Nature 462, 213-217 (12 November 2009) | doi:10.1038/nature08549; Received 26 August 2009; Accepted 1 October 2009

Human-specific transcriptional regulation of CNS development genes by FOXP2

Genevieve Konopka1,3, Jamee M. Bomar1,3, Kellen Winden1,3, Giovanni Coppola3, Zophonias O. Jonsson5, Fuying Gao3, Sophia Peng3, Todd M. Preuss6, James A. Wohlschlegel5 & Daniel H. Geschwind1,2,3,4

  1. Program in Neurogenetics,
  2. Semel Institute and Department of Psychiatry,
  3. Departments of Neurology,
  4. Human Genetics, and,
  5. Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA
  6. Division of Neuroscience and Center for Behavioral Neuroscience, Yerkes National Primate Research Center, and Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30329, USA

Correspondence to: Genevieve Konopka1,3Daniel H. Geschwind1,2,3,4 Correspondence and requests for materials should be addressed to G.K. (Email: gena@alum.mit.edu) or D.H.G. (Email: dhg@ucla.edu).

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.


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