Integrative and Comparative Biology Advance Access originally published online on May 22, 2007
Integrative and Comparative Biology 2007 47(2):234-244; doi:10.1093/icb/icm025
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Evolution of ontogeny: linking epigenetic remodeling and genetic adaptation in skeletal structures
Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, AZ 85721 USA
Correspondence: 1E-mail: rlyoung{at}email.arizona.edu
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Synopsis |
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 Synopsis Reconciling phenotypic patterns...Variation in gene expressionEvolutionary consequences:...Skeletal adaptations--what is...ConclusionsAcknowledgmentsReferences |
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Evolutionary diversifications are commonly attributed to the continued modifications of a conserved genetic toolkit of developmental pathways, such that complexity and convergence in organismal forms are assumed to be due to similarity in genetic mechanisms or environmental conditions. This approach, however, confounds the causes of organismal development with the causes of organismal differences and, as such, has only limited utility for addressing the cause of evolutionary change. Molecular mechanisms that are closely involved in both developmental response to environmental signals and major evolutionary innovations and diversifications are uniquely suited to bridge this gap by connecting explicitly the causes of within-generation variation with the causes of divergence of taxa. Developmental pathways of bone formation and a common role for bone morphogenetic proteins (BMPs) in both epigenetic bone remodeling and the evolution of major adaptive diversifications provide such opportunity. We show that variation in timing of ossification can result in similar phenotypic patterns through epigenetically induced changes in gene expression and propose that both genetic accommodation of environmentally induced developmental pathways and flexibility in development across environments evolve through heterochronic shifts in bone maturation relative to exposure to unpredictable environments. We suggest that such heterochronic shifts in ossification can not only buffer development under fluctuating environments while maintaining epigenetic sensitivity critical for normal skeletal formation, but also enable epigenetically induced gene expression to generate specialized morphological adaptations. We review studies of environmental sensitivity of BMP pathways and their regulation of formation, remodeling, and repair of cartilage and bone to examine the hypothesis that BMP-mediated skeletal adaptations are facilitated by evolved reactivity of BMPs to external signals. Surprisingly, no empirical study to date has identified the molecular mechanism behind developmental plasticity in skeletal traits. We outline a conceptual framework for future studies that focus on mediation of phenotypic plasticity in skeletal development by the patterns of BMP expression.
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Reconciling phenotypic patterns and molecular mechanisms of adaptation |
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SynopsisReconciling phenotypic patterns...Variation in gene expressionEvolutionary consequences:...Skeletal adaptations--what is...ConclusionsAcknowledgmentsReferences |
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A goal of evolutionary biology is to understand the origins of diversity. Phenotypic diversity is thought to reflect extensive genetic variation, even among closely related taxa (Lauder 1981
; Raff 1996; Carroll 2002). Because diversification often shows rapid and punctuated evolutionary patterns (Eldredge and Gould 1972; Gould and Eldredge 1993; Raff 1996), and because genes and developmental pathways are often broadly conserved, current hypothetical mechanisms for the origin and evolution of diversity invoke modifications of existing genetic networks rather than the evolution of novel genes or genetic pathways (Scott 1994; Gerhart and Kirschner 1997; Carroll 2001; Davidson 2001; Carroll 2002; Wilkins 2002; West-Eberhard 2003; Amundson 2005). Whereas this new focus advances our understanding of the mechanisms underlying the development and evolution of diversity, it is unclear how existing genetic networks can be modulated for a variety of developmental roles and contexts.
One hypothesis suggests that evolutionary change is facilitated by environmental sensitivity and by modifications of organismal development that induce selectable phenotypic variation (Fig. 1A and D). Moreover, previously neutral genetic variation may gain function under novel or stressful conditions, either through expression of allelic variation (Bergman and Siegal 2003; Hermisson and Wagner 2004; Rice 2004; Wagner and Mezey 2004; Badyaev 2005b; Larsen 2005) or through exploitation of ectopically expressed gene products with no known function (reviewed in Rodríguez-Trelles 2004; Rodríguez-Trelles et al. 2005; Yanai et al. 2006). Environmentally induced recruitment of this "hidden" variation may facilitate the generation of new and favored phenotypic variants through developmental changes induced by novel patterns of gene expression (Fig.1A–D).
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Thus, the environment can facilitate generation of morphological variants either by inducing developmental plasticity or by challenging organismal development, exposing previously unexpressed genetic variation (Fig. 1A). At the same time, the environment also selects induced phenotypes (Fig. 1E), and such selection can act on the developmental mechanism producing that phenotype (Fig. 1G). The long-term consequences of selection on environmentally induced phenotypes depend on the within-generation reliability (e.g., similarity between the signaling and selecting environments) and across-generation predictability of the environment (Oyama 2000
; West-Eberhard 2003). If the inducing environment and the selection on the induced phenotype are predictable, then selection should favor greater developmental sensitivity of phenotypes to the inducing environment (Schlichting and Pigliucci 1998; West-Eberhard 2003; Pigliucci et al. 2006). Over time, repeatability and predictability of an external signal should favor the developmental incorporation of the environmentally induced developmental pathways by favoring genotypes that reliably develop a consistent phenotype across generations (i.e., genetic accommodation; Baldwin 1896; Schmalhausen 1949; Schlichting and Pigliucci 1998; West-Eberhard 2003; Pigliucci et al. 2006).
Whereas the predictions of this hypothesis are consistent with the historical patterns of diversification (reviewed in West-Eberhard 2003), it is unclear how the developmental origins of adaptation and diversification can be integrated with the presumed modulation of existing genetic networks as a mechanistic basis for the evolution of diversity. Illustration of such integration requires a system in which the genetic network regulating adaptive diversification among taxa also mediates within-taxon developmental plasticity. Here, we suggest that genetic pathways of skeletal development fulfill this role because of their common involvement in both epigenetic regulation of growth and remodeling of cartilage and bone in response to mechanical stress as well as development of highly specialized morphological adaptations and innovations (Table 1). Thus, examination of this system provides a unique opportunity to unify the developmental origin of adaptation hypothesis with the proposed molecular mechanism of the development and evolution of diversity.
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A case study in skeletal development and adaptation
Growth and development of skeletal structures involves a series of transitions between cell proliferation and differentiation (e.g., transitions between cartilage and bone) largely regulated by expression of bone morphogenetic proteins (BMPs) (Hogan 1996
; Urist 1997; Chen et al. 2004; Tsumaki and Yoshikawa 2005). Variation in timing and spatial organization of these transitions in cell function is critical in the development of diverse phenotypes; recent studies of evolutionary innovations and adaptive radiations in vertebrate morphology have implicated variations in BMP expression as primary mechanisms inducing adaptive developmental changes in cartilage and bone (Table 1).
Changes in patterns of BMP expression typical of skeletal adaptations (Table 1) are frequently hypothesized to result from mutations in regulatory regions of BMP pathways (Terai et al. 2002; Albertson and Kocher 2006). However, this hypothesis overlooks the crucial role of environmental and other non-genetic inputs into skeletal development despite overwhelming evidence of the close relationship between external stimuli (e.g., muscle loading and diet) and the development of cartilage and bone (Herring 1993; Huiskes 2000; Rauch and Schoenau 2001; Moore 2003; Müller 2003; Lobe et al. 2006). Bone formation is a dynamic process that involves activity of many genes regulating transitions between growth and maturation of cells (Smith and Hall 1990; Atchley and Hall 1991; Atchley 1993; Hogan 1996; Skerry 2000; Chen et al. 2004; Yoon and Lyons 2004; Tsumaki and Yoshikawa 2005; Wutzl et al. 2006). Importantly, these complex genetic pathways of growth, maturation, and remodeling of cartilage and bone are largely regulated by external stress (Herring 1993; Huiskes 2000; Skerry 2000; Rauch and Schoenau 2001; Moore 2003; Müller 2003; Lobe et al. 2006). In fact, much of the variation in skeletal structures is attributed to both internal and external stresses inducing growth and differentiation (Frost 1987; Huiskes 2000; Rauch and Schoenau 2001; Mao and Nah 2004; Badyaev and Foresman 2004; Badyaev et al. 2005; Archer et al. 2006). Such sensitivity to stresses might reflect the importance of internal mechanical stresses for achieving close functional integration between soft (e.g., muscles or blood vessels) and hard tissues during developmental vascularization and innervation (Warrell and Taylor 1979; Lanyon 1984; Herring 1993; Thorogood 1993).
Here, we review the role of epigenetic regulation of cartilage and bone formation, remodeling and repair for the evolution of diversity and adaptation in skeletal structures. First, we examine factors that influence patterns of gene expression, including both epigenetic and genetic effects, and discuss their importance for morphological evolution. Second, we establish the importance of external stimuli for prenatal and postnatal gene-expression patterns, and provide evidence for the existence of individual variation in environmental sensitivity of genetic pathways. Third, we discuss the importance of environmental predictability for the evolution of induced phenotypes. Finally, we propose a hypothesis that a shift in timing of development provides a mechanism enabling not only developmental incorporation of environmentally induced phenotypes across generations, but also increased environmental sensitivity of trait development to epigenetic or environmental stimuli.
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Variation in gene expression |
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SynopsisReconciling phenotypic patterns...Variation in gene expressionEvolutionary consequences:...Skeletal adaptations--what is...ConclusionsAcknowledgmentsReferences |
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Variation in gene expression in skeletal development can result from several factors. First, external stresses on developing tissues can initiate changes in gene expression via modification of the cellular and intercellular environments (Table 2; Skerry 2000
; Rauch and Schoenau 2001; Moore 2003). Second, genetic variation resulting from mutations in regulatory regions can modify timing, location, or levels of gene expression (Terai et al. 2002). Lastly, neutral genetic variation (e.g., "hidden" allelic variation or ectopic expression) can result from either neutral, or unexpressed, variation in regulatory genes or from neutral variation in gene expression due to the complexity of regulatory networks (reviewed by Rodríguez-Trelles et al. 2005). This previously "hidden" variation can facilitate the development of phenotypic variants that might be adaptive under novel environments (Rodríguez-Trelles et al. 2005).
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Epigenetic effects: an example with BMPs
Mechanical stresses are crucially important for regulation of chondrogenesis and osteogenesis, as well as bone remodeling and repair (Herring and Lakars 1981
; Lanyon 1984; Frost 1987; Atchley et al. 1991; Herring 1993; Thorogood 1993; Huiskes 2000; Skerry 2000; Rauch and Schoenau 2001; Mao and Nah 2004). Experimental studies have implicated BMP-2, BMP-3, BMP-4, and, to a lesser extent, BMP-6 as well as Ihh and FGF-2 (know to regulate BMP expression or function) as critically important for the incorporation of external stimuli during skeletal development (Table 2). Moreover, these studies show that timing of mechanical stimulation influences the developmental response to the stimulus. During chondrogenesis BMP-2, BMP-4, and FGF-2 were upregulated under mechanical stress (Wu et al. 2001; Fong et al. 2003) and stress-induced upregulation of these genes determined the transition between growth and differentiation of chondrocytes (Pizette and Niswander 2000; Warren et al. 2003; Goldring et al. 2006). Similarly, when mechanical stimulation was applied during bone growth, BMP-4 was upregulated resulting in increased proliferation and differentiation of osteoblasts (Ikegame et al. 2001; Wu et al. 2001). At the same time, BMP-3 was markedly downregulated during experimentally stimulated bone remodeling, inhibiting bone formation and enabling cartilage differentiation (Aspenberg et al. 2000; Hino et al. 2004). Finally, when bones were experimentally damaged by artificial fractures or surgical separation, BMP-2, BMP-4, and BMP-6 were upregulated inducing growth and subsequent ossification of cartilage (Nakase et al. 1994; Sato et al. 1999; Tsuji et al. 2006).
The effects of mechanically induced expression of BMPs (especially BMP-2 and 4) on growth and development also varied with intensity and duration of mechanical stimulation (Sato et al. 1999; Wu et al. 2001; Mao and Nah 2004). For example, in cranial suture zones, upregulation of BMP-4 initially resulted in growth of osteoblasts, but under prolonged stress led to their maturation (Ikegame et al. 2001; Wu et al. 2001). This variation in phenotypic response to changes in BMP expression likely reflects dose-dependency of the effects of BMPs—a common finding in studies of regulatory networks (Hogan 1996; Davidson 2001; Mao and Nah 2004). The wide spectrum of changes in gene expression patterns that can be induced by mechanical stimulation suggests that such induction has significant evolutionary potential. Indeed, differences in timing of BMP expression are crucial for several adaptive radiations in vertebrate morphologies (Table 1).
Genetic effects
In addition to epigenetic regulation, mutations in regulatory, promoting, and processing regions of genetic pathways of bone formation can generate changes in gene expression. In particular, mutations in regulatory or processing regions allow for changes in gene expression without disrupting cohesiveness of developmental networks (Davidson 2001), and the complexity of regulatory networks represents large mutational targets (Stern 2000; Carroll et al. 2001, Siegal and Bergman 2002). Increased generation of phenotypic variation under this scenario should facilitate diversification of regulatory pathways and corresponding skeletal structures. For example, in a broad examination of molecular evolution in morphogenetic genes among cichlids, Terai et al. (2002) found allelic variation in the pro-domain of BMP-4 consistent with high levels of morphological variation; this variation was related to changes in protein folding, and thus modified downstream effects without disrupting the general function of the gene (Bryan 2002; Terai et al. 2002). However, while fortuitous mutations in regulatory regions of BMPs may facilitate adaptation in some systems, it is unlikely to be the main reason for BMP ubiquity in morphological adaptation and innovation because the lag time required for fixation of a favorable mutation far exceeds the rapid appearance of several BMP-mediated innovations (Table 1).
"Hidden" genetic effects
Patterns of gene expression are often assumed to be confined to times, locations, and levels appropriate to their specific function (Emerson 2003); however, recent studies have revealed high variability in gene-expression patterns (reviewed by Rodríguez-Trelles 2004; Rodríguez-Trelles et al. 2005; Yanai et al. 2006). In novel environments, recruitment of these "hidden" gene products may facilitate development of new phenotypic variants (Rodríguez-Trelles et al. 2005), and developmental exposure of ‘hidden’ allelic variation under stress is often documented (Bergman and Siegal 2003; Hermisson and Wagner 2004; Rice 2004; Wagner and Mezey 2004; Badyaev 2005b; Larsen 2005). Alternatively, variation in gene expression can be produced by "expression leakage," when functional expression of one gene results in non-functional expression of neighboring genes (e.g., transcriptional read-through; Rodríguez-Trelles et al. 2005; Yanai et al. 2006). Exposure of "hidden" variation in gene expression may be especially important in the origin of novel traits because it can induce novelty in the absence of pre-existing functional gene expression (Schlichting and Pigliucci 1998; Newman and Müller 2001; Yampolsky and Stoltzfus 2001; Schlichting 2003; Newman and Müller 2005; Rodríguez-Trelles et al. 2005).
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Evolutionary consequences: genetic accommodation or environmental sensitivity? |
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SynopsisReconciling phenotypic patterns...Variation in gene expressionEvolutionary consequences:...Skeletal adaptations--what is...ConclusionsAcknowledgmentsReferences |
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Novel environments can induce developmental changes by either epigenetic induction of variation in gene expression or by recruitment of existing variation in neutral allelic or ectopic expression (reviewed in Badyaev 2005a
,b; Rodríguez-Trelles et al. 2005). While the production of phenotypic variation via plasticity development and remodeling of bone is common, the mechanisms by which environmentally induced changes in gene expression can generate evolved and specialized morphological adaptations (Table 1) are poorly understood. Here we discuss inheritance of environmentally induced phenotypes and evolutionary incorporation of epigenetic signals into the normal developmental repertoire in relation to predictability of the inducing environment and selection.
Inheritance of environmentally induced phenotypes
Inheritance of environmentally induced phenotypes requires that individuals differ in sensitivity, exposure, or response to environmental signals and that these differences have a genetic component (Scheiner 1993; West-Eberhard 2003; Pigliucci et al. 2006). The first line of evidence for genetic underpinnings of environmentally induced phenotypes comes from studies of the genetics of phenotypic plasticity. The ubiquity of gene-by-environment interactions in quantitative genetics studies of phenotypic variation suggests that genetic variation in plasticity is abundant in nature and is not limited to the accumulation of neutral variation described earlier (for examples in skeletal traits see Heaney 1995; Parfitt 1997; reviewed in Scheiner 2002; Pigliucci 2005). Genetic canalization, common in complex genetic networks, can buffer organismal development from mutations; however, this canalization can break down under novel or stressful environmental conditions resulting in variable gene expression and facilitating the appearance and inheritance of induced phenotypes (reviewed in Badyaev 2005a,b). At the same time, accumulation and occurrence of both genotypic variation in plasticity and "hidden" genetic variation depends on environmental variability over time, and is thus determined by a population's evolutionary history (Meyers 2005; Rapp and Wendel 2005). However, the requirements for maintenance of genetic variation under these two scenarios differ, whereas genetic variation in developmental plasticity is maintained by fluctuating selection (de Jong 1999; de Jong and Gavrilets 2000), neutral variation is accumulated over time (Hermisson and Wagner 2004). When environmental change reveals neutral genetic variation, this previously "hidden" variation is exposed to selection resulting either in fixation or loss. Therefore, fluctuating environments that facilitate the accumulation of genetic variation in plasticity reduce levels of neutral genetic variation.
Predictability of external signals and the evolution of environmentally induced traits
The evolutionary consequences of selection on phenotypic variants depend on the reliability of external signals within a generation (Figs. 1E and 2), the predictability of the environment across generations (Fig. 2), and the source of induced variation. On the one hand, environmentally induced phenotypes resulting from exposure of "hidden" genetic variation under novel environmental conditions should lead to rapid accommodation of phenotypes through loss or fixation of previously neutral genetic variation. On the other hand, the evolutionary consequences of selection for phenotypic variants generated by developmental plasticity depend on the trans-generational predictability and the within-generational reliability of the environmental signals (Fig. 2; West-Eberhard 2003; Gluckman et al. 2007). If an environment is reliable within and across generations, then selection should predictably favor the same phenotype (Fig. 2A). Thus, genotypes consistently associated with a particular phenotype should be favored, resulting in a reduction in environmental sensitivity of trait development via genetic accommodation (Fig. 3). Similarly, if the environment is variable within, but predictable across, generations (Fig. 2B), then over time, selection should again favor the same phenotype. If, however, the environment is variable across generations but constant within a generation (e.g., in short-lived species, Young and Badyaev 2006; Young RL, Haselkorn TS, Badyaev AV, unpublished data) (Fig. 2C), then selection should favor the evolution of environmental sensitivity in trait development (e.g., longer overlap of trait development and function, Fig. 2C), ultimately producing high within-generation phenotypic variability (Fig. 3). Finally, if the environment is variable both within and across generations, then selection should favor the evolution of within-generational flexibility (Fig. 2D; e.g., high rates of remodeling bone) allowing adjustment to shifting phenotypic optima throughout an organism's lifetime (Piersma and Drent 2003).
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Skeletal adaptations—what is evolving? |
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SynopsisReconciling phenotypic patterns...Variation in gene expressionEvolutionary consequences:...Skeletal adaptations--what is...ConclusionsAcknowledgmentsReferences |
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We have shown that phenotypic variation generated by environmentally induced changes in gene expression can be inherited either via the evolution of developmental plasticity or exposure of previously "hidden" genetic variation, and that the evolutionary consequences of selection on environmentally induced phenotypes should result in either genetic accommodation, generating consistent phenotypes across environments, or the evolution of greater environmental sensitivity of development, generating high levels of phenotypic variation in each generation (Figs. 2 and 3). However, the mechanisms by which these two distinct outcomes occur remains unclear.
Given the requirement of epigenetic regulation for normal bone formation (Warrell and Taylor 1979; Lanyon 1984; Herring 1993; Thorogood 1993), any developmental change leading to loss of responsiveness to mechanical or other epigenetic signals would be detrimental. Instead, developmental incorporation of previously environmentally induced pathways and retention of sensitivity to internal inputs can be accomplished by shifts in the relative timing of development and environmental exposure (Fig. 4A). Exposure to unpredictable environmental signals commonly increases throughout ontogeny, and as organisms approach maturity and bones ossify, sensitivity of development of the trait to epigenetic signals decreases (Fig. 4A). Evolutionary shifts in timing of development in relation to organismal exposure to unpredictable environments (Fig. 4) should allow for either developmental accommodation of induced pathways or the evolution of developmental plasticity without disrupting overall epigenetic regulation of skeletal development. Under this scenario, evolutionary incorporation of induced phenotypes can result either from earlier maturation of skeletal morphologies (Fig. 4B1), or by delaying organismal exposure to the environment (Fig. 4B2), e.g., longer gestation or time until dispersal from nest. Reduced exposure of trait development to unpredictable signals should limit the diversity of induced phenotypes, thus facilitating reliable development of a particular, favored morphology (Fig. 5C; Young RL, Haselkorn TS, Badyaev AV, unpublished data). Alternatively, the evolution of developmental plasticity might result from delay in maturation (Fig. 4C1 and C2). In this case, phenotypic accommodation of external stimuli experienced early in development should enable diversity in developmental response facilitating development of locally appropriate morphologies (Fig. 5B). These heterochronic shifts in development of skeletal traits in relation to exposure to unpredictable environments are consistent with observed variation generated by environmentally induced changes in gene expression; earlier or increased expression of Ihh, BMP-2, or BMP-4 can result in premature ossification, thereby inhibiting developmental response to environmental variation (Table 2). Alternatively, delayed ossification may reflect upregulation of FGF-2, prolonging exposure to epigenetic signals (Table 2). Indeed, molecular mechanisms underlying many ecomorphological skeletal phenotypes involve heterochronic shifts in the BMP expression patterns (Table 1).
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Conclusions |
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SynopsisReconciling phenotypic patterns...Variation in gene expressionEvolutionary consequences:...Skeletal adaptations--what is...ConclusionsAcknowledgmentsReferences |
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Drawing upon concepts of evolutionary developmental biology, we show that examination of developmental pathways of bone formation provides a unique opportunity to reconcile phenotypic patterns and molecular mechanisms of morphological evolution. We suggest that both genetic accommodation of environmentally induced developmental pathways and flexibility in development across environments evolves through heterochronic shifts in bone maturation relative to exposure to unpredictable environments. Furthermore, variation in timing of developmental events, such as ossification, can result in similar phenotypic patterns through epigenetically induced changes in gene expression. Finally, we suggest that patterns of BMP expression generating phenotypic variation found in studies of morphological adaptation (Table 1) are consistent with this hypothesis. Whereas multiple morphological adaptations have been attributed to changes in expression of BMPs, the proposed hypothesis suggests that increased phenotypic plasticity in skeletal development should be likewise mediated by patterns of BMP expression. Yet, to the best of our knowledge, no empirical study to date has identified the molecular mechanism behind developmental plasticity in skeletal traits. The approaches outlined here can provide conceptual framework for such future studies by explicitly linking the mediation of phenotypic plasticity in skeletal development to the patterns of BMP expression.
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Acknowledgments |
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SynopsisReconciling phenotypic patterns...Variation in gene expressionEvolutionary consequences:...Skeletal adaptations--what is...ConclusionsAcknowledgmentsReferences |
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The authors are grateful to H. Heatwole and three anonymous reviewers for extensive comments on previous versions of this article and constructive suggestions. The authors also thank D. Acevedo Seaman, R. Duckworth, E. Landeen, K. Oh, J. Rutkowska, and E. Snell-Rood for discussions, and S. E. Vincent, S. P. Lailvaux, A. Herrel, and E. Taylor for the invitation to contribute to this symposium. This study was funded in part by the National Science Foundation grant (DEB-0608356) to R.L.Y. and by the David and Lucille Packard Fellowship to A.V.B.
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Footnotes |
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From the symposium "Ecological Dimorphisms in Vertebrates: Proximate and Ultimate Causes" presented at the annual meeting of the Society for Integration and Comparative Biology, January 3–7, 2007, at Phoenix, Arizona.
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