Human-specific transcriptional regulation of CNS development genes by FOXP2

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Abstract
The transcription factor FOXP2 is the only gene so far to have been implicated in human speech, yet it differs very little from the chimpanzee equivalent. New experiments reveal differences between the activation of downstream transcriptional targets of FOXP2 in humans and chimpanzees arising from the two amino acid differences between the two forms of FOXP2. The different gene network interactions influenced by each version of FOXP2 are also reflected in the non-overlapping brain expression patterns exhibited by chimps and humans. These data provide support for the idea that evolutionary changes to FOXP2 in the human lineage have direct consequences for human brain development and disease in the central nervous system and may have a critical role in the development of language circuitry in humans. The transcription factor FOXP2 is the only gene implicated in human speech, and yet it differs very little from the chimpanzee orthologue. Here, the two amino acids specific to humans are shown to alter FOXP2 function in vitro by conferring differential transcriptional regulation, and these observations are extended in vivo to human and chimpanzee brain. Together, these data identify transcriptional targets that may serve critical functions in language development. The signalling pathways controlling both the evolution and development of language in the human brain remain unknown. So far, the transcription factor FOXP2 (forkhead box P2) is the only gene implicated in Mendelian forms of human speech and language dysfunction1,2,3. It has been proposed that the amino acid composition in the human variant of FOXP2 has undergone accelerated evolution, and this two-amino-acid change occurred around the time of language emergence in humans4,5. However, this remains controversial, and whether the acquisition of these amino acids in human FOXP2 has any functional consequence in human neurons remains untested. Here we demonstrate that these two human-specific amino acids alter FOXP2 function by conferring differential transcriptional regulation in vitro. We extend these observations in vivo to human and chimpanzee brain, and use network analysis to identify novel relationships among the differentially expressed genes. These data provide experimental support for the functional relevance of changes in FOXP2 that occur on the human lineage, highlighting specific pathways with direct consequences for human brain development and disease in the central nervous system (CNS). Because FOXP2 has an important role in speech and language in humans, the identified targets may have a critical function in the development and evolution of language circuitry in humans.