title: Evolution of lineage-specific functions in ancient cis-regulatory modules.
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.
authors.affiliation: Division of Systems Biology, Francis Crick Institute, Mill Hill laboratories, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pauls
authors.affiliation: Cambridge Institute for Medical Research and the Wellcome Trust/MRC Cambridge Stem Cell Institute, University of Cambridge, Hills Road, Cambridge CB2 OXY, UK.
authors.forename: Debbie K
authors.initials: DK
authors.lastname: Goode
authors.affiliation: Department of Genetics, Evolution and Environment, University College London, Gower Street, London WC1 E6BT, UK.
authors.forename: Libero
authors.initials: L
authors.lastname: Petrone
authors.affiliation: Department of Genetics, Evolution and Environment, University College London, Gower Street, London WC1 E6BT, UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Oliveri
authors.affiliation: Division of Systems Biology, Francis Crick Institute, Mill Hill laboratories, The Ridgeway, Mill Hill, London NW7 1AA, UK greg.elgar@crick.ac.uk.
authors.forename: Greg
authors.initials: G
authors.lastname: Elgar
mesh_terms: D000818:Animals; D001483:Base Sequence; D002645:Chickens; D017124:Conserved Sequence; D019143:Evolution, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D059372:Nucleotide Motifs; D012045:Regulatory Sequences, Nucleic Acid; D055749:SOXB2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D023741:Takifugu; D014981:Xenopus; D015027:Zebrafish
chemical_list: D055749:SOXB2 Transcription Factors
keywords: Sox21; cis-regulatory module; conserved non-coding element; enhancer evolution; zebrafish