{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T10:13:39Z","timestamp":1790158419510,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,18]]},"group-title":"Evolutionary Biology","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["T32 GM133351"],"award-info":[{"award-number":["T32 GM133351"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 AR075415"],"award-info":[{"award-number":["R01 AR075415"]}],"id":[{"id":"https:\/\/ror.org\/006zn3t30","id-type":"ROR","asserted-by":"publisher"}]},{"award":["IOS-1846390"],"award-info":[{"award-number":["IOS-1846390"]}],"id":[{"id":"https:\/\/ror.org\/021nxhr62","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Wu Tsai Human Performance Alliance and the Joe and Clara Tsai Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Vertebrate limb bones grow at different rates within and between species to achieve a striking variety of proportions and functions. However, most coding mutations that alter bone growth in mice and humans affect the entire skeleton, pointing to\n                  <jats:italic>cis-<\/jats:italic>\n                  regulatory modularity as the primary mechanism to diversify proportion. In a search for causative loci, we previously identified 1,755 disproportionately differentially expressed genes associated with the extreme hindlimb elongation in bipedal jerboas,\n                  <jats:italic>Jaculus jaculus<\/jats:italic>\n                  , compared to laboratory mice. We then took a focused approach to identify putative\n                  <jats:italic>cis<\/jats:italic>\n                  -regulatory elements near select candidate genes in a highly fragmented draft\n                  <jats:italic>Jaculus jaculus<\/jats:italic>\n                  genome assembly. We identified an ATAC-seq peak near\n                  <jats:italic>Shox2<\/jats:italic>\n                  that was reproducible in jerboa metatarsals and not in radius\/ulna.\n                  <jats:italic>Shox2<\/jats:italic>\n                  gained a novel expression domain in jerboa metatarsals and is both necessary and sufficient to modulate mouse limb bone length. This 139 bp putative enhancer in the jerboa genome centers on a \u223c1 kb deletion of sequence found broadly throughout placental mammals. Here, we show that replicating the deletion and replacement with the 139 bp jerboa sequence in mice causes no detected phenotype. A genome-wide analysis of our ATAC-seq data using a high-quality\n                  <jats:italic>Jaculus jaculus<\/jats:italic>\n                  genome assembly replicated the peak called at this location but also identified 7,445 peaks that are similarly reproducible in metatarsals and not in radius\/ulna. Certainly not all of these peaks are causative, but it is likely that many small-effect mutations diversified proportion. It is therefore crucial to apply unbiased filters to genome-wide analyses and to not assume that the few historically favored genes will have the largest effect.\n                <\/jats:p>","DOI":"10.64898\/2026.09.17.752424","type":"posted-content","created":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T05:45:14Z","timestamp":1789796714000},"source":"Crossref","is-referenced-by-count":0,"title":["A putative\n                  <i>cis<\/i>\n                  -regulatory element near\n                  <i>Shox2<\/i>\n                  in the jerboa genome (\n                  <i>Jaculus jaculus<\/i>\n                  ) is not sufficient to alter mouse limb bone lengths"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8657-5934","authenticated-orcid":false,"given":"Galilea","family":"Guerrero","sequence":"first","affiliation":[{"name":"Department of Cell and Developmental Biology, University of California San Diego, La Jolla California, USA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0539-7424","authenticated-orcid":false,"given":"Alexander Y.","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, University of California San Diego, La Jolla California, USA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1713-158X","authenticated-orcid":false,"given":"Alexander J.","family":"Weitzel","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, University of California San Diego, La Jolla California, USA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3145-7615","authenticated-orcid":false,"given":"Erica","family":"Gacasan","sequence":"additional","affiliation":[{"name":"Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, California, USA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3024-1449","authenticated-orcid":false,"given":"Michael","family":"Hiller","sequence":"additional","affiliation":[{"name":"Senckenberg \u2013 Leibniz Institution for Biodiversity and Earth System Research, Frankfurt, Germany"},{"name":"Faculty of Biosciences, Goethe University Frankfurt, Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5493-9502","authenticated-orcid":false,"given":"Robert","family":"Sah","sequence":"additional","affiliation":[{"name":"Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, California, USA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5892-8838","authenticated-orcid":false,"given":"Kimberly L.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, University of California San Diego, La Jolla California, USA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092302551168000_2026.09.17.752424v1.1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0050234"},{"key":"2026092302551168000_2026.09.17.752424v1.2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.5.2406"},{"key":"2026092302551168000_2026.09.17.752424v1.3","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.111997"},{"key":"2026092302551168000_2026.09.17.752424v1.4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005738"},{"key":"2026092302551168000_2026.09.17.752424v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.02.018"},{"key":"2026092302551168000_2026.09.17.752424v1.6","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn3943"},{"key":"2026092302551168000_2026.09.17.752424v1.7","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.5.695"},{"key":"2026092302551168000_2026.09.17.752424v1.8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510544103"},{"key":"2026092302551168000_2026.09.17.752424v1.9","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01885"},{"key":"2026092302551168000_2026.09.17.752424v1.10","unstructured":"Comet Technologies Canada Inc. 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