Ultraconservation identifies a small subset of extremely constrained developmental enhancers

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While experimental studies have suggested that non-coding ultraconserved DNA elements are central nodes in the regulatory circuitry that specifies mammalian embryonic development, the possible functional relevance of their>200bp of perfect sequence conservation between human-mouse-rat remains obscure 1,2. Here we have compared the in vivo enhancer activity of a genome-wide set of 231 non-exonic sequences with ultraconserved cores to that of 206 sequences that are under equivalently severe human-rodent constraint (ultra-like), but lack perfect sequence conservation. In transgenic mouse assays, 50percent of the ultraconserved and 50percent of the ultra-like conserved elements reproducibly functioned as tissue-specific enhancers at embryonic day 11.5. In ... continued below

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Pennacchio, Len A.; Visel, Axel; Prabhakar, Shyam; Akiyama, Jennifer A.; Shoukry, Malak; Lewis, Keith D. et al. October 1, 2007.

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While experimental studies have suggested that non-coding ultraconserved DNA elements are central nodes in the regulatory circuitry that specifies mammalian embryonic development, the possible functional relevance of their>200bp of perfect sequence conservation between human-mouse-rat remains obscure 1,2. Here we have compared the in vivo enhancer activity of a genome-wide set of 231 non-exonic sequences with ultraconserved cores to that of 206 sequences that are under equivalently severe human-rodent constraint (ultra-like), but lack perfect sequence conservation. In transgenic mouse assays, 50percent of the ultraconserved and 50percent of the ultra-like conserved elements reproducibly functioned as tissue-specific enhancers at embryonic day 11.5. In this in vivo assay, we observed that ultraconserved enhancers and constrained non-ultraconserved enhancers targeted expression to a similar spectrum of tissues with a particular enrichment in the developing central nervous system. A human genome-wide comparative screen uncovered ~;;2,600 non-coding elements that evolved under ultra-like human-rodent constraint and are similarly enriched near transcriptional regulators and developmental genes as the much smaller number of ultraconserved elements. These data indicate that ultraconserved elements possessing absolute human-rodent sequence conservation are not distinct from other non-coding elements that are under comparable purifying selection in mammals and suggest they are principal constituents of the cis-regulatory framework of mammalian development.

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27p

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  • Journal Name: Nature Genetics; Journal Volume: 40; Journal Issue: 2; Related Information: Journal Publication Date: February 2008

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  • Report No.: LBNL-487E
  • Grant Number: DE-AC02-05CH11231
  • Office of Scientific & Technical Information Report Number: 934681
  • Archival Resource Key: ark:/67531/metadc893117

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  • October 1, 2007

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  • Sept. 27, 2016, 1:39 a.m.

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  • Oct. 3, 2016, 2:23 p.m.

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Pennacchio, Len A.; Visel, Axel; Prabhakar, Shyam; Akiyama, Jennifer A.; Shoukry, Malak; Lewis, Keith D. et al. Ultraconservation identifies a small subset of extremely constrained developmental enhancers, article, October 1, 2007; Berkeley, California. (digital.library.unt.edu/ark:/67531/metadc893117/: accessed June 18, 2018), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.