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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2018,1,30]]},"abstract":"<jats:p>\n                    Acquisition of new\n                    <jats:italic>cis<\/jats:italic>\n                    -regulatory elements (CREs) can cause alteration of developmental gene regulation and may introduce morphological novelty in evolution. Although structural variation in the genome generated by chromosomal rearrangement is one possible source of new CREs, only a few examples are known, except for cases of retrotransposition. In this study, we show the acquisition of novel regulatory sequences as a result of large genomic insertion in the spontaneous mouse mutation Hammer toe (\n                    <jats:italic>Hm<\/jats:italic>\n                    ).\n                    <jats:italic>Hm<\/jats:italic>\n                    mice exhibit syndactyly with webbing, due to suppression of interdigital cell death in limb development. We reveal that, in the\n                    <jats:italic>Hm<\/jats:italic>\n                    genome, a 150-kb noncoding DNA fragment from chromosome 14 is inserted into the region upstream of the Sonic hedgehog (\n                    <jats:italic>Shh<\/jats:italic>\n                    ) promoter in chromosome 5. Phenotyping of mouse embryos with a series of CRISPR\/Cas9-aided partial deletion of the 150-kb insert clearly indicated that two different regions are necessary for the syndactyly phenotype of\n                    <jats:italic>Hm<\/jats:italic>\n                    . We found that each of the two regions contains at least one enhancer for interdigital regulation. These results show that a set of enhancers brought by the large genomic insertion elicits the interdigital\n                    <jats:italic>Shh<\/jats:italic>\n                    expression and the\n                    <jats:italic>Hm<\/jats:italic>\n                    phenotype. Transcriptome analysis indicates that ectopic expression of\n                    <jats:italic>Shh<\/jats:italic>\n                    up-regulates Chordin (\n                    <jats:italic>Chrd<\/jats:italic>\n                    ) that antagonizes bone morphogenetic protein signaling in the interdigital region. Indeed,\n                    <jats:italic>Chrd-<\/jats:italic>\n                    overexpressing transgenic mice recapitulated syndactyly with webbing. Thus, the\n                    <jats:italic>Hm<\/jats:italic>\n                    mutation provides an insight into enhancer acquisition as a source of creation of novel gene regulation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1713339115","type":"journal-article","created":{"date-parts":[[2017,12,18]],"date-time":"2017-12-18T15:16:01Z","timestamp":1513610161000},"page":"1021-1026","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":16,"title":["Enhancer adoption caused by genomic insertion elicits interdigital\n                    <i>Shh<\/i>\n                    expression and syndactyly in mouse"],"prefix":"10.1073","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1712-6833","authenticated-orcid":false,"given":"Kousuke","family":"Mouri","sequence":"first","affiliation":[{"name":"Mammalian Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Sagai","sequence":"additional","affiliation":[{"name":"Mammalian Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiteru","family":"Maeno","sequence":"additional","affiliation":[{"name":"Mammalian Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Amano","sequence":"additional","affiliation":[{"name":"Mammalian Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0728-7548","authenticated-orcid":false,"given":"Atsushi","family":"Toyoda","sequence":"additional","affiliation":[{"name":"Comparative Genomics Laboratory, Center for Information Biology, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiko","family":"Shiroishi","sequence":"additional","affiliation":[{"name":"Mammalian Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2017,12,18]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1038\/nature04597","article-title":"Repeated morphological evolution through cis-regulatory changes in a pleiotropic gene","volume":"440","author":"Prud\u2019homme B","year":"2006","unstructured":"B Prud\u2019homme, , Repeated morphological evolution through cis-regulatory changes in a pleiotropic gene. 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