Transcriptional Interference Regulates the Evolutionary Development of Speech.

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° to 90° as in primitive primates. To our surprise, we found that a previously unknown primate-specific gene had been disrupted in the family. 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 . We used transgenic mouse modelling to identify two additional long-range enhancers within that regulate expression in the wrist. Disruption of in the affected family blocked the transcription of across the 3 enhancers in association with a reduction in expression and retrograde development of the larynx and wrist. Furthermore, we describe how developed a human-specific promoter through the expansion of a penta-nucleotide direct repeat that first emerged de novo in the promoter of 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 with human having the strongest promoter. Our research indicates a dual evolutionary role for the incremental increases in transcriptional interference of 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 transcription in the affected family.