Biologists have long been interested in why organisms appear to be well-suited to the environments in which they find themselves. Historically, there have been two main explanations: Lamarckism - organisms change over the course of their lifetimes in ways that make them more suited to their environment, and these beneficial attributes are then transmitted to their offspring, or Darwinism - organisms are largely fixed during their lifetimes, but those that are best suited to their environment survive and/or reproduce best, passing their attributes to their offspring. These two explanations are not mutually exclusive, but this dichotomy was reinforced during the mid-1900’s, when Lamarckism was largely rejected while Darwinism was enshrined in what was called the Modern Synthesis of evolutionary biology (Huxley, 1942; Graham, 2016; Bonduriansky and Day, 2018).

The above dichotomy is clearly simplistic and virtually all biologists recognize some important subtleties that blur the distinction between the two. For example, within-generation plasticity, where a given genotype can produce different phenotypes as a function of environmental conditions, is both well-documented and central to current evolutionary thought (Schlichting and Pigliucci, 1998). This does not pose any significant challenge to Darwinism since environmentally-induced phenotypes are not transmitted to offspring. As a result, there is a clear separation between what is called acclimation (adaptive changes in a plastic phenotype within a generation) and evolutionary adaptation (changes in allele frequency across generations). Acclimation is an individual-level phenomenon whereby adaptive changes occur within individual organisms, while evolutionary adaptation is a population-level phenomenon whereby adaptation occurs through a change in the (genetic) composition of a population. Furthermore, the developmental capacity for acclimation through plasticity is, itself, an organismal characteristic that has presumably evolved through evolutionary adaption at the population level.

Within-generation plasticity is ubiquitous but there are also well-known examples in which plastic responses appear to extend from parent to offspring. Maternal effects, in which the environmental conditions of a mother affect the phenotype of their offspring, are probably the best-known examples (Mousseau and Fox, 1998; Marshall and Uller, 2007; Uller, 2008). Such effects can occur, both because mothers transmit many cytoplasmic constituents to their offspring through oocytes, but also because parents in many species (both females and males) provide parental care that can shape the phenotype of their offspring. Nevertheless, it is often reasonable to conceptualize these effects as being mediated by the environment of the offspring rather than that of the parent if we view parental care, and even the conditions under which a female’s oocytes develop, as part of the offspring’s environment. Indeed, this is why studies of evolutionary adaptation often keep organisms in a common environment for multiple generations prior to study, so that these kinds of transient parental effects are ‘washed out’ of the system.

This view of maternal effects as passive, carryover effects from the parental generation is also overly simplistic, and examples are known where parents affect offspring phenotype in an adaptive way (Mousseau and Fox, 1998; Agrawal et al., 1999; Marshall and Uller, 2007; West-Eberhard, 2003). For example, in Daphnia parental exposure to chemical cues indicative of predators result in offspring developing protective armor that reduce their susceptibility to predation. Such effects presumably do not simply result from passive carryover of maternal conditions. Instead, they require an evolved mechanism that actively resets offspring developmental programs each generation in ways that enhance their fitness.

Each of the above phenomena have been readily accommodated by evolutionary theory that originates with the Modern Synthesis by conceptualizing both within- and between-generation adaptive plastic responses as arising from a flexible developmental program that has, itself, evolved through natural selection acting on genetic variation. However, the discovery that plastic changes in phenotype can be transmitted across more than one generation (Jablonka and Lamb, 2005; Jablonka and Raz, 2009; Bonduriansky and Day, 2018) suggests that the line between Lamarckism and Darwinism is more blurred. This is true for at least two reasons.

First, as the number of generations that separate the ancestor and descendent populations increases, it becomes less tenable to conceptualize a descendent individuals’ phenotype as being shaped by direct exposure to the environmental conditions in the ancestral generation. This is why a distinction is often made between intergenerational plasticity, where direct exposure is plausible, and transgenerational plasticity, where it is not (Box 1). The existence of transgenerational plasticity suggests that some form of information, in addition to that carried by the genetic material, is faithfully transmitted over multiple generations. This view is further reinforced by examples of transgenerational effects that are paternally mediated, but where it appears that nothing other than sperm is transmitted by males. Indeed, molecular mechanisms of nongenetic inheritance involving DNA methylation, post-translational modification of histones, and small non-coding RNA have been elucidated in detail (Bošković and Rando, 2018; Henderson and Jacobsen, 2007; Skvortsova et al., 2018).

Second, if the faithful transmission of nongenetic information across multiple generations is commonplace, then this information can, itself, act as a substrate of variation on which natural selection can act. This would blur the line between Lamarckism and Darwinism because any adaptive change in phenotype that occurs between ancestral and descendent populations might then be due to at least three different processes (or any combination thereof): (a) a change in the genetic composition of the population via natural selection (i.e., evolutionary adaption), (b) a change in the nongenetic composition of the population via natural selection, or (c) an induced (i.e., plastic) change in the nongenetic information in the ancestral population that is passed onward to descendants (i.e., adaptive, multigenerational plasticity).

The impact that recent discoveries of nongenetic inheritance and multigenerational plasticity will have on evolutionary theory depends on the relative importance of each of the above three processes. The finding that either selection acting on nongenetic variation is common (i.e., b) or that adaptive, plastic, changes in traits are often transmitted across multiple generations (i.e., c) would represent a significant advance in evolutionary biology. However, here we will confine our attention to the distinction between (c) and (a/b). The key difference is that processes (a) and (b) both involve natural selection operating on variation whereas (c) does not.

To provide compelling evidence for the existence of adaptive multigenerational plasticity we believe that studies should do at least three things: (1) demonstrate that an environmental response is transmitted across generations (i.e., that multigenerational plasticity occurs); (2) demonstrate that multigenerational plasticity improves descendant fitness (i.e., that it is adaptive); and (3) provide an explanation for the mechanistic basis of the phenomenon. To achieve criterion (1) environmental induction of heritable variation needs to be demonstrated, as opposed to selection on existing variation being solely responsible for altered progeny phenotype (Box 2). This requires consideration of potential genetic or nongenetic variation in the experimental strains used (e.g., How clonal are they, what are their mutation and epimutation rates, and what is their effective population size?) and evaluation of potential sources of selection during the experiment (e.g., lethality and differences in fecundity or progeny quality). To achieve criterion (2) explicit tests of the fitness consequences of multigenerational plasticity under ecologically relevant conditions need to be conducted. And to achieve criterion (3) a chain of causality must be defined between environmental stimulus, molecular and cellular mechanisms generating heritable nongenetic variation, and consequential changes in descendant organismal phenotype, typically involving changes in gene expression. Such mechanistic insight is critical to rule out mutation and other potential confounders that could lead to incorrect interpretations.

Box 2.

Distinguishing adaptive multigenerational plasticity from selection on nongenetic variation.

Box 2—figure 1

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The nematode Caenorhabditis elegans is a small, mostly free-living roundworm that consumes a diet of opportunistic microbes on decaying plant matter (Félix and Braendle, 2010; Schulenburg and Félix, 2017). Like other animals, C. elegans suffers myriad slings and arrows in the wild including biotic (e.g., pathogens, predators, and fluctuating food availability) and abiotic (e.g., temperature, salt, etc) stressors. C. elegans is a premier model system with a number of attributes facilitating investigation of genetic, molecular, and cellular mechanisms governing development, behavior, and aging (Corsi et al., 2015). In particular, C. elegans can complete its lifecycle in as little as three days, making it an exceptionally tractable system for multigenerational studies. Since it primarily relies on self-fertilization as a hermaphrodite, C. elegans can be essentially isogenic, especially lab strains. It also displays substantial phenotypic plasticity, and a variety of molecular and cellular mechanisms of nongenetic inheritance have been characterized in C. elegans (Minkina and Hunter, 2018; Perez and Lehner, 2019; Sommer, 2020). Together these properties make C. elegans a uniquely powerful metazoan model to investigate the potential of adaptive multigenerational plasticity.

Below we review and critique the existing literature on adaptive multigenerational plasticity in C. elegans. Many papers claim to have demonstrated adaptive multigenerational plasticity, but we believe important shortcomings exist in individual studies and in the field as a whole.

The ecological and evolutionary significance of nongenetic inheritance hinges on its adaptive value. Extensive research has focused on molecular mechanisms of epigenetic inheritance, but the physiological and adaptive significance of epigenetic inheritance beyond genome surveillance and germline integrity remains obscure (Minkina and Hunter, 2018; Perez and Lehner, 2019). We therefore focus on heritable organismal responses to ecologically relevant conditions. However, it should be noted that our understanding of the dynamics of environmental conditions experienced by natural populations is poor. The frequency, duration, and regularity of specific stressors is not known, and so it is difficult to infer how observed phenotypic responses would actually affect fitness in the wild. Theory suggests that evolution of nongenetic predictive adaptive responses requires variation but sufficient regularity in environmental dynamics such that conditions experienced in one generation serve as reliable cues about future generations (Botero et al., 2015; Proulx and Teotónio, 2017). Otherwise, alternative responses such as phenotypic diversification (i.e., bet hedging) or adaptation through natural selection on genetic variation are expected to predominate.

We believe evidence is mounting in favor of adaptive multigenerational plasticity in C. elegans. However, the case for it could be made stronger by integrating more evolutionary theory into experimental design. For example, distinguishing between selection on pre-existing nongenetic variation and environmental induction of variation is paramount to demonstrating adaptive multigenerational plasticity (Box 2). Inter-individual phenotypic variation is surprisingly common among isogenic C. elegans populations, affecting development, behavior, stress resistance, and RNAi responses (Alcazar et al., 2008; Burga et al., 2011; Jobson et al., 2015; Kimble and Hirsh, 1979; Perez et al., 2017; Rea et al., 2005; Stern et al., 2017; Sulston and Horvitz, 1977). The sources of this nongenetic variation are not well understood, but selection may nevertheless act on it. Evolutionary adaptation through selection on pre-exisiting nongenetic variation also represents a substantial departure from classical views, but this is distinct from adaptive multigenerational plasticity, which posits a heritable, environmentally induced, adaptive, plastic response. Selection on nongenetic variation could also be involved if the induced phenotype increases fitness, but the change in progeny phenotype cannot be based solely on selection, which would reflect evolutionary rather than environmental adaptation. Researchers should be vigilant about the possibility of both viability and fecundity selection, both controlling for it and reporting methodological details pertaining to it (e.g., the number of animals used and the effective population size of their source, whether differential survival or other life-history traits provided an opportunity for selection, etc.). It will be more difficult to monitor selection at the level of gametes or mitochondria, but researchers can at least be mindful of these possibilities.

Given the possibility of selection on pre-existing nongenetic variation, it would be valuable to characterize such variation. For example, the extent of variation in small RNA expression or heritable histone modifications among individuals in wild and laboratory populations could be determined. Rates of change in expression of small regulatory RNAs ('epimutation' rates) has recently been characterized in mutation accumulation lines (experimental strains propagated over many generations with an effective population size of one to minimize effects of selection), revealing that changes arise frequently but typically last only a few generations (Beltran et al., 2020). Such measurements could also be performed in single worms from the wild, from experimental populations, and across generations. This would allow the rate of change to be better characterized along with the degree of variation in populations with different effective sizes. Such measurements could also be performed with selection. Such characterization of epigenetic variation would address whether there is sufficient variation in a founder population to enable adaptation through selection, or, alternatively, if a putative example of adaptive multigenerational plasticity involves epigenetic changes at the population level that cannot be accounted for by selection, implying induction.

It is important to focus on ecologically relevant fitness-proximate traits and to connect nongenetic mechanisms with plasticity, including its induction, inheritance, and expression in progeny. Mechanistic insight will help avoid artefacts, making a stronger case for adaptive multigenerational plasticity. Mechanisms of germline transmission of epigenetic information (small RNAs and histone marks in particular) are receiving a great deal of attention, but much of this work is without environmental or organismal context. It should be recognized that many molecular phenomena may be nonadaptive or neutral with respect to organismal phenotype (Lynch, 2007). In addition, purported cases of adaptive multigenerational plasticity implicate different transmission mechanisms, while the generality of any one mechanism or the relationship among different mechanisms has not been established. Additional sources of nongenetic variation (e.g., altered mitochondria, prions, etc) also deserve greater attention. Understanding the specificity of heritable adaptive responses, and how many distinct responses can be channeled across generations, requires deeper insight into germline transmission mechanisms.

The induction and expression of plasticity needs to be elucidated mechanistically. For example, do germ cells respond autonomously to environmental conditions, or is a somatic response propagated to the germline? The discovery of RNAi illustrated that gene silencing information, either double-stranded RNA or something derived from it, can move from somatic tissues to the germline to influence progeny phenotype (Fire et al., 1998). Genes required for systemic RNAi (spreading of silencing) have been identified (Jose and Hunter, 2007; Winston et al., 2002; Winston et al., 2007), genes required for germline inheritance of RNAi have been identified (Buckley et al., 2012; Spracklin et al., 2017), neuronally-derived small RNAs can influence progeny gene expression (Devanapally et al., 2015), and it has been suggested that such soma-to-germline communication mediates adaptive transgenerational responses (Posner et al., 2019). However, an explicit role of such a mechanism in the context of adaptive multigenerational plasticity has not been demonstrated. Alternatively, (neuro)endocrine signals emanating from the soma could influence germline physiology and inheritance, as shown for insulin/IGF signaling during osmotic stress (Burton et al., 2017).

It is also unclear how nongenetic changes in the germline shape complex traits in descendants. A variety of observations support the possibility that known epigenetic mechanisms such as histone modification or small RNA regulation can influence progeny gene expression, but such a link between epigenetic mechanism and plasticity of the trait in question is lacking from all purported cases of adaptive multigenerational plasticity.

Ultimately, investigation of ecologically relevant traits over a few generations and in limited conditions is not enough. Potential trade-offs complicate interpretation of the fitness consequences of plasticity. For example, there is a trade-off between intergenerational adaptation to osmotic stress and anoxia resistance (Frazier and Roth, 2009), and early life starvation increases resistance to both starvation and heat in progeny (Jobson et al., 2015). Environmental correlations between these stressors are unknown, and these observations complicate experimental interpretations. In addition, two days of starvation at the onset of reproduction in C. remanei appears to increase fitness in the exposed generation but decrease fitness in the next generation, suggesting costs paid for in progeny quality (Mautz et al., 2020), again complicating experimental interpretations.

Given such complications, experimental evolution and other explicit tests of fitness (e.g., competition studies) are critical. Experimental evolution in C. elegans and C. remanei suggests that anticipatory maternal effects, which fall under the umbrella of adaptive multigenerational plasticity, can evolve in scenarios where environmental conditions in one generation reliably predict conditions in the next generation (Dey et al., 2016; Lind et al., 2020). Furthermore, experimental evolution and modeling of more complex scenarios suggests that anticipatory responses acting over two generations can also evolve (Proulx et al., 2019). These studies demonstrate the power of experimental evolution. Future studies investigating additional conditions, environmental dynamics, and genotypes have the potential to reveal what sorts of adaptive multigenerational plastic responses can evolve and if they resemble the documented cases of multigenerational plasticity.

It will also be valuable to identify genes involved in adaptive multigenerational plasticity. If such plasticity evolved through natural selection of genetic variation, as we believe, then it is critical to identify the genes involved. Identification of 'switch' genes governing within-generation plasticity in nematodes has been important to show that plasticity is consistent with the Modern Synthesis (Sommer, 2020). Because different ecological contexts are likely to select for different durations of plasticity as a quantitative trait, it would be valuable to identify genes that affect the perdurance of multigenerational plasticity, as has been done for gene silencing by RNAi (Houri-Ze'evi et al., 2016; Perales et al., 2018). Analysis of genes known to be involved in epigenetic inheritance is a great starting place and underway already, but there are also excellent resources for studying the genetic basis of natural variation in C. elegans (Cook et al., 2017). For example, penetrance of a temperature-dependent mortal germline phenotype varies among wild strains. This is presumably a non-adaptive trait, but it is an example of transgenerational plasticity, and a natural genetic variant affecting it has been identified (Frézal et al., 2018).

It is an exciting time for research on nongenetic inheritance and its potential role in environmental adaption in C. elegans and other multicellular organisms. We believe that closing gaps in our mechanistic understanding and addressing theoretical concerns pertaining to adaptive multigenerational plasticity will ultimately be required if this research is to have a substantial impact on mainstream views about evolutionary adaptation.

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Author details

1. L Ryan Baugh

   Department of Biology, Center for Genomics and Computational Biology, Duke University, Durham, United States

   For correspondence

   ryan.baugh@duke.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2148-5492

2. Troy Day

   Departments of Mathematics and Statistics, Department of Biology, Queens University, Kingston, Canada

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1052-6140

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