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.
Highlights
Humans have adapted in many ways since the split from chimpanzees around six to seven million years ago, and some of these adaptations have involved classic selective sweeps, which leave recognizable signatures in the pattern of genetic variation surrounding the selected locus.[1]
We have previously calculated neutrality statistics in 10 kb windows across the genome from whole-genome sequence data in 179 individuals from three continental regions.[15]. These statistics can be used for assessing the evidence of positive selection at any locus or group of loci. To do this in a robust fashion, we developed an algorithm that, for any given gene list of interest, (1) generates unmatched and matched lists (n 1⁄4 1,000) of control genes from the Ensembl database, (2) collates summary statistics for positive selection from the 1000 Genomes data, (3) determines whether or not these summary statistics are significantly different between the target genes and controls, and (4) identifies outliers from the gene list as specific candidates for signals of positive selection
Establishment of a Pipeline for Detecting Positive Selection in a Chosen Set of Genes We first tested our algorithm by using lists of known positively selected and nonselected genes identified from reports in the literature.[2,15,26]
Summary
Humans have adapted in many ways since the split from chimpanzees around six to seven million years ago, and some of these adaptations have involved classic selective sweeps, which leave recognizable signatures in the pattern of genetic variation surrounding the selected locus.[1]. One gene that has been extensively investigated, both for genomic patterns indicative of selective sweeps and in functional studies, is forkhead box P2 (FOXP2 [MIM 605317]) (see Fisher and Scharff[3] for a review). This gene was originally identified from mutations that led to a dominant Mendelian speech and language disorder in a three-generation family and in an independent chromosomal translocation case.[4] Mutations of FOXP2 are rare but have since been identified in several additional families affected by speech and language problems.[5,6,7] After human
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