{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T17:08:09Z","timestamp":1789232889701,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,10]]},"group-title":"Genetics","reference-count":108,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01 HD102030"],"award-info":[{"award-number":["R01 HD102030"]}],"id":[{"id":"https:\/\/ror.org\/04byxyr05","id-type":"ROR","asserted-by":"publisher"}]},{"award":["F32 HD108935"],"award-info":[{"award-number":["F32 HD108935"]}],"id":[{"id":"https:\/\/ror.org\/04byxyr05","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/021nxhr62","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/01zkd3118","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Many human developmental processes proceed over a prolonged timescale compared to other primates, a phenomenon known as heterochrony. Human accelerated regions (HARs), which encode transcriptional enhancers with human-specific activity, have been implicated in the evolution of novel human traits. However, their contributions to changes in developmental timing remain unknown. Using single-nucleus RNA sequencing and developmental trajectory analyses in a genetically humanized mouse model of the HAR\n                  <jats:italic>HACNS1<\/jats:italic>\n                  , we show that\n                  <jats:italic>HACNS1<\/jats:italic>\n                  drives heterochronic shifts in opposite directions during craniofacial and limb development. In pharyngeal arches,\n                  <jats:italic>HACNS1<\/jats:italic>\n                  delays chondrocyte differentiation and the expression of genes involved in cartilage and skeletal maturation. In contrast, in the limb buds,\n                  <jats:italic>HACNS1<\/jats:italic>\n                  accelerates chondrogenesis and promotes earlier expression of differentiation-associated genes. Consistent with these transcriptomic shifts, SOX9-expressing pre-cartilaginous domains are more diffuse in the pharyngeal arches, but the condensed domains are expanded in the limb buds. Gene regulatory network inference suggests that\n                  <jats:italic>HACNS1<\/jats:italic>\n                  -driven heterochronic shifts are due to changes in the expression of its target gene\n                  <jats:italic>Gbx2<\/jats:italic>\n                  and resulting downstream effects on the regulatory networks through which\n                  <jats:italic>Gbx2<\/jats:italic>\n                  functions. Our findings demonstrate that a single human-specific gene regulatory change can alter developmental timing, providing a potential mechanism for how uniquely human genetic changes reshaped conserved developmental programs.\n                <\/jats:p>","DOI":"10.64898\/2026.09.08.750211","type":"posted-content","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T20:25:12Z","timestamp":1789071912000},"source":"Crossref","is-referenced-by-count":0,"title":["A Human Accelerated Region Drives Opposing Heterochronic Changes in Craniofacial and Limb Development"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1913-7202","authenticated-orcid":false,"given":"Yu","family":"Ji","sequence":"first","affiliation":[{"name":"Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matheo","family":"Morales","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marybeth","family":"Baumgartner","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9632-5835","authenticated-orcid":false,"given":"James P.","family":"Noonan","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA"},{"name":"Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA"},{"name":"Wu Tsai Institute, Yale University, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091209450704000_2026.09.08.750211v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2014.06.015"},{"key":"2026091209450704000_2026.09.08.750211v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-023-00675-z"},{"key":"2026091209450704000_2026.09.08.750211v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07521-x"},{"key":"2026091209450704000_2026.09.08.750211v1.4","doi-asserted-by":"publisher","DOI":"10.3389\/fnhum.2013.00707"},{"key":"2026091209450704000_2026.09.08.750211v1.5","doi-asserted-by":"publisher","DOI":"10.1002\/evan.70001"},{"key":"2026091209450704000_2026.09.08.750211v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.034"},{"key":"2026091209450704000_2026.09.08.750211v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2024.08.021"},{"key":"2026091209450704000_2026.09.08.750211v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2024.102259"},{"key":"2026091209450704000_2026.09.08.750211v1.9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.0020168"},{"key":"2026091209450704000_2026.09.08.750211v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/nature05113"},{"key":"2026091209450704000_2026.09.08.750211v1.11","doi-asserted-by":"publisher","DOI":"10.1126\/science.1130738"},{"key":"2026091209450704000_2026.09.08.750211v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/nature10530"},{"key":"2026091209450704000_2026.09.08.750211v1.13","doi-asserted-by":"publisher","DOI":"10.1126\/science.1159974"},{"key":"2026091209450704000_2026.09.08.750211v1.14","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2013.0025"},{"key":"2026091209450704000_2026.09.08.750211v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2015.01.041"},{"key":"2026091209450704000_2026.09.08.750211v1.16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2021722118"},{"key":"2026091209450704000_2026.09.08.750211v1.17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2007049118"},{"key":"2026091209450704000_2026.09.08.750211v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.12.026"},{"key":"2026091209450704000_2026.09.08.750211v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09002-1"},{"key":"2026091209450704000_2026.09.08.750211v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.01.007"},{"key":"2026091209450704000_2026.09.08.750211v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2026.02.009"},{"key":"2026091209450704000_2026.09.08.750211v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27899-w"},{"key":"2026091209450704000_2026.09.08.750211v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2005.05.023"},{"key":"2026091209450704000_2026.09.08.750211v1.24","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abb0119"},{"key":"2026091209450704000_2026.09.08.750211v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2025.101814"},{"key":"2026091209450704000_2026.09.08.750211v1.26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0175673"},{"key":"2026091209450704000_2026.09.08.750211v1.27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0504750102"},{"key":"2026091209450704000_2026.09.08.750211v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2019.07.008"},{"key":"2026091209450704000_2026.09.08.750211v1.29","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.00821"},{"key":"2026091209450704000_2026.09.08.750211v1.30","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.24671"},{"key":"2026091209450704000_2026.09.08.750211v1.31","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2026091209450704000_2026.09.08.750211v1.32","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2015.00169"},{"key":"2026091209450704000_2026.09.08.750211v1.33","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1769009"},{"key":"2026091209450704000_2026.09.08.750211v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2010.08.015"},{"key":"2026091209450704000_2026.09.08.750211v1.35","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1017802"},{"key":"2026091209450704000_2026.09.08.750211v1.36","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20071694"},{"key":"2026091209450704000_2026.09.08.750211v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2023.02.011"},{"key":"2026091209450704000_2026.09.08.750211v1.38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510544103"},{"key":"2026091209450704000_2026.09.08.750211v1.39","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2017.00023"},{"key":"2026091209450704000_2026.09.08.750211v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.morpho.2025.100965"},{"key":"2026091209450704000_2026.09.08.750211v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0336-3"},{"key":"2026091209450704000_2026.09.08.750211v1.42","doi-asserted-by":"publisher","DOI":"10.2307\/2346101"},{"key":"2026091209450704000_2026.09.08.750211v1.43","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar3131"},{"key":"2026091209450704000_2026.09.08.750211v1.44","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-018-4772-0"},{"key":"2026091209450704000_2026.09.08.750211v1.45","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a008334"},{"key":"2026091209450704000_2026.09.08.750211v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.tice.2024.102380"},{"key":"2026091209450704000_2026.09.08.750211v1.47","doi-asserted-by":"publisher","DOI":"10.1242\/dev.126.3.495"},{"key":"2026091209450704000_2026.09.08.750211v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4773(01)00574-3"},{"key":"2026091209450704000_2026.09.08.750211v1.49","doi-asserted-by":"publisher","DOI":"10.1242\/dev.040048"},{"key":"2026091209450704000_2026.09.08.750211v1.50","doi-asserted-by":"publisher","DOI":"10.1093\/stmcls\/sxad001"},{"key":"2026091209450704000_2026.09.08.750211v1.51","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25179291"},{"key":"2026091209450704000_2026.09.08.750211v1.52","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2859"},{"key":"2026091209450704000_2026.09.08.750211v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4628"},{"key":"2026091209450704000_2026.09.08.750211v1.54","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-14766-3"},{"key":"2026091209450704000_2026.09.08.750211v1.55","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4773(01)00383-5"},{"key":"2026091209450704000_2026.09.08.750211v1.56","doi-asserted-by":"publisher","DOI":"10.1242\/dev.200082"},{"key":"2026091209450704000_2026.09.08.750211v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2009.08.019"},{"key":"2026091209450704000_2026.09.08.750211v1.58","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200312045"},{"key":"2026091209450704000_2026.09.08.750211v1.59","doi-asserted-by":"publisher","DOI":"10.1016\/j.mod.2018.01.002"},{"key":"2026091209450704000_2026.09.08.750211v1.60","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad210"},{"key":"2026091209450704000_2026.09.08.750211v1.61","doi-asserted-by":"publisher","DOI":"10.1242\/dev.062802"},{"key":"2026091209450704000_2026.09.08.750211v1.62","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2014.12.007"},{"key":"2026091209450704000_2026.09.08.750211v1.63","doi-asserted-by":"publisher","DOI":"10.3390\/jdb3040158"},{"key":"2026091209450704000_2026.09.08.750211v1.64","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10177-1"},{"key":"2026091209450704000_2026.09.08.750211v1.65","doi-asserted-by":"publisher","DOI":"10.1242\/dev.008441"},{"key":"2026091209450704000_2026.09.08.750211v1.66","doi-asserted-by":"publisher","DOI":"10.1101\/gr.213066.116"},{"key":"2026091209450704000_2026.09.08.750211v1.67","doi-asserted-by":"publisher","DOI":"10.1126\/science.aal2913"},{"key":"2026091209450704000_2026.09.08.750211v1.68","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38953-0"},{"key":"2026091209450704000_2026.09.08.750211v1.69","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1219"},{"key":"2026091209450704000_2026.09.08.750211v1.70","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0086025"},{"key":"2026091209450704000_2026.09.08.750211v1.71","doi-asserted-by":"publisher","DOI":"10.1111\/j.1525-142X.2007.00161.x"},{"key":"2026091209450704000_2026.09.08.750211v1.72","doi-asserted-by":"publisher","DOI":"10.1186\/2041-9139-2-21"},{"key":"2026091209450704000_2026.09.08.750211v1.73","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2022.0080"},{"key":"2026091209450704000_2026.09.08.750211v1.74","doi-asserted-by":"publisher","DOI":"10.1111\/j.0021-8782.2004.00296.x"},{"key":"2026091209450704000_2026.09.08.750211v1.75","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7580.2008.00866.x"},{"key":"2026091209450704000_2026.09.08.750211v1.76","doi-asserted-by":"publisher","DOI":"10.1111\/joa.12197"},{"key":"2026091209450704000_2026.09.08.750211v1.77","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-59171-8"},{"key":"2026091209450704000_2026.09.08.750211v1.78","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msy109"},{"key":"2026091209450704000_2026.09.08.750211v1.79","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adc9507"},{"key":"2026091209450704000_2026.09.08.750211v1.80","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-60665-w"},{"key":"2026091209450704000_2026.09.08.750211v1.81","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.20796"},{"key":"2026091209450704000_2026.09.08.750211v1.82","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2017.03.028"},{"key":"2026091209450704000_2026.09.08.750211v1.83","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.057"},{"key":"2026091209450704000_2026.09.08.750211v1.84","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abq4884"},{"key":"2026091209450704000_2026.09.08.750211v1.85","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.10.040"},{"key":"2026091209450704000_2026.09.08.750211v1.86","doi-asserted-by":"publisher","DOI":"10.1093\/gbe\/evag121"},{"key":"2026091209450704000_2026.09.08.750211v1.87","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0158628"},{"key":"2026091209450704000_2026.09.08.750211v1.88","unstructured":"Andrews, S. (2010). Fast\u01eaC: a quality control tool for high throughput sequence data."},{"key":"2026091209450704000_2026.09.08.750211v1.89","first-page":"10","article-title":"Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet","volume":"17","year":"2011","journal-title":"journal"},{"key":"2026091209450704000_2026.09.08.750211v1.90","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1923"},{"key":"2026091209450704000_2026.09.08.750211v1.91","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352"},{"key":"2026091209450704000_2026.09.08.750211v1.92","unstructured":"Broad Institute Sequencing, P. Picard Toolkit. http:\/\/broadinstitute.github.io\/picard."},{"key":"2026091209450704000_2026.09.08.750211v1.93","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2012.101"},{"key":"2026091209450704000_2026.09.08.750211v1.94","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01685-z"},{"key":"2026091209450704000_2026.09.08.750211v1.95","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2026091209450704000_2026.09.08.750211v1.96","doi-asserted-by":"publisher","DOI":"10.1101\/2021.05.05.442755"},{"key":"2026091209450704000_2026.09.08.750211v1.97","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01767-y"},{"key":"2026091209450704000_2026.09.08.750211v1.98","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2019.03.003"},{"key":"2026091209450704000_2026.09.08.750211v1.99","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0969-x"},{"key":"2026091209450704000_2026.09.08.750211v1.100","unstructured":"Kolde, R. (2025). pheatmap: Pretty Heatmaps. R package version 1.0.13, https:\/\/github.com\/raivokolde\/pheatmap."},{"key":"2026091209450704000_2026.09.08.750211v1.101","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"2026091209450704000_2026.09.08.750211v1.102","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18035-1"},{"key":"2026091209450704000_2026.09.08.750211v1.103","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv145"},{"key":"2026091209450704000_2026.09.08.750211v1.104","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq033"},{"key":"2026091209450704000_2026.09.08.750211v1.105","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.05.061"},{"key":"2026091209450704000_2026.09.08.750211v1.106","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4463"},{"key":"2026091209450704000_2026.09.08.750211v1.107","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2649-2"},{"key":"2026091209450704000_2026.09.08.750211v1.108","doi-asserted-by":"crossref","first-page":"e0355108","DOI":"10.1371\/journal.pone.0355108","article-title":"igraph 1.0 enables fast and robust network analysis across programming languages","volume":"21","year":"2026","journal-title":"PloS one"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.08.750211","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T16:45:14Z","timestamp":1789231514000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.09.08.750211"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":108,"URL":"https:\/\/doi.org\/10.64898\/2026.09.08.750211","relation":{},"subject":[],"published":{"date-parts":[[2026,9,10]]},"subtype":"preprint"}}