Abstract
Morphological evolution is driven both by coding sequence variation and by changes in regulatory sequences. However, how cis-regulatory modules (CRMs) evolve to generate entirely novel expression domains is largely unknown. Here, we reconstruct the evolutionary history of a lens enhancer located within a CRM that not only predates the lens, a vertebrate innovation, but bilaterian animals in general. Alignments of orthologous sequences from different deuterostomes sub-divide the CRM into a deeply conserved core and a more divergent flanking region. We demonstrate that all deuterostome flanking regions, including invertebrate sequences, activate gene expression in the zebrafish lens through the same ancient cluster of activator sites. However, levels of gene expression vary between species due to the presence of repressor motifs in flanking region and core. These repressor motifs are responsible for the relatively weak enhancer activity of tetrapod flanking regions. Ray-finned fish, however, have gained two additional lineage-specific activator motifs which in combination with the ancient cluster of activators and the core constitute a potent lens enhancer. The exploitation and modification of existing regulatory potential in flanking regions but not in the highly conserved core might represent a more general model for the emergence of novel regulatory functions in complex CRMs.
Highlights
Cis-regulatory modules (CRMs) play a critical role in establishing complex and dynamic gene expression patterns in the embryo
An alignment of CNE17, which is located immediately downstream of the Sox21/SoxB2 gene, across deuterostomes shows that the degree of sequence identity varies in different regions of the vertebrate conserved noncoding elements (CNEs)
We note in the introduction that the criteria for the evolution of novel expression domains via co-option of enhancers are the presence of pre-existing cryptic enhancer activity in the novel domain encoded within the ancestral sequence, while robust expression is dependent on both ancestral and novel sequence motifs [12]
Summary
Cis-regulatory modules (CRMs) play a critical role in establishing complex and dynamic gene expression patterns in the embryo. In contrast to coding sequences, many CRM sequences are poorly conserved even between closely related species The exception to this is a set of CRMs that we previously termed conserved noncoding elements (CNEs), which have been identified in all vertebrates from fish to mammals [1,2,3,4]. These sequences are clustered around developmental genes such as transcription factors and signalling molecules and, as shown in numerous reporter assays, are able to induce tissue-specific expression patterns during development [3,4]. One vertebrate CNE in particular, linked to vertebrate Sox genes, has been identified in cephalochordates,
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