title: Widespread differences in cortex DNA methylation of the "language gene" CNTNAP2 between humans and chimpanzees.
abstract: CNTNAP2, one of the largest genes in the human genome, has been linked to human-specific language abilities and neurodevelopmental disorders. Our hypothesis is that epigenetic rather than genetic changes have accelerated the evolution of the human brain. To compare the cortex DNA methylation patterns of human and chimpanzee CNTNAP2 at ultra-high resolution, we combined methylated DNA immunoprecipitation (MeDIP) with NimbleGen tiling arrays for the orthologous gene and flanking sequences. Approximately 1.59 Mb of the 2.51 Mb target region could be aligned and analyzed with a customized algorithm in both species. More than one fifth (0.34 Mb) of the analyzed sequence throughout the entire gene displayed significant methylation differences between six human and five chimpanzee cortices. One of the most striking interspecies differences with 28% methylation in human and 59% in chimpanzee cortex (by bisulfite pyrosequencing) lies in a region 300 bp upstream of human SNP rs7794745 which has been associated with autism and parent-of-origin effects. Quantitative real-time RT PCR revealed that the protein-coding splice variant CNTNAP2-201 is 1.6-fold upregulated in human cortex, compared with the chimpanzee. Transcripts CNTNAP2-001, -002, and -003 did not show skewed allelic expression, which argues against CNTNAP2 imprinting, at least in adult human brain. Collectively, our results suggest widespread cortex DNA methylation changes in CNTNAP2 since the human-chimpanzee split, supporting a role for CNTNAP2 fine-regulation in human-specific language and communication traits.
authors.affiliation: Institute for Human Genetics; Julius Maximilian University; Würzburg, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schneider
authors.affiliation: Institute for Human Genetics; Julius Maximilian University; Würzburg, Germany.
authors.forename: Nady
authors.initials: N
authors.lastname: El Hajj
authors.affiliation: Institute for Human Genetics; Julius Maximilian University; Würzburg, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Richter
authors.affiliation: Institute for Human Genetics; Julius Maximilian University; Würzburg, Germany.
authors.forename: Justin
authors.initials: J
authors.lastname: Roche-Santiago
authors.affiliation: Institute for Human Genetics; Julius Maximilian University; Würzburg, Germany.
authors.forename: Indrajit
authors.initials: I
authors.lastname: Nanda
authors.affiliation: Institute for Human Genetics; University of Freiburg; Freiburg, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Schempp
authors.affiliation: Clinical Neurochemistry Laboratory; Department of Psychiatry; University Hospital; Würzburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Riederer
authors.affiliation: Institute of Legal Medicine; University Medical Center; Mainz, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Navarro
authors.affiliation: Biomedical Primate Research Center; Rijswijk, The Netherlands.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Bontrop
authors.affiliation: Biomedical Primate Research Center; Rijswijk, The Netherlands.
authors.forename: Ivanela
authors.initials: I
authors.lastname: Kondova
authors.affiliation: Laboratory for Microarray Applications; IZKF; Julius Maximilians University; Würzburg, Germany.
authors.forename: Claus Jürgen
authors.initials: CJ
authors.lastname: Scholz
authors.affiliation: Institute for Human Genetics; Julius Maximilian University; Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haaf
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D002648:Child; D019175:DNA Methylation / Q000502:physiology*; D005260:Female; D006801:Humans; D007802:Language; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D002679:Pan troglodytes; D019154:Protein Splicing; D013045:Species Specificity; D055815:Young Adult
chemical_list: C403049:CNTNAP2 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins
keywords: CNTNAP2; DNA methylation; human brain evolution; human-chimpanzee comparison; human-specific communication; language