origins of differentiation via phenotypic plasticity

EVOLUTION & DEVELOPMENT

5:1, 98–105 (2003)

©

BLACKWELL PUBLISHING, INC.

98

Origins of differentiation via phenotypic plasticity

Carl D. Schlichting

Ecology & Evolutionary Biology, University of Connecticut, Storrs, CT 06269-0043, USA

Correspondence (e-mail: [email protected])

SUMMARY

How cell types of multicellular organisms cameto be differentiated is still an open issue. Here I offer a modelthat posits that the origins of some cell differentiation patternswere originally passive outcomes of environmental effects.As cells’ contact with the external environment was dimin-ished, their patterns of gene expression were altered, due tochanges in concentrations of externally supplied substances.Later, as multicellular growth continued, the relationships ofcell layers to each other shifted, producing concentration gra-

dients of signaling molecules. These gradients emanatedboth from the external cell layer toward the inside and frominternal cell layers to adjacent layers. In this scenario then,differentiation arose initially as a by-product of the changingpatterns of gene expression and of the complex mixtures andchanging concentrations of substances passing among lay-ers. Subsequent selection would operate to stabilize the ex-pression patterns in those cell layers whose phenotypesprovide a fitness advantage to the organism.

INTRODUCTION

Multicellularity has clearly arisen numerous times in eukary-otes (Fig. 1): Buss (1987) estimated 17 origins, and perhapseven certain bacteria could be considered to be multicellular(e.g., Shapiro 1998; Jelsbak and Søgaard-Andersen 2002).Several extant model systems of simple organisms are beingexplored for clues to the origins of multicellularity: the cel-lular slime molds, including

Dictyostelium

(first studied in-tensively by Bonner, e.g., Bonner 1957); the volvocine greenalgae (Kirk 1999); and the mesozoans, an animal phylumlacking an extracellular matrix (Czaker 2000). The origin ofmulticellularity is an interesting problem, with a variety ofperspectives (see, e.g., Buss 1987; Ruvinsky 1997; Kaiser2001; Michod and Roze 2001), but it is the origin of the dif-ferentiation in those multicellular groups that I investigatefurther here.

The production of differentiated cell types is a hallmarkof multicellular organisms. Indeed, this feature undoubtedlyplayed a significant role in their subsequent success by fos-tering division of labor (Buss 1987; Bonner 1988; Bell andMooers 1997; Bull 1999). The degree of differentiationranges from minimal, with only two cell types in some cel-lular slime molds and green algae, to extreme, with well over100 types of cells in some chordate groups (Bell and Mooers1997; Surani 2001). Differential gene expression is recog-nized as the key to cell differentiation in all multicellularorganisms. However, the origins of differentiation remainunclear.

Differentiation in extant animals and plants with theirmultiple cells, tissues, and organs is an extraordinarily intri-

cate process, and a wealth of information has been accumu-lated on its details (Gilbert 2000). The larger picture of howthese details are integrated is only now beginning to emerge(Davidson et al. 2002), and the array of cascades, feedbackloops, and suppressors of gene expression is impressivelycomplex. Because extant patterns of control are likely to beorders of magnitude more intricate than the system in theprogenitor, the clues to the origins of these processes arelikely to be obscured by the innovation and elaboration thathas taken place in the ensuing millennia.

Buss’s 1987 book,

The Evolution of Individuality

, re-mains the most in-depth examination of the topic. He definedthe central problem as “the incompatibility of maintainingcooperation among cells while simultaneously increasing di-versity” (Buss 1987, p. 35). He envisioned the origin of dif-ferent cell types as the result of competition between wild-type and mutant cell lineages within the undifferentiatedmulticellular organism. According to Buss (1987, p. 76), thefate of the new mutant lineage hinged on its interaction withthe external environment, its mastery of the internal environ-ment (competitive success at capturing nutrition), and itseventually gaining access to the germ line. Patterns of differ-entiation would subsequently be derived as the successfulcell lineages would “replay [the] sequence of interactions”(p. 78) between lineages.

Although overall the book is a masterful treatise, seeingthis competitive scenario through to its conclusion of coex-istence and division of labor is problematic (Gilbert 1992).The main dilemma is the fate of the original cell line: If thisline no longer contributes to the germplasm, how are both itsphenotype and that of the mutant line maintained in future

Schlichting

Origin of differentiation

99

generations? A recent model also has pointed out limitationsto the degree of specialization possible in mixed genotypesystems (Wahl 2002).

Here I present a model for the evolution of differentiationthat circumvents the problems posed by having different ge-notypes in the same group of cells. I take the approach of re-turning to those early days, envisioning the process of firstforming a multicellular organism. Building on current under-standing, I reconstruct the sequence of events and their con-sequences for an organism as it grows. The perspective I useis that of the developmental reaction norm, proposed bySchlichting and Pigliucci (1998). There we briefly discussedthe developmental process itself as a reaction norm (pp. 257and 289–292): This view considered individual cells as ge-notypes that are exposed to changing internal and externalenvironmental conditions and that react to these changes ingenotype specific fashion.

When we consider internal environments, we often takefor granted that the internal conditions of an organism repre-sent a specific environmental milieu. Similarly, we routinelyforget just how pervasive environmental influences are in therelationship between genotype and phenotype (Gilbert 2001;Schlichting 2003a). Even nucleic acids and enzymes havereaction norms. DNA and RNA typically function onlywithin particular ranges of temperature and pH, as do en-zymes and other proteins. In a sensational example, someAntarctic fish produce “heat” shock proteins at 5

�

C (Maresca

et al. 1988), due to evolution not in the protein itself but inits regulation.

A number of other authors have made proposals that con-tain one or more components of the model proposed here.Here I bring together these ideas and extend the metaphor ofdevelopment as a reaction norm to provide a scenario for anorigin of differentiation in multicellular organisms.

THE MODEL: DIFFERENTIATION AS PLASTICITY

The key features and sequence of events of the model are asfollows:

I. Changes in the local environment around a cell occurnaturally as new cells are added during growth (Fig.2). As cells’ contact with the external environmentwas diminished, their patterns of gene expressionwould be altered, due to changes in concentrations ofexternally supplied substances.

II. Changes in gene expression of new cells arise pas-sively, mediated directly by the changes in the envi-ronment of individual cells (Fig. 3). As multicellulargrowth continued, the relationships of cell layers toeach other would also shift, producing concentrationgradients of signaling molecules. These gradients wouldemanate both from the external cell layer toward the in-side and from internal cell layers to adjacent layers.

Fig. 1. A sketch of eukaryotic phylogeny, depict-ing major clades, and those with multicellularforms. Traditional multicellularity: organismswith numerous differentiated cell types. Divisionof labor: groups with few differentiated cell typesbut at least somatic vs. reproductive forms in asingle “organism.”

100 EVOLUTION & DEVELOPMENT

Vol. 5, No. 1, January–February 2003

III. Altered gene expression patterns result in new cellphenotypes (i.e., differentiated cell types). Differen-tiation, then, can arise initially as a by-product of thechanging patterns of gene expression, and the in-creasingly complex mixtures and changing concen-trations of substances passing among layers results inchanges in morphological phenotypes of cells.

IV. Certain of these new cell phenotypes will result in afitness gain for the group of cells. These phenotypesmay be due to expression of existing adaptive plasticresponses or as a result of the expression of hiddenplastic capabilities. New mutations will also providevariation in reaction norms.

V. Subsequently, selection will favor the canalization ofthis expression pattern (i.e., genetic assimilation).Evolutionary change will operate to stabilize the ex-pression patterns in those cell layers whose pheno-types provide a fitness advantage to the organism.

A number of authors have proposed one or more of thesepoints, and I briefly review these antecedents here. For easeof navigation, I discuss the points made by the authors, fol-lowed by the Roman numeral of the above stage to which itcorresponds.

De Loof (1993) proposed that the initial step in differen-tiation is the generation of polarized cells. In many animalsthe embryo is already polarized; in others the stimulus for

polarization might be environmental. Derivatives of polar-ized cells will differ in the properties of the plasma mem-brane or cytoskeleton (I). These differences will be propa-gated in the cell clusters that form subsequently, leading togroups of differentiated cells with different patterns of pro-tein synthesis and cell morphology and physiology (III). An-other work with a theme of differentiation as a reaction normis that of Wolpert (1994), who proposed a model of the evo-lutionary transition from a unicellular to a multicellular ani-mal. He envisioned environmentally induced alterations inthe cell cycle (I) as the factor initiating multicellularity andthat these alterations could subsequently be fixed through theprocess of genetic assimilation (V). Curiously, Wolpert in-vokes not the environment but nonequivalence and gene du-plication as the sources of cell differentiation. Sarà (1996)argued for the importance of epigenetic inheritance of envi-ronmentally induced states of gene expression and morphol-ogy (II and III); adaptive mutations can be genetically assim-ilated to create “new” traits (V).

Schlichting and Pigliucci (1998) discussed numbers I–IIIand V: “[T]he simple addition of more cells creates an inte-rior versus exterior and establishes . . . a gradient of differentexposures to the outside environment” (I; p. 290). “[D]evel-opment is itself a temporal reaction norm, as cells express (orsilence) genes depending on the local ‘environment’” (II;p. 257). “[C]ells may expose unexpressed portions of theirreaction norms in the ‘new’ internal environments created by

Fig. 2. Diagram depicting changes in the“environment” (shading) of cells asgrowth proceeds from a single cell (e.g., azygote) to a multicellular form.

Fig. 3. Representation of changes in gene expression that may be produced by alterations of the environmental conditions experi-enced by cells at different distances or different numbers of cell layers from the external environment. E, external influence; I, internalinfluence.

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101

growth” (III; p. 291). “[T]he evolution of development itself hasbeen a continual process of genetic assimilation” (V; p. 316).

Surani (2001) discussed the ability of pluripotent stemcells to produce the array of differentiated cells of adult hu-mans, noting that the “distinguishing features of cells arisefrom an orderly selection of genes that are expressed” (III). Akey feature of such cells is their ability to “lock in” those geneexpression patterns via epigenetic mechanisms such as methyl-ation of DNA (V).

Brand et al. (2001) considered plant development in rela-tion to responses to internal environmental information.They noted that although plant cells themselves do not move,their relative positions within a meristem change after celldivisions (I), leading to changes in gene expression profiles(II) and thus also their functions (III). They observed thatmeristematic cells must constantly assess their position andsignal others cells with this information.

Newman and Müller (2001) proposed an extended modelof the origin of new characters via epigenetic interactions ofcells with both external environments and the changing in-ternal environments produced by growth (I). Differentiationwould arise as the result of plastic responses directed by theinnate physical properties of cells and tissues (III). Subse-quently, “physical morphogenesis would be secondarily cap-tured and routinized by genetic circuitry” (V; p. 314).

EVIDENCE

I. Simple growth of a multicellular form itself results in changes in the numbers and spatial relationships of cells, that is, it creates newinternal environmental conditions

Evidence that internal environmental conditions change asorganisms grow comes in a variety of forms. Bouget et al.(1998) showed for embryos of

Fucus

(a brown alga) that af-ter cell polarization at the two-cell stage by a light signal,pattern formation is produced by positional control and is notdetermined by specific cell lineages. In

Arabidopsis

, both tri-chome and stomatal spatial patterns are determined by dis-tance from existing trichomes/stomata and are also indepen-dent of cell lineage (Schnittger et al. 1999; Geisler et al. 2000).

The wealth of studies on

Drosophila

embryonic develop-ment clearly indicate that positional information is vital todetermining cell fate (e.g., Hatini and Dinardo 2001; Houch-mandzadeh et al. 2002). The same is true of the fate of neuralstem cells—identity is determined by the particular locationof the cell in the neuroectoderm (Temple 2001).

II. Changes in environmental conditions elicit changes in patterns of gene expression

Although alterations of phenotypic traits mediated by exter-nal environmental changes are well known for all types of

organisms (Bradshaw 1965; Shapiro 1976; Schlichting 1986;Harvell 1990; Gotthard and Nylin 1995; Gilbert 2001), thelinks to changes in gene expression have rarely been demon-strated. The advent of microarray analysis has allowed easy il-lustration of changes in gene expression patterns in responseto changes in the external environmental conditions (e.g.,Riehle et al. 2001; Seki et al. 2001; Tusher et al. 2001).

Walter and Biggin (1996) found that binding of DNA of

even-skipped

and

fushi-tarazu

was altered substantiallywhen performed in vitro compared with in vivo. Piatigorsky(1998) discovered that the expression of the

alpha B-crystallin

gene (encoding a small heat shock protein) in the cornea de-pends partially on induction by internal environmental influ-ences. These examples point out the importance of the localmilieu for generating the changes in gene expression thatmust underlie common patterns of embryonic induction.

A revealing example of the complexity of local (internal)control of gene expression is the case of

endo16

in the sea ur-chin embryo, which is expressed at three times during devel-opment: at the blastula stage to specify the endomesoderm,at gastrula stage in the archenteron, and later only in the mid-gut (Yuh and Davidson 1996). It accomplishes this by usingnine transcription factors on two

cis

-regulatory modules thatoperate both alone and interactively depending on the cellu-lar environment (Yuh et al. 2001). Further enhancement andrepression are achieved by four additional modules, withbinding sites for 12 transcription factors.

III. Plasticity of gene expression resultsin production of different cell types

In a review of pluripotent stem cells, Donovan and Gearhart(2001) noted that in vitro differentiation of these cells hasbeen achieved by “manipulating their environment by trialand error.” A variety of studies has shown that altering geneexpression patterns in particular tissues can result in the pro-duction of new morphological structures. For example, Pienet al. (2001) created transgenic plants with localized induc-tion of expansin genes in meristems, resulting in the expres-sion of the developmental cascade of leaf formation. In par-ticular environmental conditions,

Candida albicans

has theability to plastically switch between a round budding growthform and a hyphal growth form: These forms have differentpatterns of gene expression and pathogenicity (Soll 2002).

I–III

Many studies of pattern formation have emphasized the im-portance of internal environments, morphogen gradients,and ensuing changes in gene expression leading to changesin cell type in developing organisms (Gilbert 2000; Gurdonand Bourillot 2001; Irish and Jenik 2001; Scheres 2001). Aclassic example of differentiation following from a separa-tion of internal and external cells is the mammalian blasto-cyst (Gilbert 2000). At the eight-cell stage, all cells are di-



rectly exposed to the “external” conditions. By the 16-cellmorula there is the first distinction between internal and ex-ternal cells. Most external cells will form the trophoblast, theprecursor to the chorion, whereas the internal cells (and sev-eral derivatives of external cells) will produce the inner cellmass. Subsequent differentiation of the inner cell mass isagain position dependent: Cells in contact with the blastocelewill eventually form the yolk sac, and those adjacent to thetrophoblast will produce amnionic and embryonic tissues. Anumber of studies have now identified distinctive patterns ofgene expression and methylation for these tissues (Pesce andSchöler 2001; Pelton et al. 2002; Santos et al. 2002).

IV. Some of these new phenotypes providethe multicellular organism with survival or reproductive advantages

There are innumerable examples of presumably adaptivefeatures of organisms that may have arisen via responses tointernal environmental influences, but which are now part of“programmed” inductive differentiation. There are fewer ex-amples that allow us to directly address both the mechanismand the adaptive nature of plastic changes in the pattern of in-ductive differentiation. One interesting example is the workof Emlen and Nijhout (1999) on the beetle

Onthophagus taurus

with dimorphic males: Only those achieving a certain sizethreshold produce horns. Application of juvenile hormone in thelast larval instar results in allocation switches between cell types:Males produce smaller horns than expected but larger compoundeyes, indicating plastic responses that reallocate resources be-tween exoskeleton and eyes. It has been shown that males withlarger horns have an advantage when competing for mates(Emlen 2000; Moczek and Emlen 2000; Nijhout, this issue).

There is a variety of examples of increased fitness of uni-cellular organisms that change phenotypes in response to en-vironmental change. For example, Kawai et al. (2001) foundthat fission yeast cells lacking functional

tor1

(a protein ki-nase) have slow growth rates and do not initiate sexual repro-duction when nitrogen starved. Expression of Tor1 appearsto be related to adaptive response to a variety of environmen-tal stresses. Likewise, there are good demonstrations thatphysiological or morphological plastic responses can pro-vide significant adaptive advantages for multicellular organ-isms (e.g., Schmitt et al. 1995; Baldwin 1999; Weinig 2000;Avila-Sakar et al. 2001; van Kleunen and Fischer 2001).

V. The facultative phenotypic expression resulting from plasticity is canalized so that cell phenotypes become constitutively expressed

Volvox carteri

is a multicellular green algae with only twocell types: Somatic cells are flagellated and positively photo-tactic but do not divide after differentiation; the unflagellatedgonidia function only in reproduction. Stark et al. (2001) ex-amined the details of how the gene

regA

enforces the dichot-

omy between these cell fates, finding two enhancers that pro-mote expression of

regA

in somatic cells and a silencer thatinhibits

regA

transcription and results in production of thegonidia.

If cell types are initially produced in response to environ-mental signals, what are the mechanisms that keep themfrom changing again in response to other signals (Irvine andRauskolb 2001)? Newman and Müller (2001, p. 307) statedthe problem in this way: without mechanisms for stabilizingcharacter expression, “the ‘heritability’ of the multicellularstate would have depended on the persistence of the new ex-ternal conditions.” The key requirement, then, is for mecha-nisms of canalization. These have been increasingly investi-gated (e.g., methylation, Surani 2001), and Meyerowitz(2002) briefly reviewed those known in plants and animals.

EPIGENETICS AND PLASTICITY

The evidence from modern systems is congruent with themodel proposed above for an origin of differentiation arisingfrom plastic responses of cells to signals in their local (inter-nal) environment. Gene expression patterns can be signifi-cantly altered by both external and internal environmentalconditions. Plastic responses in physiology and morphologyare well documented, as are their effects on fitness. And ourunderstanding of the machinery for fixing the phenotypes ofdifferentiated cells and their offspring is increasing.

The process by which all this can be achieved is geneticassimilation: A phenotype that is produced initially as a plas-tic response is converted to a constitutive phenotype, viamodifications of the genetic system (Waddington 1942;Schmalhausen 1949). As pointed out by Schlichting and Pig-liucci (1998) and Newman and Müller (2001), developmen-tal sequences that begin as plastic responses to changingconditions can be canalized by means of the construction ofgenetic architecture that fixes phenotypic states by limitingsubsequent responsiveness to environmental cues (internalor external).

What are the differences in the model proposed initiallyby Schlichting and Pigliucci (1998) and extended here fromthat of Newman and Müller (2001)? Although Newman andMüller note that morphogenetic changes can play a role incontrolling gene activity (p. 310), such changes in gene ex-pression do not play a prominent role in their model (pointII). We are in agreement that the initial stages of differentia-tion would have been generated strictly randomly: “the ori-gins of ontogeny were probably purely

passive

” (Schlichtingand Pigliucci 1998, p. 290), and “innovations initially origi-nate as ‘pure’ consequences of ubiquitous material and de-velopmental propensities” (Newman and Müller 2001, p.312). In fact, simulation models of morphogenesis have alsofound that differentiation originates spontaneously as a by-

Schlichting


103

product of growth (Furusawa and Kaneko 2000; Hogeweg2000a,b). However, we diverge strongly in our notions ofhow such novel forms subsequently become established.Most significant are the departures of our views of the rolesof natural selection and genetic variation in producing the ul-timate diversity of form.

Newman and Müller (2001) suggested that these eventsare still random, the results of frozen accidents: “While notevery physically attainable multicellular form would neces-sarily prosper, many strikingly different kinds would. . . .with no requirement for competition or differential fitness”(p. 309). In their view, selection on genetic variants wouldhave become an important force only after establishment ofthe body plans. In fact, they propose that “Genetic change . . .with respect to morphology . . . mainly plays a consolidatingrole rather than an innovative one” (p. 315).

With these views I disagree vigorously. The diversityof multicellular forms would be initiated as by-products ofplastic responses, but the ultimate success of these formswould be due to modifications based on existing or newlyproduced genetic variants. These variants could have theirown distinctive reaction norms to the environmental changesproduced by growth. Variants that enhanced the fitness ofthe multicellular group would be propagated via natural se-lection. As Newman and Müller (2001) pointed out, furtherenvironmental change can yet again modify phenotypic ex-pressions, but again any novelties would have to prove theirmettle against existing forms.

Newman and Müller (2001) also suggested that mecha-nisms of genetic integration evolved after the origins of multi-cellular forms, but there is no reason to believe that integra-tion and modularity were absent in any of the ancestors ofmodern multicellular organisms. The distinctive patterns ofgene expression in bacteria and yeast in response to environ-mental variation clearly indicate strong compartmentaliza-tion of gene functions in single-celled creatures (e.g., Eisenet al. 1998). Although it is true that many of the cell pheno-types produced in early multicellular organisms may havebeen “random” responses to novel internal environmentalvariation, existing mechanisms of plastic responses mayhave played a significant role as well. These two possibilitiessuggest a hypothesis that can be tested.

If the plastic responses of cells formed the basis for earlydifferentiation patterns, then the particular form of responseto the internal environmental variation has two potentialsources. The first source would be the set of preexisting plas-tic responses in the single-celled ancestors. This wouldlikely be a diverse group, because the external cues in thoseancient aquatic environments would have included an arrayof physical and chemical factors (e.g., pH, salinity, O

2

andCO

2

concentrations, and levels of inorganic chemicals), aswell as the biotic diversity of predators, parasites, and con-specifics. Some of these preexisting systems of adaptive

plasticity could be used and modified to develop responsesto the changes brought about by growth. If this is the case,then a comparison of systems of responses to cues will be in-structive: The mechanisms of signaling and responses to

ex-ternal

cues of the unicellular or colonial relatives of the ances-tral progenitor should be similar to mechanisms of response to

internal

cues in the modern multicellular descendant.The second source of phenotypic responses would lie in

the

hidden reaction norm

of the organism. This is the set ofplastic responses that are elicited in reaction to novel envi-ronmental cues (Schlichting and Pigliucci 1998; Schlichting2003b). Although hidden reaction norms are largely unex-plored, a smattering of studies indicate a surprising amountof genetic variability hidden by regulatory systems. Thisvariation is released when environmental parameters exceedthe boundaries within which the canalization system oper-ates (Schlichting and Pigliucci 1998; Gibson et al. 1999;Newman and Müller 2001; Queitsch et al. 2002). For exam-ple, Szafraniec et al. (2001) showed that a yeast strain thataccumulated more new mutations because of a mutant mis-match-repair protein showed no ill effects until it was sub-jected to thermal shock. Phenocopies, plastic responses thatmimic the effects of known mutations, are better known ex-amples of components of the hidden reaction norm (e.g.,Goldschmidt 1940; Ho et al. 1983; Chow and Chan 1999).As in the case of random mutational variation, unselectedphenotypes generated from the hidden reaction norm wouldhave a low probability of being adaptive.

CONCLUSIONS

A model of the origin of multicellular differentiation patternsvia plastic responses of cells to changing environmental con-ditions during growth is clearly plausible. I have proposedone test of this hypothesis. Other approaches to investigatingthis issue could come from experimental work with unicellu-lar organisms that occasionally exhibit cell adhesion via mu-tations or perhaps even in novel environments. These couldbe examined for both the changes in gene expression and thephysiological and morphological phenotypic responses. Inaddition to the volvocine green algae (Kirk 2000), anotherinteresting system already studied for its plasticity is thegreen alga

Scenedesmus

, which produces a variety of forms(ranging from single cells to four-cell colonies) that vary insize and spination patterns (Trainor 1995, 1996). Theseforms are produced in response to seasonal and local envi-ronmental variation.

In the current processes of development, the differentia-tion of cell types is

still the result of plastic responses by theprecursor cells—

it is the further differentiation of thesecells, under typical environmental conditions, that has beenprohibited during the evolutionary process (i.e., canaliza-



tion) (Newman and Müller 2001). Buss (1987) pointed outthe key importance of mutations that would produce regula-tion. In fact, the evolution of systems of regulatory gene con-trol are necessary because one of the emergent properties ofgrowth-as-differentiation is a genetic architecture dominatedby pleiotropy and epistasis: Many characteristics of the multi-cellular phenotype will be highly genetically correlated(Schlichting and Pigliucci 1998, p. 291).

Differentiation and canalization processes have com-monly been referred to as

epigenetics

, a term that maintainsa distinction between responses to external and internal en-vironmental variation. This distinction, however, really onlyrefers to the signal source, not to the site of its effect: All “en-vironmental” signals must be received and processed by indi-vidual cells (Schlichting 2003a). All phenotypic responses,whether changes in gene expression, metabolic activity,growth, or behavior, are ultimately stimulated by such sig-nals. In addition, the effectiveness of the path from signal re-ception to response will ultimately be measured in the cur-rency of fitness (survival or reproduction) regardless of thesignal’s initial source. Thus, the processes that we routinelyrefer to as “epigenetic” can be perhaps usefully considered asplastic responses to environmental stimuli. In this light, thetheories and models of evolution of organisms in heterogeneousenvironments might be profitably applied to the evolutionof development and the plasticity of cell form and function.

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