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Cell. 2016 Oct 20;167(3):633-642.e11. doi: 10.1016/j.cell.2016.09.028.

Progressive Loss of Function in a Limb Enhancer during Snake Evolution.

Author information

1
MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
2
Department of Biology, Stanford University, Stanford, CA 94305, USA.
3
Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
4
MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA.
5
MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA. Electronic address: lapennacchio@lbl.gov.
6
MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA; School of Natural Sciences, University of California, Merced, CA 95343, USA. Electronic address: avisel@lbl.gov.

Abstract

The evolution of body shape is thought to be tightly coupled to changes in regulatory sequences, but specific molecular events associated with major morphological transitions in vertebrates have remained elusive. We identified snake-specific sequence changes within an otherwise highly conserved long-range limb enhancer of Sonic hedgehog (Shh). Transgenic mouse reporter assays revealed that the in vivo activity pattern of the enhancer is conserved across a wide range of vertebrates, including fish, but not in snakes. Genomic substitution of the mouse enhancer with its human or fish ortholog results in normal limb development. In contrast, replacement with snake orthologs caused severe limb reduction. Synthetic restoration of a single transcription factor binding site lost in the snake lineage reinstated full in vivo function to the snake enhancer. Our results demonstrate changes in a regulatory sequence associated with a major body plan transition and highlight the role of enhancers in morphological evolution. PAPERCLIP.

KEYWORDS:

CRISPR/Cas9; Sonic hedgehog (Shh); ZRS; cis-regulatory element; enhancer; evo-devo; genome editing; limb development; morphological evolution; snakes

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PMID:
27768887
PMCID:
PMC5484524
DOI:
10.1016/j.cell.2016.09.028
[Indexed for MEDLINE]
Free PMC Article

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