Progressive Loss of Function in a Limb Enhancer during Snake Evolution

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...

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Bibliographic Details
Published in:Cell Vol. 167; no. 3; p. 633
Main Authors: Kvon, Evgeny Z, Kamneva, Olga K, Melo, Uirá S, Barozzi, Iros, Osterwalder, Marco, Mannion, Brandon J, Tissières, Virginie, Pickle, Catherine S, Plajzer-Frick, Ingrid, Lee, Elizabeth A, Kato, Momoe, Garvin, Tyler H, Akiyama, Jennifer A, Afzal, Veena, Lopez-Rios, Javier, Rubin, Edward M, Dickel, Diane E, Pennacchio, Len A, Visel, Axel
Format: Journal Article
Language:English
Published: United States 20.10.2016
Subjects:
Animals
Base Sequence
Biological Evolution
Enhancer Elements, Genetic
Evolution, Molecular
Extremities - growth & development
Gene Knock-In Techniques
Hedgehog Proteins - genetics
Mice
Mice, Transgenic
Mutation
Phylogeny
Snakes - classification
Snakes - genetics
evo-devo
limb development
genome editing
Sonic hedgehog (Shh)
enhancer
CRISPR/Cas9
cis-regulatory element
morphological evolution
ZRS
snakes
ISSN:1097-4172, 1097-4172
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Summary: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.
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2016.09.028