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regulating proteins were found to include multiple individual cis-regulatory elements (CREs), with each CRE typically comprising binding sites for multiple distinct transcription factors and controlling gene expression within a discrete spatial domain in a developing animal. The realization that the total expression pattern of a gene was the sum of many parts, each directed by distinct CREs, marked a profound change in concepts of gene regulation. The modular arrangement of CREs also had clear implications for evolutionary genetics, because it suggested a mechanism for how selective changes in gene expression and morphology could evolve in one part of the body, independent of other parts (Carroll, 1995). The conservation of the biochemical activity of regulatory proteins, the divergence of their expression patterns across taxa, and the modular organization of CREs provided the basis for the general proposal that gene expression evolution, and therefore morphological evolution, would occur primarily through changes in cis-regulatory sequences controlling gene transcription (Carroll, 1995).

However, the evolutionary significance of the properties of CREs was not widely recognized at the time and, in our view, may still not be fully appreciated. We think there are several possible reasons for this (Carroll, 2005b). First, there is a much longer history of the analysis of coding sequences in evolutionary and population genetics. Second, the role of gene duplication has also long figured prominently in ideas about evolutionary novelty (Ohno, 1970). In contrast, the recognition of the complexity and evolutionary potential of CREs is more recent and has emerged primarily from molecular developmental genetics, outside of the primary literature of evolutionary genetics. And finally, there have been few detailed functional studies of CRE evolution. Most studies have focused on the functional conservation of CREs (Ludwig et al., 2000, 2005; Wratten et al., 2006). Until very recently, there have been very few direct empirical examples linking CRE evolution to morphological evolution (Belting et al., 1998; Wang and Chamberlin, 2002). As a result, beyond the growing acceptance of why regulatory evolution plays a role in morphological evolution, our understanding of how regulatory evolution occurs has been limited.

The elucidation of the mechanisms of CRE evolution in morphological diversification has required the identification of appropriate experimental systems. Because coding sequences are usually sufficiently conserved to identify orthologous sequences among different phyla, it was naïvely assumed initially that the same would hold true for CREs, and that functional comparison of divergent CREs from distantly related taxa would be possible. However, it was progressively realized that the turnover rate of noncoding DNA is much higher than for coding sequences, largely because of looser functional constraints, making orthologous sequence



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