{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T04:34:27Z","timestamp":1762058067143,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,7,4]],"date-time":"2022-07-04T00:00:00Z","timestamp":1656892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"services of the Vanderbilt Transgenic Mouse\/ES Cell Shared Resource (TMESCSR) core facility","award":["970859","30999","HD047880","T32GM080178"],"award-info":[{"award-number":["970859","30999","HD047880","T32GM080178"]}]},{"name":"Ingham Institute of Applied Medical Research","award":["970859","30999","HD047880","T32GM080178"],"award-info":[{"award-number":["970859","30999","HD047880","T32GM080178"]}]},{"DOI":"10.13039\/501100000925","name":"Australian National Health and Medical Research Council (NHMRC)","doi-asserted-by":"publisher","award":["970859","30999","HD047880","T32GM080178"],"award-info":[{"award-number":["970859","30999","HD047880","T32GM080178"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Garnett Passe and Rodney Williams Memorial Foundation Research Grant and United States Scoliosis Research Society","award":["970859","30999","HD047880","T32GM080178"],"award-info":[{"award-number":["970859","30999","HD047880","T32GM080178"]}]},{"DOI":"10.13039\/100000002","name":"United States National Institutes of Health (NIH)","doi-asserted-by":"publisher","award":["970859","30999","HD047880","T32GM080178"],"award-info":[{"award-number":["970859","30999","HD047880","T32GM080178"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH Genetics Training","award":["970859","30999","HD047880","T32GM080178"],"award-info":[{"award-number":["970859","30999","HD047880","T32GM080178"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The human capacity to speak is fundamental to our advanced intellectual, technological and social development. Yet so very little is known regarding the evolutionary genetics of speech or its relationship with the broader aspects of evolutionary development in primates. In this study, we describe a large family with evolutionary retrograde development of the larynx and wrist. The family presented with severe speech impairment and incremental retrograde elongations of the pisiform in the wrist that limited wrist rotation from 180\u00b0 to 90\u00b0 as in primitive primates. To our surprise, we found that a previously unknown primate-specific gene TOSPEAK had been disrupted in the family. TOSPEAK emerged de novo in an ancestor of extant primates across a 540 kb region of the genome with a pre-existing highly conserved long-range laryngeal enhancer for a neighbouring bone morphogenetic protein gene GDF6. We used transgenic mouse modelling to identify two additional GDF6 long-range enhancers within TOSPEAK that regulate GDF6 expression in the wrist. Disruption of TOSPEAK in the affected family blocked the transcription of TOSPEAK across the 3 GDF6 enhancers in association with a reduction in GDF6 expression and retrograde development of the larynx and wrist. Furthermore, we describe how TOSPEAK developed a human-specific promoter through the expansion of a penta-nucleotide direct repeat that first emerged de novo in the promoter of TOSPEAK in gibbon. This repeat subsequently expanded incrementally in higher hominids to form an overlapping series of Sp1\/KLF transcription factor consensus binding sites in human that correlated with incremental increases in the promoter strength of TOSPEAK with human having the strongest promoter. Our research indicates a dual evolutionary role for the incremental increases in TOSPEAK transcriptional interference of GDF6 enhancers in the incremental evolutionary development of the wrist and larynx in hominids and the human capacity to speak and their retrogression with the reduction of TOSPEAK transcription in the affected family.<\/jats:p>","DOI":"10.3390\/genes13071195","type":"journal-article","created":{"date-parts":[[2022,7,4]],"date-time":"2022-07-04T11:15:05Z","timestamp":1656933305000},"page":"1195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Transcriptional Interference Regulates the Evolutionary Development of Speech"],"prefix":"10.3390","volume":"13","author":[{"given":"Douglas P.","family":"Mortlock","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN 37232-0700, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi-Ming","family":"Fang","sequence":"additional","affiliation":[{"name":"Discipline of Psychiatry, Ingham Institute, University of New South Wales, 1 Campbell Street Liverpool, Sydney, NSW 2170, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly J.","family":"Chandler","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN 37232-0700, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN 37232-0700, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lissett R.","family":"Bickford","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN 37232-0700, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles E.","family":"de Bock","sequence":"additional","affiliation":[{"name":"Children\u2019s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW 2052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6296-8306","authenticated-orcid":false,"given":"Valsamma","family":"Eapen","sequence":"additional","affiliation":[{"name":"Discipline of Psychiatry, Ingham Institute, University of New South Wales, 1 Campbell Street Liverpool, Sydney, NSW 2170, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7196-9623","authenticated-orcid":false,"given":"Raymond A.","family":"Clarke","sequence":"additional","affiliation":[{"name":"Discipline of Psychiatry, Ingham Institute, University of New South Wales, 1 Campbell Street Liverpool, Sydney, NSW 2170, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1353\/hub.2011.a438026","article-title":"Genes, language, cognition, and culture: Towards productive inquiry","volume":"83","author":"Fitch","year":"2011","journal-title":"Hum. 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