title: FOXP2 targets show evidence of positive selection in European populations.
abstract: Forkhead box P2 (FOXP2) is a highly conserved transcription factor that has been implicated in human speech and language disorders and plays important roles in the plasticity of the developing brain. The pattern of nucleotide polymorphisms in FOXP2 in modern populations suggests that it has been the target of positive (Darwinian) selection during recent human evolution. In our study, we searched for evidence of selection that might have followed FOXP2 adaptations in modern humans. We examined whether or not putative FOXP2 targets identified by chromatin-immunoprecipitation genomic screening show evidence of positive selection. We developed an algorithm that, for any given gene list, systematically generates matched lists of control genes from the Ensembl database, collates summary statistics for three frequency-spectrum-based neutrality tests from the low-coverage resequencing data of the 1000 Genomes Project, and determines whether these statistics are significantly different between the given gene targets and the set of controls. Overall, there was strong evidence of selection of FOXP2 targets in Europeans, but not in the Han Chinese, Japanese, or Yoruba populations. Significant outliers included several genes linked to cellular movement, reproduction, development, and immune cell trafficking, and 13 of these constituted a significant network associated with cardiac arteriopathy. Strong signals of selection were observed for CNTNAP2 and RBFOX1, key neurally expressed genes that have been consistently identified as direct FOXP2 targets in multiple studies and that have themselves been associated with neurodevelopmental disorders involving language dysfunction.
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. qa1@sanger.ac.uk
authors.forename: Qasim
authors.initials: Q
authors.lastname: Ayub
authors.forename: Bryndis
authors.initials: B
authors.lastname: Yngvadottir
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Yali
authors.initials: Y
authors.lastname: Xue
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.forename: Sonja C
authors.initials: SC
authors.lastname: Vernes
authors.forename: Simon E
authors.initials: SE
authors.lastname: Fisher
authors.forename: Chris
authors.initials: C
authors.lastname: Tyler-Smith
mesh_terms: D000465:Algorithms; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D030541:Databases, Genetic; D051858:Forkhead Transcription Factors / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics; D012641:Selection, Genetic / Q000235:genetics*; D044465:White People / Q000235:genetics*
chemical_list: C403049:CNTNAP2 protein, human; C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins