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377 Epigenetics: Linking Genotype and Phenotype in Development and Evolution, ed. Benedikt Hallgrímsson and Brian K. Hall. Copyright  by The Regents of the University of California. All rights of reproduction in any form reserved. 21 The epigenetics of Dysmorphology CRANIOSYNOSTOSIS AS AN EXAMPLE Christopher J. Percival and Joan T. Richtsmeier conTenTs The Epigenetics of Craniofacial Dysmorphology A Broad View of Craniofacial Development The Epigenetics of Craniosynostosis Genes and Gene Networks Mechanical Interactions External Environmental Interactions Discussion and Conclusion Acknowledgments References Important discoveries in the field of evolutionary developmental biology have added significantly to our understanding of the evolution of developmental processes and the production of novel phenotypes, thereby advancing our knowledge of the molecular bases of genetic disease. This is especially true in the field of craniofacial biology, where anomalies of the head and neck account for 75% of all congenital birth defects (Chai and Maxson, 2006). Advances in the understanding of craniofacial dysmorphogenesis have come from varying approaches. Perhaps the most successful approach over the past 20 years has been the genetic mapping of diseases using human samples followed by a focused investigation of the function of the identified gene(s) and its association with craniofacial growth and development. These approaches have resulted in the identification of disease-causing mutations, but only in a few cases have these identifications brought us closer to an understanding of the actual production of dysmorphology. The overall absence of satisfactory explanations of the genotype–phenotype continuum in craniofacial anomalies reveals a general lack of understanding of phenogenetics, the connection between biological phenotypes and their underlying genetic bases (Weiss, 2005; Weiss and Buchanan, 2004). Phenogenetic phenomena, like hierarchies of regulatory cascades or nested epigenetic networks, provide a structural connection between genes and phenotypes (Carroll 378 epigenetics in evolution and disease et al., 2001; Davidson, 2001; Wilkins, 2002; Weiss and Buchanan, 2004; Weiss, 2005). At a more coarse scale, phenogenetic phenomena include processes such as regional differentiation by dynamic inductive signaling and repetitive patterning by quantitative interactions, which affect interactions among populations of cells (Weiss, 2005). The complexity of these phenomena and the processes that underlie them explains why the proximate function of a single mutation is rarely sufficient to account for more than a subset of associated syndromic phenotypes even in diseases that are plainly genetic . True understanding of a genetic disease requires the design of a process-based strategy for a solution to the genotype–phenotype conundrum (Weiss, 2005; Buchanan et al., 2009). Our current state of knowledge and technical capacity requires that we discover genotype– phenotype relationships in a piece-by-piece fashion (but see Chen et al., 2008). Epigenetics provides a theoretical framework from which to study the intricate networks of interactions that make up development, to design experiments to uncover these relationships, and ultimately to join them together. Epigenetics, in its strictest sense, refers to the interactions between genes, with other transcribed portions of the genome, and between the products of both (for further discussion, see Chapter 3, this volume). The emergent properties of the complex networks of molecular interactions occurring through a variety of regulatory mechanisms may be the starting point for an explanation of the phenotypic variation that exists among individuals with the same “genes.” However, interactions at higher levels, between cells, tissues, and the external environment, contribute in a major way to the production of the phenotype. By extending the definition of epigenetics to include interactions at levels above the gene, the complexity of the interactions involved in the production of phenotypic variation is revealed. Physical interactions between cells can lead to changes in gene expression and the movement of cell populations (Radlanski and Renz, 2006). Mechanical forces of strain and compression have been shown to regulate the speed of transcription in certain cells and the form of associated skeletal elements (Mao et al., 2003; Sun et al., 2004; Opperman and Rawlins, 2005). Environmental perturbations can lead to shifts in gene expression (Lopez-Maury et al., 2008; Li et al., 2008), influencing the phenotypes of individuals. These environmentally based phenotypic variants are often discussed in terms of norms of reaction and phenotypic plasticity (Sultan and Stearns, 2005; Grether, 2005). While the engine for development may be based on the molecular machinery of transcription , regulation, and expression of genes and gene products, the production of gross phenotypic form is driven by interactions at intercellular and higher levels. THe ePIgeneTIcs of cRAnIofAcIAl DysmoRPHology This chapter focuses on the epigenetic basis of craniofacial dysmorphology. With the understanding that certain...

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