Copyright © 2007 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 81, Issue 6, 1144-1157, 1 December 2007
doi:10.1086/522237
Article
Identification of the Transcriptional Targets of FOXP2, a Gene Linked to Speech and Language, in Developing Human Brain
Elizabeth Spiteria, Genevieve Konopkaa, Giovanni Coppolaa, Jamee Bomara, Michael Oldhama, Jing Oua, Sonja C. Vernesc, Simon E. Fisherc, Bing Rend and Daniel H. Geschwinda, b, 
, 
a Program in Neurogenetics, Department of Neurology, University of California–Los Angeles, Los Angeles
b Semel Institute and Department of Human Genetics, David Geffen School of Medicine, University of California–Los Angeles, Los Angeles
c Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
d Ludwig Institute for Cancer Research, University of California–San Diego School of Medicine, La Jolla
Address for correspondence and reprints: Dr. Daniel H. Geschwind, Department of Neurology, Reed Neurological Research Center, University of California–Los Angeles, 710 Westwood Plaza, Room 1-145, Los Angeles, CA 90095-1769Abstract
Mutations in FOXP2, a member of the forkhead family of transcription factor genes, are the only known cause of developmental speech and language disorders in humans. To date, there are no known targets of human FOXP2 in the nervous system. The identification of FOXP2 targets in the developing human brain, therefore, provides a unique tool with which to explore the development of human language and speech. Here, we define FOXP2 targets in human basal ganglia (BG) and inferior frontal cortex (IFC) by use of chromatin immunoprecipitation followed by microarray analysis (ChIP-chip) and validate the functional regulation of targets in vitro. ChIP-chip identified 285 FOXP2 targets in fetal human brain; statistically significant overlap of targets in BG and IFC indicates a core set of 34 transcriptional targets of FOXP2. We identified targets specific to IFC or BG that were not observed in lung, suggesting important regional and tissue differences in FOXP2 activity. Many target genes are known to play critical roles in specific aspects of central nervous system patterning or development, such as neurite outgrowth, as well as plasticity. Subsets of the FOXP2 transcriptional targets are either under positive selection in humans or differentially expressed between human and chimpanzee brain. This is the first ChIP-chip study to use human brain tissue, making the FOXP2-target genes identified in these studies important to understanding the pathways regulating speech and language in the developing human brain. These data provide the first insight into the functional network of genes directly regulated by FOXP2 in human brain and by evolutionary comparisons, highlighting genes likely to be involved in the development of human higher-order cognitive processes.
Article Information
PubMed
Related Articles
- Relevance of Connexin Deafness (DFNB1) to Human Evolution Relevance of Connexin Deafness (DFNB1) to Human Evolution
The American Journal of Human Genetics, Volume 74, Issue 6, 1 June 2004, Pages 1081-1087
Walter E. Nance and Michael J. Kearsey
AbstractThe connexins are the subunits of a family of proteins that form gap junctions, allowing ions and small molecules to move between adjacent cells. At least four connexins are expressed in the ear, and, although there are known mutations at >100 loci that can cause deafness, those involving DFNB1, in the interval 13q11–q12 containing the GJB2 and GJB6 genes coding for connexins 26 and 30, are the most frequent cause of recessive deafness in many populations. We have suggested that the combined effects of relaxed selection and linguistic homogamy can explain the high frequency of connexin deafness and may have doubled its incidence in this country during the past 200 years. In this report, we show by computer simulation that assortative mating, in fact, can accelerate dramatically the genetic response to relaxed selection. Along with the effects of gene drift and consanguinity, assortative mating also may have played a key role in the joint evolution and accelerated fixation of genes for speech after they first appeared in Homo sapiens 100,000–150,000 years ago.
Abstract | | - Evolutionary Forces Shape the Human RFPL1,2,3 Genes toward a...Evolutionary Forces Shape the Human RFPL1,2,3 Genes toward a Role in Neocortex Development
The American Journal of Human Genetics, Volume 83, Issue 2, 8 August 2008, Pages 208-218
Jérôme Bonnefont, Sergey I. Nikolaev, Anselme L. Perrier, Song Guo, Laetitia Cartier, Silvia Sorce, Térèse Laforge, Laetitia Aubry, Philipp Khaitovich, Marc Peschanski, Stylianos E. Antonarakis and Karl-Heinz Krause
AbstractThe size and organization of the brain neocortex has dramatically changed during primate evolution. This is probably due to the emergence of novel genes after duplication events, evolutionary changes in gene expression, and/or acceleration in protein evolution. Here, we describe a human Ret finger protein-like (hRFPL)1,2,3 gene cluster on chromosome 22, which is transactivated by the corticogenic transcription factor Pax6. High hRFPL1,2,3 transcript levels were detected at the onset of neurogenesis in differentiating human embryonic stem cells and in the developing human neocortex, whereas the unique murine RFPL gene is expressed in liver but not in neural tissue. Study of the evolutionary history of the RFPL gene family revealed that the RFPL1,2,3 gene ancestor emerged after the Euarchonta-Glires split. Subsequent duplication events led to the presence of multiple RFPL1,2,3 genes in Catarrhini (∼34 mya) resulting in an increase in gene copy number in the hominoid lineage. In Catarrhini, RFPL1,2,3 expression profile diverged toward the neocortex and cerebellum over the liver. Importantly, humans showed a striking increase in cortical RFPL1,2,3 expression in comparison to their cerebellum, and to chimpanzee and macaque neocortex. Acceleration in RFPL-protein evolution was also observed with signs of positive selection in the RFPL1,2,3 cluster and two neofunctionalization events (acquisition of a specific RFPL-Defining Motif in all RFPLs and of a N-terminal 29 amino-acid sequence in catarrhinian RFPL1,2,3). Thus, we propose that the recent emergence and multiplication of the RFPL1,2,3 genes contribute to changes in primate neocortex size and/or organization.
Abstract | | - Human Genomic Deletions Mediated by Recombination between Al...Human Genomic Deletions Mediated by Recombination between Alu Elements
The American Journal of Human Genetics, Volume 79, Issue 1, 1 July 2006, Pages 41-53
Shurjo K. Sen, Kyudong Han, Jianxin Wang, Jungnam Lee, Hui Wang, Pauline A. Callinan, Matthew Dyer, Richard Cordaux, Ping Liang and Mark A. Batzer
AbstractRecombination between Alu elements results in genomic deletions associated with many human genetic disorders. Here, we compare the reference human and chimpanzee genomes to determine the magnitude of this recombination process in the human lineage since the human-chimpanzee divergence ∼6 million years ago. Combining computational data mining and wet-bench experimental verification, we identified 492 human-specific deletions (for a total of ∼400 kb) attributable to this process, a significant component of the insertion/deletion spectrum of the human genome. The majority of the deletions (295 of 492) coincide with known or predicted genes (including 3 that deleted functional exons, as compared with orthologous chimpanzee genes), which implicates this process in creating a substantial portion of the genomic differences between humans and chimpanzees. Overall, we found that Alu recombination-mediated genomic deletion has had a much higher impact than was inferred from previously identified isolated events and that it continues to contribute to the dynamic nature of the human genome.
Abstract | | - …more
