Co-option of stress mechanisms in the origin of evolutionary novelties

HISTORICAL AMBIGUITY

Stress has a complicated conceptual history (Csermely 1998; Abbott 2001). The concept originated in the context of qualitative medical diagnoses of mental or nervous diseases and later was adopted in the quantitative physiology of organisms and human sociology. Contained within these diverse contexts is an ambiguity reflected in the use of “stress” as both noun and verb (Kültz 2020). The original context exhibited a split between a concern with stressors of modern life and the experience of or response to stress (Abbott 2001, ch. 2). In biological research, this ambiguity grew in two ways. First, stress as a phenomenon can exist at different levels of organization in living systems (genome, organelle, cells, tissues, organs, organisms, populations), including social groups and societal institutions (e.g., “stress tests” for banks). The same applies to the stress response (e.g., the genomic, cellular, or organismal stress responses). Therefore, stressor and response may not be confined to the same level of organization, which leaves an increased number of possibilities to track both empirically and theoretically (i.e., many-many relationships). Second, these multi-level stressors and responses were studied by diverse disciplinary approaches that gave specialized meaning to the concept, especially for the purposes of facilitating measurement (i.e., operationalization) and mathematical modeling. This yielded contradictory terminologies in different branches of science studying stress. These distinct conceptions, sometimes captured by subtle changes in language (e.g., distress), are in various ways interdependent and resist a simple core or essential definition of the term “stress.”

A less-observed facet of this complicated history is a common commitment to the generic nature of stress, both as phenomenon and response. Whether an increased pace of “modern life” or elevated temperatures during ontogeny, stressors were typically general environmental phenomena (e.g., “noise”) and evoked a generic stress response. This was codified in the work of Hans Selye who founded the modern physiological investigation of stress (Selye 1932, 1955). Unlike a bacterial pathogen that colonized and affected a particular organ or functional system, stress applied ubiquitously to the organism. This nonspecificity of stress combined with another ambiguity for stress: the direction of its valence (i.e., positive or negative). Although most research into stress conceives of it as negative, such as high levels of toxins that induce protein unfolding or the production of reactive oxygen species (ROS), it also has been recognized as beneficial to a degree, especially in phenomena like dose-response or hormesis (Calabrese 2018). Just as some but not too much friction is important for locomotion, a moderate amount of challenge is necessary for normal functioning and even protective against the negative impact derived from intense stressors later in life.

These historical considerations might suggest that attempts to univocally answer the question “what is stress?” are misguided and even that using the term “stress” in evolutionary explanations might lead to more confusion than insight. However, the emphasis on the generic nature of stress and the ambiguities manifested by the concept can serve as a guide to investigating the evolutionary relevance and significance of stress. To pursue this task, we need an explicit characterization of stress and several allied concepts. Importantly, we do not claim that our characterization is uniquely accurate; in fact, many of our distinctions are broadly accepted but not always represented with the same terminology (see, e.g., Selye 1955; Romero et al. 2009; Koolhaas et al. 2011; Del Giudice et al. 2018; Kültz 2020). Instead, we seek to resolve ambiguity with respect to how stress as a phenomenon may have played distinctive roles in evolution and how stress responses at different levels of organization are conducive to evolutionary innovation (e.g., Erkenbrack et al. 2018; König and Nedelcu 2020; Schaap 2021).

STRESS: CHARACTERIZED AND CONTEXTUALIZED

In a recent attempt to clarify the meaning of stress for physiological investigation, Kültz recognized the difficulties associated with the concept: “Establishing a succinct definition of ‘stress’ that manages to capture its scientific basis in a universal and unambiguous manner is challenging” (Kültz 2020, p. 1). Kültz sought a complete derivation of stress and allied concepts from analogies with physics. This has some distinct advantages in offering a precise vocabulary, but it also exposes a lacuna: a framework built from the theoretical resources of materials science lacks any account of autopoiesis—the capacity of and need for a biological system to engage in self-maintenance (Maturana and Varela 1972).

Autopoiesis is a form of autonomy and often taken to be distinctive of living organisms (Moreno and Mossio 2015). Although absent from many biological discussions of stress, in part because they concentrate on neuroendocrine systems and behavior in mammalian model organisms (e.g., Romero et al. 2009; Koolhaas et al. 2011), it is crucial for modeling the main features of both stress phenomena and responses, and therefore prompts a specific characterization of stress-related concepts. The damage that stressors cause and the organism's attempt to counteract it by stress responses only make sense when recognizing that organisms maintain their integrity through continual re-constitution of their molecular component parts.

A stressor is any deviation in the value of an external environmental or internal milieu variable from the range of values that is favorable for the autopoietic stability of an entity. This use of “autopoiesis” diverges somewhat from standard uses because we also apply it to organismal subunits, such as organs or tissues—autopoietic stability obtains at different levels of organization. However, it retains core elements associated with the designation: (1) a thermodynamically unlikely material system that needs energy and material turnover (metabolism) to maintain itself; (2) a homeostatic system that is organized so as to compensate for environmental and internally generated perturbations, thereby attaining and sustaining a dynamic equilibrium (e.g., homeothermy); and (3) a self-producing and self-organizing system that continuously replaces components and replenishes activities in the process of maintenance (e.g., protein turnover in a cell or cellular replacement in an epithelium).1 The implication is that the category “stressor” is inherently relational because its members (i.e., internal or external environmental deviations) are defined in relation to a normal autopoietic range of states. In other words, the notion of a stressor is not reducible to the magnitude or intensity of a physical or chemical variable; it must be characterized with respect to the effect of such a variable on an entity with a capacity for maintaining its functioning and integrity. A stressor is always defined in terms of the context of the organic system that is affected by it; 60°C is not stressful for simple thermophiles, but it is for a mammal.

Strain is the metabolic and physiological cost imposed on the organism or other autopoietic entity by attempts to counter the effects of a stressor at some level of organization. The response of the self-maintaining entity to a stressor can be divided into three regimes: homeostatic, stress (sensu stricto), and failure. In the homeostatic regime, regulatory mechanisms compensate for the effect of a stressor such that the strain is below a threshold at which autopoietic processes of the entity incur damage (i.e., the rate of replacement compensates for the damage happening to the system). Homeostatic mechanisms, unlike stress response mechanisms, attempt to directly control the stressor variable (e.g., body temperature or fluid osmolarity).

In the stress regime, the entity or system experiences a higher degree or rate of damage due to the extent of deviation from equilibrium (e.g., body temperature is high despite homeostatic effort, leading to damage) or collateral damage due to the strain induced by homeostatic effort (e.g., the associated metabolic strain leads to an accumulation of ROS that damages DNA, proteins, and lipids). Here, the amount or rate of damage starts to exceed compensation by normal homeostatic mechanisms. In response to this damage, the system deploys mechanisms that attempt to compensate once the threshold between homeostatic and stress regimes is crossed (e.g., response and repair pathways for both DNA and protein damage): this is the stress response in the strict sense. The negative metabolic and physiological effects of the stress regime are generic (i.e., not specific to the nature of the stressor) and include DNA damage, protein misfolding, and chemical degradation of lipids (e.g., peroxidation), as well as programmed cell death in multicellular organisms.

In the failure regime, the accumulated damage reaches a breaking point where the investment in homeostatic effort is causing more damage than can be repaired by the stress response. The failure regime refers to a declining state of the self-maintaining entity that is a consequence of the effects of a stressor, which leads to a progressively increasing accumulation of damage from which the entity cannot recover.2

The term “stress response” picks out the processes by which the self-maintaining unit seeks to limit and repair the damage caused by excessive strain (i.e., in the stress regime). These processes are often generic precisely because different stressors can have similar kinds of negative metabolic and physiological consequences. Thus, both the strain and the stress response are typically generic in character because there are numerous relationships between different normal autopoietic ranges of states at distinct levels of organization and the impact of a stressor on those ranges at one or more levels. Consequently, the stress response is not usually matched to the stressor with any specificity; it is a generalized attempt on the part of the autopoietic entity to avoid entering the failure regime.

In behavioral and physiological stress research, the term allostasis has been introduced to describe “maintaining viability through change,” such as changes in the activation of the vertebrate hypothalamic-pituitary-adrenal axis in response to environmental cues that typically signal the potential presence of threats even when no genuine threat (yet) exists (Sterling and Eyer 1988; Wingfield and Sapolsky 2003; Del Giudice et al. 2013, 2018). This has parallels with the stress response because it also is a change in the mode of reaction to environmental challenges. However, allostasis goes beyond a stress response to actual damage because it is anticipatory—the stress response is activated prior to stressor exposure and therefore prior to metabolic and physiological effects that accompany the stress regime. For instance, the availability of free fatty acids (FFAs) to a cell can lead to the overproduction of ROS and thus genes expressed in the oxidative stress response can be activated by molecules that sense the presence of FFAs, so-called xenosensors, even before ROS levels in the cell actually increase (Schönfeld and Wojtczak 2008; Klotz and Steinbrenner 2017; Sies and Jones 2020). These anticipatory mechanisms are critical for the co-option of stress mechanisms into normal development and physiology.

This characterization of stress and allied concepts might not be satisfactory to many practitioners in various fields where stress plays a central conceptual role, such as mammalian physiology or behavioral biology and psychology. In these fields, stress responses manifest in highly specialized and complex ways that only have a distant echo to the stress phenomenon that must have occurred in our distant unicellular ancestors. We think the emphasis on anticipatory stress responses in areas of physiology and behavioral sciences is justified in those contexts (Levine et al. 1991; McEwen and Wingfield 2003; Romero et al. 2009; Koolhaas et al. 2011). However, these are evolutionarily derived states. The multiplicity of stress concepts in various fields reflects the fact that different disciplines work with systems harboring different levels of evolved complexity and thus focus on different manifestations of the way living systems deal with actual or perceived stressors.

EVOLUTIONARY IMPLICATIONS

Two features emerge from our characterization of the stress concept and allied notions (Box 1). First, the stress response (activated in the stress regime), in contrast to regulation in the homeostatic regime (part of normal physiology), involves a radical reprogramming of metabolism and gene expression in the autopoietic entity, such as a cell or in physiological endocrine signaling. Thus, stress responses are under the control of regulatory mechanisms that switch a gene expression or metabolic profile to an alternative state. Importantly, this ability to switch between different regulatory states is also necessary during the development of multicellular organisms, especially for cell fate decisions. Regulatory state switching is a key reason why cellular stress response mechanisms are likely to be co-opted into the evolution of novel cell types, thereby facilitating cell fate decisions that underlie new cell type identities (see below, Cell Types and Cell Type Differentiation).

Second, the possibility of allostatic anticipation can facilitate more specific matching relationships between stressors (or any other signals) and a stress response. This can normalize stress response mechanisms under predictable life history events—the stressor can be replaced by an endocrine or paracrine signal and thereby become integrated into the normal physiology or development of a species. Consider again the anticipation of oxidative stress, which depends on the detection of molecules in the environment that, once incorporated into cellular metabolism, will lead to the production of ROS, such as FFAs (Sies and Jones 2020). These are broken down preferentially in the peroxisomes of cells where each FFA molecule leads to the production of many molecules of hydrogen peroxide (one H₂O₂ for each two carbon atoms). The detection of FFAs is performed by proteins that belong to a class of transcription factors called nuclear receptors (NRs), which function both as signal receptors (e.g., for steroids like testosterone, estrogen, or progesterone) and as xenosensors in anticipatory allostasis. NRs comprise a gene family, having evolved from a single ancestral NR. A phylogenetic reconstruction of the gene family showed that the oldest known NR lineage belongs to a FFA receptor in a sponge species (Bridgham et al. 2010). This finding is consistent with the hypothesis that the role of NR as signal receptors in development and physiology is derived from an ancestral function as a xenosensor. The developmental functions of steroid receptors are evolutionarily derived from preexisting xenosensor functioning because of anticipatory allostasis mechanisms.

MODELS OF EVOLUTIONARY CHANGE FACILITATED BY STRESS

We are now able to distinguish two different models of evolutionary change that are facilitated by stress (Fig. 1). There is a large body of evidence showing a generalized increase of phenotypic variation when organisms or distinct subsystems at different levels of organization experience strain from a stressor, pushing an autopoietic entity into the stress regime. The corresponding stress response increases the availability of potentially beneficial variants, which makes it possible for adaptation to occur more rapidly than via standing genetic variation (Fig. 1A) (Rutherford and Lindquist 1998). As noted (What “Everyone” Knows about Stress and Evolution), this model—stress-induced evolutionary adaptation—is a member of a broader family of models of evolutionary change based on plasticity where the stress response is one type of plastic response to environmental variation (Fig. 1B; Weber and Depew 2003; West-Eberhard 2003; Badyaev 2005b; Badyaev Alexander 2009; Ehrenreich and Pfennig 2016; Badyaev et al. 2017). An environmentally induced trait becomes undergirded by heritable genetic variation, such as when individuals with different genotypes show different phenotypic responses or different degrees of plasticity (e.g., Rothman et al. 2021), and then natural selection can preserve, augment, and refine these traits occurring in a beneficial direction or remove detrimental plasticity. Eventually, these phenotypes become anchored by genetic alterations and no longer require the distinctive environmental factor to trigger the relevant trait (Fig. 1A, B).

Evolutionary adaptation due to induced plasticity is a more encompassing category because the environmental change need not arise from a stressor that pushes an entity beyond homeostasis into the stress regime (Scheiner 1993; Pigliucci 2001; Murren et al. 2015). The only requirement is some degree of genotype by environment interaction. However, the same basic principle applies: a generalized increase of phenotypic variation that facilitates more rapid adaptive evolutionary change. These models illuminate how quantitative traits, such as size or shape, change through time to maintain an adaptive fit with the environment, indicating how adaptation takes advantage of the consequences of stress. Although it is possible that this quantitative transformation might yield a qualitatively distinct phenotype (West-Eberhard 2003; Levis and Pfennig 2019; Levis et al. 2020; Pfennig 2021), the qualitative change is typically not a new character but rather a novel character state (i.e., a polyphenism), such as a distinct color morph or a different feeding strategy within a life history (Wagner 2014).

In contrast, a distinct type of model for evolutionary change facilitated by stress is SIEI (sensu Wagner et al. 2019). This model incorporates the fact that the stress response involves a switch between regulatory states during the transition from homeostatic to stress regime (Evolutionary Implications). During the evolutionary process, this regulatory shift can lead to a change from one form of variability to another because a distinct set of regulatory genes is active under stress conditions and therefore becomes subject to natural selection. An evolutionary scenario of SIEI in three steps can be illustrated by reference to examples from the evolution of NRs and mammalian embryo attachment: (1) evolution of anticipatory allostatic mechanisms, (2) integration of these allostatic mechanisms into normal physiology, and (3) evolutionary transformation of the stress response into a novel character (e.g., a new cell type). This scenario can apply to any autopoietic unit found in living systems (Fig. 1C).

When stressors are a regular feature of an organism's environment, mechanisms that allow organisms to anticipate future stress evolve. This is possible because features of the environment can be used to predict the arrival of a stressor to activate the stress response network; these features predict strain before the stressor can cause real damage. At the cellular level, this is often mediated by xenosensors, which detect the presence of toxins in the environment that eventually would lead to cell stress of one sort or another. Many xenosensors are NRs, a class of proteins that also play a key role in endocrine and paracrine signaling in multicellular organisms (see above). It is precisely this overlap that is pertinent for the next step of the SIEI scenario: the integration of allostatic mechanisms into normal physiology.

A further refinement of the allostatic response occurs when xenosensors come under the control of internal physiological signals. Well known examples are steroid receptors that mediate hormonal signals from sex hormones and metabolic hormones, such as glucocorticoids. A phylogenetic study of these proteins demonstrated that xenosensors and hormone receptors are related as a monophyletic group of genes (Bridgham et al. 2010). Furthermore, a key cell type identity molecule (Hepatic Nuclear Factor 4) is closely related to FFA receptors and can still bind these molecules (Bridgham et al. 2010). This implies that the specialized hormone and other NRs that are physiological signals evolved from xenosensors that ancestrally regulated the anticipatory, allostatic stress response.

Another scenario that points in this direction is the role of inflammatory mediators in normal cell differentiation. The attachment of an embryo to the uterine lining leads to a transient inflammatory process (the “attachment reaction”) in which typical inflammatory mediators are expressed, such as IL1, IL6, and PGE2 (Mor et al. 2011). Additionally, stromal cells of the endometrium differentiate into decidual cells that are necessary for successful implantation and placenta formation. This differentiation requires PGE2 signals along with the ovarian hormone progesterone (Stadtmauer and Wagner 2021). One of the primary molecules of the inflammatory signal cascade, triggered by embryo attachment, has been co-opted into the differentiation of a novel cell type: decidual cells. The likely change that facilitated the co-option of PGE2 into cell differentiation was the progesterone receptor evolving to switch the PGE2 receptor type from EP4 to EP2. EP2 activates the PKA pathway and turns off the PI4K/Akt pathway; PKA signaling is necessary for decidual cell differentiation (Fig. 2; Stadtmauer and Wagner 2021).

Once the activation of the regulatory network that controls the stress response is integrated into appropriate developmental or physiological conditions, the stabilized output of the stress response network can become subject to natural selection. In the case of eutherians, “appropriate physiological conditions” have been identified for the endometrium. First, progesterone indicates to the uterus that an ovulation has occurred and thus a preimplantation embryo could be in route. The second signal comes from the inflammatory attachment reaction, which yields the production of PGE2. A combination of progesterone and PGE2 indicates that an embryo is arriving, and the uterus prepares for embryo implantation by differentiation of decidual cells. However, a sustained implantation of the embryo requires that these signals not activate the wound healing process; they should only lead to a tissue state that tolerates the presence of the embryo. If the functional output of the decidual cells was wound-activated fibroblasts, then the uterus would seek to repair the wound caused by the embryo. Instead, decidual cells must permit and regulate the implantation process, which is accomplished by the suppression of gene expression in decidual cells that supports wound healing (Nancy et al. 2018) and production of effector and signaling genes such as Laminin, prolactin, and IGFBP1 (Gellersen and Brosens 2014). These features suggest that transcription factor networks controlling the stress response can be co-opted into controlling new phenotypes for new functions.

Thus, the SIEI model concentrates on the mechanistic nature of the stress response and addresses its evolutionary transformation into a derived trait. The stress response of an autopoietic unit is initially protective, mitigating or shielding that unit from damage. In the regular stress response, this halts movement of the autopoietic unit from the stress regime toward the failure regime and returns it to a homeostatic regime. However, over evolutionary time, the regulatory response can become a source for and eventually directly control a new phenotype. Xenosensors (i.e., NRs that sense the presence of toxins) can evolve to become receptors for intra-organismal signals, such as hormones and prostaglandins, thereby integrating stress response mechanisms into the normal physiology of the organism.

Crucially, SIEI models involve both the evolutionary emergence of a new character and the replacement of an environmental trigger (i.e., the stressor) by a physiological signal. What initially was a generic stress response becomes co-opted or stabilized into a new gene regulatory state that represents a novel trait. This transforms the process of protection into a state of compensation. The new trait is specifically poised for activation in the context of a signal or a combination of signals, rather than generally ready to respond to stress. Although variation is always present in this evolutionary process, its generic increase within the stress regime is not in view on the SIEI model. Rather, the existing ability to switch between regulatory states associated with homeostatic and stress regimes, such as inflammation, is incorporated into a specific organismal context through permanent allostatic anticipation. This yields a new, individualized trait that can be fine-tuned by selection for this compensatory role. A cellular response to toxic by-products of metabolism, such as ROS, can become a signal to initiate routine cell differentiation or physiological changes during an organism's life history—the stress response mechanisms themselves are co-opted (Arbiser et al. 2002; Cliff and Dalton 2017).

WHAT ARE THE CONSEQUENCES OF CO-OPTION?

The consequences of co-option are the set of causal powers that a gene or GRN components and their organization contribute to the mechanistic basis of a new character, such as beetle horns, a pigment pattern, the posterior lobe, or a novel cell type (DiFrisco et al. 2020). In the case of a beetle horn, the claim is that the expression of the leg outgrowth GRN has the consequence of directly endowing a region on the back of the beetle with the capacity to have localized outgrowth and proximo-distal differentiation. Explanatory co-option claims typically do not imply that the new structure is a duplicate of the ancestral structure controlled by the GRN; if so, we would speak of a duplicated leg rather than a beetle horn or an eyespot (i.e., there is a novel character identity). In this new context, the co-opted GRN is modified and expressed such that it governs a different phenotypic outcome than in the original developmental context, such as the partial redeployment of the spiracle network in the origin of the posterior lobe of male genitalia (Glassford et al. 2015).

WHAT IS THE COST OF CO-OPTION?

Contemplating the consequences of co-option immediately leads to a consideration of costs. The cost of co-option is the set of detrimental side effects of the co-opted process. For example, the claim that embryo implantation in mammals evolved through the co-option of a mucosal inflammatory reaction in response to embryo attachment (Chavan et al. 2017; Griffith et al. 2017; Stadtmauer and Wagner 2020) involves several, hypothesized beneficial consequences, such as the induction of vascularization and vascular permeability, which might enhance nutrient transfer to the embryo and fetus. However, the same explanatory hypothesis of co-option must address the fact that a generic inflammatory process would not only be potentially beneficial, but also likely harmful, such as via neutrophil recruitment that would attack the embryo. The generic inflammatory process must be modified at the site of embryo attachment and implantation to suppress these negative effects associated with inflammatory processes. This could be addressed in terms of an associated suppression of both IL-17, a key factor in recruiting neutrophils that can cause extensive tissue damage, and PGF1a signaling, which contributes to smooth muscle contractions that can lead to fetal extrusion (Chavan et al. 2021). Considering the costs is necessary to securing an explanatory notion of co-option.

WHAT OPPORTUNITIES DOES CO-OPTION AFFORD?

Opportunities are mechanistic aspects of the co-opted process that do not derive directly from the ancestral causal capacities of the GRN, but rather became possible after the co-option event. Even though these mechanistic aspects were not initially operative, their evolution is enabled or facilitated by the co-opted mechanisms operating in the new structure (DiFrisco et al. 2020). These opportunities from co-opted causal capacities can arise both in space (e.g., different corporeal locations) or time (e.g., at different life history stages). For example, in Gonium (a multicellular volvocale green alga), the retinoblastoma gene (RB) and cyclinD (cycD) cooperate to regulate gene expression during cell division, but in postmitotic cells these proteins also regulate the expression of cell adhesion genes, which are necessary for maintaining cell aggregation (Olson and Nedelcu 2016). These cell adhesion genes are not regulated by RB/cycD in single-celled, algal relatives, such as Chlamydomonas. Hence, the co-option of cell cycle genes in the origin of multicellularity afforded the opportunity for those genes to acquire control over new target genes after the co-option event.

Therefore, to move beyond the descriptive sense of co-option to an explanatory notion, the requisite mechanistic details for why the genetic co-option of network components and their organization explains the origin of a new character can be gleaned from explicit answers to: (a) the developmental, mechanistic consequences of the co-option, (b) the associated costs arising from detrimental side effects to those consequences, and (c) the identification of opportunities afforded by the causal capacities in new locations or at different times, elaborated from those present in the co-opted GRN or character-identity mechanisms (DiFrisco et al. 2020).

CELL TYPES AND CELL TYPE DIFFERENTIATION

The best documented examples of SIEI pertain to the evolutionary origination of novel cell types. Cell types are distinct phenotypic units that are subject to evolutionary change and typically specialized for a functional role within a multicellular organism (Arendt et al. 2016). Increase in the number of discernible cell types is a major mode of body plan evolution. Extant animals vary in the number of cell types from 5 to 30 in Trichoplax (Grell and Benwitz 1971; Smith et al. 2014) to over 500 in mammals (Vickaryous and Hall 2006). For a handful of cases, there is evidence for the co-option of cellular stress mechanisms in their evolutionary origin.

Soma-germline differentiation in volvocine algae

Among the 27 independent cases of the evolution of multicellularity, the origin of soma-germline differentiation in volvocine algae is arguably the best understood example (Davison and Michod 2021). Within this group, soma-germline differentiation has evolved repeatedly and relatively recently (Umen 2020). Two model species represent the opposite extremes along an axis between unicellular and differentiated multicellularity: Chlamydomonas reinhardtii and Volvox carteri (hereafter, Chlamydomonas and Volvox). Between these extremes are multicellular species without stable soma-germline differentiation, such as Gonium pectorale and Eudorina elegans (Fig. 3A).

Two populations of cells are produced during Volvox development: a large number of small cells (<8 μm in diameter) and a smaller number of large cells (Kirk et al. 1993). Somatic cells differentiate exclusively from small cells, whereas large cells form the proliferative germline. Somatic differentiation requires the transcription factor regA, which represses the expression of nuclear encoded proteins of the chloroplast and thus inhibits parts of the photosynthetic pathway (König and Nedelcu 2020). The closest homolog of regA in the single-celled Chlamydomonas is RLS1, which is a component of the cellular stress response pathway under nutrient limitation. Besides sequence similarity, the homology of regA and RSL1 is supported by the fact that regA is also activated in Volvox under stress conditions, such as light exposure after extended darkness.

A variety of experimental evidence (e.g., Kirk et al. 1999; summarized in König and Nedelcu 2016) implies that the somatic differentiation pathway evolved by the co-option of an ancestral cellular stress response into the control of somatic cell type differentiation (Nedelcu and Michod 2006, 2020). The critical role of cell size in somatic cell differentiation might explain this connection; small cells with large chloroplasts are vulnerable to oxidative stress because the volume of the chloroplast stroma decreases faster than the surface area. The chloroplast stroma is the site that consumes the metabolites produced at the chloroplast membranes, which makes a metabolic imbalance in smaller cells more likely. Overall, these data suggest that soma-germline differentiation is homologous to switching between proliferative phases of the life cycle to a survival stage in response to unfavorable conditions (i.e., the cellular stress response) in single-celled algae. The logic of somatic cell type origin involves a temporal alternation in cell state (proliferative vs. dormant) becoming transformed into a spatial, synchronous differentiation—the simultaneous presence of germline and somatic cells in the organism.

DEVELOPMENTAL PATHWAYS, TISSUES, AND ORGANS

Stress mechanisms have not only been detected in connection with the evolutionary origin of cell types; whole tissues and organs have been proposed to carry the imprint of a stress-induced origin. Two that have received substantial attention are the origins of eyes in animals and the process of dorsal closure during insect development. We also highlight cuticle differentiation in Arabidopsis and cetacean epidermis origination.