The second analysis does the
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Transposon dynamics andtheepigenetic switch hypothesis
same for papers on transposons. These analyses together provide a gauge of relative
scientific interest in these two topics among the four disciplines over the past fifty
years.
Epigenetic commitments
It is widely recognized that the term epigenetic is ambiguous, and it is rarely pos-
sible to glean a definition of this term from a research paper. However, it is usually
possible to discern certain logical commitments based on what authors say about
epigenetic phenomena. For the purposes of our analysis, we propose two dimensions
along which such commitments can be seen to vary. The first dimension involves
authors’ heritability commitment. In classifying some modification to DNA as epi-
genetic, one might simply be referring to a basic mark (e.g., a methylation pattern or
histone modification) that is conspicuously associated with DNA. Minimally, there
need be no commitment as to whether that mark is inherited by daughter cells or for
how long. A stronger commitment maintains that epigenetic marks are transmitted
mitotically when cells divide, but remains agnostic about transmission by meiosis.
A third level of commitment proposes limited meiotic cell division, such as when an
epigenetic mark is transmitted to offspring but no further. Finally, the strongest com-
mitment proposes open-ended meiotic transmission. This is the level of commitment
that is often associated with the epigenetic switch hypothesis. These definitions are
summarized and operationally defined in Table1.
The second dimension concerns authors’ functional interpretation of epigenetic
marks. None of the heritability commitments just outlined implies that an epige-
netic mark is functional. We think it is crucial not to conflate heritability commit-
ments with functional interpretations because both have different epistemic criteria.
Advances in sequencing technology have greatly simplified the ability to detect epi-
genetic marks and their varying degrees of heritability. As the ENCODE contro-
versy reminds us, assessing function is much more difficult and often contentious.
A related concern is that if function is conflated with inheritance, researchers might
gravitate toward a particular functional interpretation without demanding adequate
evidence. Carrie Deans and Keith Maggert note that this is in fact a common mis-
take: “It’s not that histone modification and DNA methylation are not correlated
with gene expression differences—they are—but the possibility that they may be
responsive rather than causal has not been disproved” [33]. The list of functional
roles analyzed in our study are outlined in Table2.
Qualitative analyses
To compare heritability commitments and functional interpretations across disci-
plines over time, we focused on the top twenty-five most cited papers about epi-
genetics under the topic of DNA for each five-year interval from 1995 to 2019.
The reason for not going back further is that one of the Web of Science categories
(evolution) has fewer than twenty-five papers per five-year period prior to 1995 and
would have biased our comparisons. To categorize the heritability commitments
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Table 1 Four conceptions of epigenetic phenomena with varying strengths of heritability commitments
Inheritance Commitment Operational definition
Basic mark The presence or absence of some mark is associated with DNA (e.g.,
methylation, histone modification), but its heritability is unspecified
Applied to abstracts describing differences in epigenetic factors over time
or comparing epigenetic similarities/differences among cells, but making
no explicit mention of whether those factors are heritable
Mitotic inheritance Some mark associated with DNA is transmitted by mitotic cell division Applied to abstracts explicitly mentioning mitotic transmission and/or
describing the persistence throughout division in a somatic cell lineage
Limited meiotic inheritance Some mark associated with DNA persists through meiotic cell division
and/or is transmitted over a limited number of sexual generations
Applied to abstracts explicitly mentioning epigenetic transmission from
parent to offspring up to the F2 generation
Open-ended inheritance Some mark associated with DNA persists indefinitely through meiotic
cell division and/or is transmitted over a large number of sexual
generations
Applied to abstracts explicitly proposing a multi-generational epigenetic
influence (e.g., “transmitted over many generations”) or equating the
heritability of epigenetic marks with genes. This level of commitment is
often associated with the epigenetic switch hypothesis
Table 2 Four functional roles commonly associated with epigenetic marks
Functional role Explanation Operational definition
Disease relation Some epigenetic mark associated with a disease (e.g., tumor growth)
is thought to influence its promotion or suppression
Applied to abstracts implicating an epigenetic mark in some disease, but
not to those explicitly proposing that the mark is involved in normal
gene expression or phenotypic development
Transposon suppression Some epigenetic mark is thought to normally function in the suppres-
sion of TE activity
Applied to abstracts explicitly assigning this functional role to epige-
netic marks, but not to those proposing that TE activity is part of an
epigenetic mechanism for adaptive phenotypic plasticity
Regulation Some epigenetic mark is thought to normally function in the regula-
tion of a gene and/or trait
Applied to abstracts proposing that an epigenetic mark regulates gene
expression or trait development
Phenotypic adaptation Some epigenetic mark is thought to regulate genes in ways that adapt
the organism to its environment, either by adaptively modifying the
phenotype to environmental changes or by stabilizing a beneficial
phenotype
Applied to abstracts explicitly proposing that epigenetic marks preserve
adaptive phenotypes or suggesting that they function in adaptive
phenotypic plasticity. This interpretation is often associated with the
epigenetic switch hypothesis
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Transposon dynamics andtheepigenetic switch hypothesis
and functional interpretations of each paper, we carefully examined each title and
abstract and classified the paper according to the operational definitions outlined in
Tables1 and 2. Only one heritability commitment and one functional interpretation
was assigned to each article.
Results
Our quantitative results are consistent with the trend reported by Haig [19]: there
is a sharp rise in the proportion of epigenetics papers beginning in the mid-1990s
(Fig.1). In the most recent interval (2015–2019), there were in total 316,191 papers
on the topic of DNA. Within just this part of our sample, looking only at our four
focal disciplines, a whopping 19% mentioned epigenetics in the title, keywords, or
abstract. However, there was considerable variation among disciplines over time in
their enthusiasm for the topic. Proximal biology is an early adopter, with biomedi-
cine and general biology showing a more delayed response. By contrast, the delayed
and relatively small amount of enthusiasm coming from evolution is striking. This
discipline begins warming to epigenetics only after 2005, and its contribution to the
pool of papers on epigenetics remains low.
Compared to epigenetics, overall enthusiasm for the topic of transposons is rela-
tively low, never exceeding 2% of the total papers on DNA. Across all disciplines
there is a spike in transposon research beginning in the early to mid-1980s (Fig.2).
Evolution and general biology show steady increases in the proportions of papers on
transposons. By contrast, biomedicine initially shows interest in transposons in the
late 1980s and early 1990s, but this interest tapers in the late 1990s and starts declin-
ing in the early 2000s.
The pattern exhibited by proximal biology is more complicated. Interest in trans-
posons picks up in the late 1980s, flattens during the 1990s, and picks up again in
the early 2000s. Only in the last five years has interest in transposons started to
decline in proximal biology. Our consistency check revealed a divergence among the
categories comprised by this discipline. Within cell biology, developmental biology,
and genetics heredity, the proportional interest in transposons begins to decline only
in the last five years. However, in the field of biochemistry and molecular biology,
the decline begins much earlier and follows a pattern similar to biomedicine.
Turning to our qualitative analysis of heritability commitments, in analyzing
these data we were interested in whether a particular commitment is dominant in a
given discipline and whether the disciplinary prevalence of commitments changes
over the twenty-five-year period. The results reveal that general biology exhibits a
broad mixture of heritability commitments, as might be expected if this discipline is
regarded as a baseline (Fig.3a). A large and stable percentage of papers across the
entire period (32–42%) make basic reference to epigenetic marks without specifying
heritability. There appears to be a slightly growing trend in commitments to mitotic
inheritance, from 8 to 10% of papers in the 1990s to 25–28% in the most recent dec-
ade. Commitments to limited meiotic inheritance have remained stable at 20–30%,
with a slight dip to 7% between 2010 and 2014. The least common commitment is to
open-ended inheritance, accounting for 5–10% of papers throughout.
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Biomedicine exhibits a simpler pattern, with a dominant majority of papers
across the entire period (more than 60%) referring to epigenetic marks of inde-
terminate heritability and a slight increase in commitments to mitotic inheritance
over the last decade (Fig.3b). The majority of papers in proximal biology also
refer to epigenetic marks of indeterminate heritability, ranging from 42 to 72%
(Fig. 3c). However, in the two most recent intervals, commitments to mitotic
inheritance have been roughly equal to commitments to bare marks (32–39%). In
both biomedicine and proximal biology, commitments to limited meiotic inher-
itance are quite infrequent (consistently less than 10%), with almost no papers
committing to open-ended inheritance. This trend is in sharp contrast to that seen
in evolution, where open-ended inheritance is the most popular commitment,
ranging from 42% of papers in the 1990s to around 33% of papers in the most
recent decade (Fig.3d). The next most common commitment in evolution is to
basic epigenetic marks with unspecified heritability (consistently 25–35%). The
Fig. 1 Percentages of papers in the Web of Science on the general topic of DNA mentioning epigenetics
in the title, abstract, or keywords, viewed in five-year intervals across four biological disciplines
Fig. 2 Percentages of papers in the Web of Science on the general topic of DNA mentioning transposons
in the title, abstract, or keywords, viewed in five-year intervals across four biological disciplines (plus
biochemical and molecular biology, a subdiscipline of proximal biology)
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Transposon dynamics andtheepigenetic switch hypothesis
Fig. 3 Breakdown of heritability commitments reflected in abstracts of twenty-five most cited articles on
DNA/epigenetics in the Web of Science per five-year interval in (A) general biology, (B) biomedicine,
(C) proximal biology, and (D) evolution
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S.Linquist, B.Fullerton
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discipline has shown a slight increase in commitments to limited meiotic inherit-
ance in recent years, but very few commitments to mitotic inheritance.
Now turning to our second qualitative analysis, in analyzing these data we were
interested in whether a particular functionalinterpretation is dominant in a given dis-
cipline and whether the disciplinary prevalence of functional interpretation changes
over the twenty-five-year period. Within general biology regulation is the dominant
functional interpretation of epigenetic marks (Fig.4a). However, this interpretation
seems to peak in the early 2000s, when it accounts for 80% of papers, falling to
35% in the most recent interval. In biomedicine, it is perhaps no surprise that the
most common functional interpretation is relevant to disease, with disease-related
functions represented in over 80% of papers for all but one interval, 2010–2014,
when functional interest in regulation briefly spikes to 37% (Fig.4b). By contrast, in
proximal biology, regulation (38–61%) and disease (24–36%) are the two most pop-
ular functional interpretations (Fig. 4c). Interestingly, there is a low but persistent
interest in TE suppression (2–7%) among proximal biology papers across the entire
period. Evolution again diverges from other disciplines. Here there is a shift from a
majority interest in regulation, roughly 70% in 1995–2004, to a majority interest in
adaptation, growing from 52% in 2005–2009 to 86% in 2015–2019 (Fig.4d). Evolu-
tion is the only discipline that shows such a sharp and dramatic swing in the preva-
lent functional interpretation of epigenetic markers.
Discussion
Our analyses in this study were motivated by the question of whether transposon
dynamics are neglected by researchers interested in epigenetics generally, as they
seem to be by some proponents of the epigenetic switch hypothesis. TE coevolution-
ary dynamics have been largely understood since the mid-1980s. So when it comes
to examples like the agouti mice, where phenotypic effects are caused by methyla-
tion of a known TE insertion, one might expect researchers to entertain TE dynam-
ics as a viable alternative to the presence of an epigenetic switch. Yet such consid-
eration is somewhat rare.
It has been suggested that the disciplines of molecular biology and genomics are
out of touch with advances in evolutionary theory [8, 9, 30]. If this is correct, then
one would expect to see less enthusiasm for epigenetics in evolution than in proxi-
mal biology or biomedicine. This prediction is borne out in Fig. 1, where evolu-
tion shows a delayed and relatively muted interest in epigenetics compared to other
disciplines. Figure2 exhibits declining interest in transposons in biomedicine and
in molecular biology, though not in the other categories comprised by proximal
biology (cell biology, developmental biology, and genetics). It is difficult to under-
stand why, as TEs are increasingly recognized as major constituents of eukaryotic
genomes, and given their known mutagenic effects, the biomedical sciences are
gradually becoming less interested in transposable elements. At the very least, one
would expect an increased interest both in epigenetics and in transposons in bio-
medicine, as with the other disciplines in our sample.
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Transposon dynamics andtheepigenetic switch hypothesis
Fig. 4 Breakdown of functional interpretations of epigenetic marks reflected in abstracts of twenty-five
most cited articles on DNA/epigenetics in the Web of Science per five-year interval in (A) general biol-
ogy, (B) biomedicine, (C) proximal biology, and (D) evolution
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S.Linquist, B.Fullerton
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What explains evolution’s delayed and relatively muted interest in epigenetics
compared to other disciplines? Believers in the epigenetic revolution might take this
reticence to suggest that evolution is a conservative discipline, clinging to the dogma
of gene centrism. Alternatively, the discipline’s greater familiarity with transposon
dynamics and genome evolution might mean that its practitioners are simply less
enamored by functional interpretations that ignore these factors. Likewise, the lim-
ited influence of large-scale funding organizations on evolution compared to bio-
medicine and proximal biology might also explain the differential enthusiasm for
epigenetics across these disciplines. For whatever reason, evolutionary thinkers have
been slower to jump on the epigenetic bandwagon. Perhaps questionnaire methods
could help to answer the finer-grained question of why exactly this is the case.
It should be kept in mind that evolution papers on epigenetics have embraced
a different, generally stronger set of heritability commitments and functional inter-
pretations than similar papers in proximal biology, biomedicine, and to some extent
general biology—frequently positing open-ended or limited meiotic transmis-
sion of marks and increasingly interpreting the function of epigenetic phenomena
in terms of phenotypic adaptation. Putting these findings together, one could say
that although the topic of epigenetics is relatively unpopular in evolutionary circles,
those thinkers who do embrace epigenetics are more extreme in both their heritabil-
ity commitments and functional interpretations. Also noteworthy is the sea change
in functional interpretations that occurs in the mid-2000s, away from basic gene
regulation and toward adaptive responses to environmental changes. This coincides
with the publication of Jablonka and Lamb’s influential book [12] and could reflect
its impact on evolutionary thinking.
It is noteworthy that biomedicine and proximal biology largely overlap in their
heritability commitments and adopt quite similar functional interpretations. Despite
the general concern that epigenetics research is fraught with ambiguity [20, 33], our
analysis suggests that at least in these disciplines, authors mean roughly the same
thing by “epigenetic.” The same can be said neither for general biology, where there
is much more diversity in heritability commitments and functional interpretations,
nor of course for evolution.
In sum, our results support the suspicion that interest in transposons is not just
overshadowed by enthusiasm for epigenetics; rather, in some fields where enthu-
siasm for epigenetics is most prevalent (biomedicine, biochemistry, and molecular
biology), interest in TE dynamics is actually on the decline. We suspect that this
trend could lead researchers in these disciplines to uncritically embrace certain func-
tional interpretations, such as the epigenetic switch hypothesis, without due consid-
eration of alternative explanations. We hope that our findings will inspire further
interest in transposon dynamics, especially among researchers drawn to the idea of
an epigenetic revolution.
Acknowledgements Thanks to W. Ford Doolittle, David Haig, and an anonymous reviewer for helpful
comments on an early draft. Katelyn MacDougald provided exceptional editorial assistance. Any remain-
ing errors are the result of our oversight. Stefan Linquist is supported in part by funding from the Social
Sciences and Humanities Research Council of Canada.
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Transposon dynamics andtheepigenetic switch hypothesis
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References
1. Feinberg, Andrew P., and Bert Vogelstein. 1983. Hypomethylation distinguishes genes of some
human cancers from their normal counterparts. Nature 301: 89–92.
2. Feinberg, Andrew P. 2007. Phenotypic plasticity and the epigenetics of human disease. Nature 447:
433–440.
3. Waterland, Robert A., and Randy L. Jirtle. 2003. Transposable elements: Targets for early nutri-
tional effects on epigenetic gene regulation. Molecular and Cellular Biology 23: 5293–5300.
4. Bjornsson, Hans T., M. Daniele Fallin, and Andrew P. Feinberg. 2004. An integrated epigenetic and
genetic approach to common human disease. Trends in Genetics 20: 350–358.
5. ENCODE Project Consortium. 2012. An integrated encyclopedia of DNA elements in the human
genome. Nature 489: 57–74.
6. Elliott, Tyler A., and T. Ryan Gregory. 2015. What’s in a genome? The C-value enigma and the
evolution of eukaryotic genome content. Philosophical Transactions of the Royal Society B 370:
20140331. https:// doi. org/ 10. 1098/ rstb. 2014. 0331.
7. Eddy, Sean R. 2012. The C-value paradox, junk DNA and ENCODE. Current Biology 22(21):
R898. https:// doi. org/ 10. 1016/j. cub. 2012. 10. 002.
8. Doolittle, W. Ford. 2013. Is junk DNA bunk? A critique of ENCODE. Proceedings of the National
Academy of Sciences 110: 5294–5300.
9. Graur, Dan, Yichen Zheng, Nicholas Price, Ricardo B.R. Azevedo, Rebecca A. Zufall, and Eran
Elhaik. 2013. On the immortality of television sets: “Function” in the human genome according to
the evolution-free gospel of ENCODE. Genome Biology and Evolution 5: 578–590.
10. Elliott, Tyler A., Stefan Linquist, and T. Ryan Gregory. 2014. Conceptual and empirical challenges
of ascribing functions to transposable elements. American Naturalist 184: 14–24.
11. Germain, Pierre-Luc, Emanuele Ratti, and Federico Boem. 2014. Junk or functional DNA?
ENCODE and the function controversy. Biology and Philosophy 29: 807–831.
12. Jablonka, Eva, and Marion J. Lamb. 2005. Evolution in four dimensions genetic, epigenetic, behav-
ioral, and symbolic variation in the history of life. Cambridge: MIT Press.
13. Bonduriansky, Russell, and Troy Day. 2018. Extended heredity: A new understanding of inheritance
and evolution. Princeton: Princeton University Press.
14. Gannett, Lisa. 1999. What’s in a cause? The pragmatic dimensions of genetic explanations. Biology
and Philosophy 14: 349–373.
15. Rheinberger, Hans-Jörg. 2000. Gene concepts: Fragments from the perspective of molecular biol-
ogy. In The concept of the gene in development and evolution: Historical and epistemological per-
spectives, ed. Peter J. Beurton, Raphael Falk, and Hans-Jörg Rheinberger, 219–239. Cambridge:
Cambridge University Press.
16. Griffiths, Paul E., and Karola Stotz. 2006. Genes in the postgenomic era. Theoretical Medicine and
Bioethics 27: 499–521.
17. Godfrey-Smith, Peter. 2007. Is it a revolution? Biology and Philosophy 22: 429–427.
18. Haig, David. 2007. Weismann rules! Okay? Epigenetics and the Lamarckian temptation. Biology
and Philosophy 22: 415–428.
19. Haig, David. 2012. Commentary: The epidemiology of epigenetics. International Journal of Epide-
miology 41: 13–16.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

154
S.Linquist, B.Fullerton
1 3
20. Häfner, Sophia J., and Anders H. Lund. 2016. Great expectations: Epigenetics and the meandering
path from bench to bedside. Biomedical Journal 39: 166–176.
21. Sánchez-Tójar, Alfredo, Malgorzata Lagisz, Nicholas P. Moran, Shinichi Nakagawa, Daniel W.A.
Nobel, and Klaus Reinhold. 2020. The jury is still out regarding the generality of adaptive ‘transgen-
erational’ effects. Ecology Letters 23: 1715–1718.
22. Dolinoy, Dana C., Dale Huang, and Randy L. Jirtle. 2007. Maternal nutrient supplementation
counteracts bisphenol A-induced DNA hypomethylation in early development. Proceedings of the
National Academy of Sciences 104: 13056–13061.
23. Kidwell, Margaret G., and Damon R. Lisch. 2001. Perspective: Transposable elements, parasitic
DNA, and genome evolution. Evolution 55: 1–24.
24. Kidwell, Margaret G., and Damon R. Lisch. 1998. Transposons unbound. Nature 393: 22–23.
25. Wessler, Susan R. 1996. Plant retrotransposons: Turned on by stress. Current Biology 6: 959–961.
26. McClintock, Barbara. 1984. The significance of responses of the genome to challenge. Science 226:
792–801.
27. Lisch, Damon, and Jeffrey L. Bennetzen. 2011. Transposable element origins of epigenetic gene
regulation. Current Opinion in Plant Biology 14: 156–161.
28. Haig, David. 2016. Transposable elements: Self-seekers of the germline, team players of the soma.
BioEssays 38: 1158–1166.
29. Hickey, Donal A. 1982. Selfish DNA: A sexually-transmitted nuclear parasite. Genetics 101:
519–531.
30. Brunet, Tyler D.P., and W. Ford Doolittle. 2015. Multilevel selection theory and the evolutionary
functions of transposable elements. Genome Biology and Evolution 7: 2445–2457.
31. Palazzo, Alexander F., and T. Ryan Gregory. 2014. The case for junk DNA. PLOS Genetics 10(5):
e1004351. https:// doi. org/ 10. 1371/ journ al. pgen. 10043 51.
32. Linquist, Stefan, W. Ford Doolittle, and Alexander F. Palazzo. 2020. Getting clear about the F-word
in genomics. PLOS Genetics 16(4): e1008702. https:// doi. org/ 10. 1371/ journ al. pgen. 10087 02.
33. Deans, Carrie, and Keith A. Maggert. 2015. What do you mean, “epigenetic”? Genetics 199:
887–896.
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