Transcriptional Interference Regulates the Evolutionary Development of Speech

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dc.contributor.authorMortlock, Douglas P.en
dc.contributor.authorFang, Zhi-Mingen
dc.contributor.authorChandler, Kelly J.en
dc.contributor.authorHou, Yueen
dc.contributor.authorBickford, Lissett R.en
dc.contributor.authorde Bock, Charles E.en
dc.contributor.authorEapen, Valsammaen
dc.contributor.authorClarke, Raymond A.en
dc.date.accessioned2022-07-08T12:04:44Zen
dc.date.available2022-07-08T12:04:44Zen
dc.date.issued2022-07-04en
dc.date.updated2022-07-08T11:55:09Zen
dc.description.abstractThe 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&deg; to 90&deg; as in primitive primates. To our surprise, we found that a previously unknown primate-specific gene <i>TOSPEAK</i> had been disrupted in the family. <i>TOSPEAK</i> 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 <i>GDF6</i>. We used transgenic mouse modelling to identify two additional <i>GDF6</i> long-range enhancers within <i>TOSPEAK</i> that regulate <i>GDF6</i> expression in the wrist. Disruption of <i>TOSPEAK</i> in the affected family blocked the transcription of <i>TOSPEAK</i> across the 3 <i>GDF6</i> enhancers in association with a reduction in <i>GDF6</i> expression and retrograde development of the larynx and wrist. Furthermore, we describe how <i>TOSPEAK</i> developed a human-specific promoter through the expansion of a penta-nucleotide direct repeat that first emerged de novo in the promoter of <i>TOSPEAK</i> 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 <i>TOSPEAK</i> with human having the strongest promoter. Our research indicates a dual evolutionary role for the incremental increases in <i>TOSPEAK</i> transcriptional interference of <i>GDF6</i> 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 <i>TOSPEAK</i> transcription in the affected family.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMortlock, D.P.; Fang, Z.-M.; Chandler, K.J.; Hou, Y.; Bickford, L.R.; de Bock, C.E.; Eapen, V.; Clarke, R.A. Transcriptional Interference Regulates the Evolutionary Development of Speech. Genes 2022, 13, 1195.en
dc.identifier.doihttps://doi.org/10.3390/genes13071195en
dc.identifier.urihttp://hdl.handle.net/10919/111174en
dc.language.isoenen
dc.publisherMDPIen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectlarynxen
dc.subjectpisiformen
dc.subjectwrist evolutionen
dc.subjectprimate geneen
dc.subjectprimate evolutionen
dc.subjectbone morphogenetic proteinen
dc.subjecttranscriptional interferenceen
dc.subjectoverlapping geneen
dc.subjectgene complexen
dc.subjectGDF6en
dc.titleTranscriptional Interference Regulates the Evolutionary Development of Speechen
dc.title.serialGenesen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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