The timing of selection at the human FOXP2 gene.
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ABSTRACT:
SUBMITTER: Coop G
PROVIDER: S-EPMC2429961 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:FOXP2, initially identified for its role in human speech, contains two nonsynonymous substitutions derived in the human lineage. Evidence for a recent selective sweep in Homo sapiens, however, is at odds with the presence of these substitutions in archaic hominins. Here, we comprehensively reanalyze FOXP2 in hundreds of globally distributed genomes to test for recent selection. We do not find evidence of recent positive or balancing selection at FOXP2. Instead, the original signal appears to have been due to sample composition. Our tests do identify an intronic region that is enriched for highly conserved sites that are polymorphic among humans, compatible with a loss of function in humans. This region is lowly expressed in relevant tissue types that were tested via RNA-seq in human prefrontal cortex and RT-PCR in immortalized human brain cells. Our results represent a substantial revision to the adaptive history of FOXP2, a gene regarded as vital to human evolution.
| S-EPMC6128738 | biostudies-literature
Project description:The recent descriptions of widespread random monoallelic expression (RMAE) of genes distributed throughout the autosomal genome indicate that there are more genes subject to RMAE on autosomes than the number of genes on the X chromosome where X-inactivation dictates RMAE of X-linked genes. Several of the autosomal genes that undergo RMAE have independently been implicated in human Mendelian disorders. Thus, parsing the relationship between allele-specific expression of these genes and disease is of interest. Mutations in the human forkhead box P2 gene, FOXP2, cause developmental verbal dyspraxia with profound speech and language deficits. Here, we show that the human FOXP2 gene undergoes RMAE. Studying an individual with developmental verbal dyspraxia, we identify a deletion 3 Mb away from the FOXP2 gene, which impacts FOXP2 gene expression in cis. Together these data suggest the intriguing possibility that RMAE impacts the haploinsufficiency phenotypes observed for FOXP2 mutations.
| S-EPMC4460484 | biostudies-literature
Project description: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.
| S-EPMC3644635 | biostudies-literature
Project description:The FOXP2 transcription factor is one of the most well-known genes to have been implicated in developmental speech and language disorders. Rare mutations disrupting the function of this gene have been described in different families and cases. In a large three-generation family carrying a missense mutation, neuroimaging studies revealed significant effects on brain structure and function, most notably in the inferior frontal gyrus, caudate nucleus, and cerebellum. After the identification of rare disruptive FOXP2 variants impacting on brain structure, several reports proposed that common variants at this locus may also have detectable effects on the brain, extending beyond disorder into normal phenotypic variation. These neuroimaging genetics studies used groups of between 14 and 96 participants. The current study assessed effects of common FOXP2 variants on neuroanatomy using voxel-based morphometry (VBM) and volumetric techniques in a sample of >1300 people from the general population. In a first targeted stage we analyzed single nucleotide polymorphisms (SNPs) claimed to have effects in prior smaller studies (rs2253478, rs12533005, rs2396753, rs6980093, rs7784315, rs17137124, rs10230558, rs7782412, rs1456031), beginning with regions proposed in the relevant papers, then assessing impact across the entire brain. In the second gene-wide stage, we tested all common FOXP2 variation, focusing on volumetry of those regions most strongly implicated from analyses of rare disruptive mutations. Despite using a sample that is more than 10 times that used for prior studies of common FOXP2 variation, we found no evidence for effects of SNPs on variability in neuroanatomy in the general population. Thus, the impact of this gene on brain structure may be largely limited to extreme cases of rare disruptive alleles. Alternatively, effects of common variants at this gene exist but are too subtle to be detected with standard volumetric techniques.
| S-EPMC4076884 | biostudies-literature
Project description:The interplay of divergent selection and gene flow is key to understanding how populations adapt to local environments and how new species form. Here, we use DNA polymorphism data and genome-wide variation in recombination rate to jointly infer the strength and timing of selection, as well as the baseline level of gene flow under various demographic scenarios. We model how divergent selection leads to a genome-wide negative correlation between recombination rate and genetic differentiation among populations. Our theory shows that the selection density (i.e., the selection coefficient per base pair) is a key parameter underlying this relationship. We then develop a procedure for parameter estimation that accounts for the confounding effect of background selection. Applying this method to two datasets from Mimulus guttatus, we infer a strong signal of adaptive divergence in the face of gene flow between populations growing on and off phytotoxic serpentine soils. However, the genome-wide intensity of this selection is not exceptional compared with what M. guttatus populations may typically experience when adapting to local conditions. We also find that selection against genome-wide introgression from the selfing sister species M. nasutus has acted to maintain a barrier between these two species over at least the last 250 ky. Our study provides a theoretical framework for linking genome-wide patterns of divergence and recombination with the underlying evolutionary mechanisms that drive this differentiation.
| S-EPMC5502586 | biostudies-literature
Project description:FOXP2 encodes a transcription factor involved in speech and language acquisition. Growing evidence now suggests that dysregulated FOXP2 activity may also be instrumental in human oncogenesis, along the lines of other cardinal developmental transcription factors such as DLX5 and DLX6 [1-4]. Several FOXP familymembers are directly involved during cancer initiation, maintenance and progression in the adult [5-8]. This may comprise either a pro-oncogenic activity or a deficient tumor-suppressor role, depending upon cell types and associated signaling pathways. While FOXP2 is expressed in numerous cell types, its expression has been found to be down-regulated in breast cancer [9], hepatocellular carcinoma [8] and gastric cancer biopsies [10]. Conversely, overexpressed FOXP2 has been reported in multiple myelomas, MGUS (Monoclonal Gammopathy of Undetermined Significance), several subtypes of lymphomas [5,11], as well as in neuroblastomas [12] and ERG fusion-negative prostate cancers [13]. According to functional evidences reported in breast cancer [9] and survey of recent transcriptomic and proteomic analyses of different tumor biopsies, we postulate that FOXP2 dysregulation may play a main role throughout cancer initiation and progression. In some cancer conditions, FOXP2 levels are now considered as a critical diagnostic marker of neoplastic cells, and in many situations, they even bear strong prognostic value [5]. Whether FOXP2 may further become a therapeutic target is an actively explored lead. Knowledge reviewed here may help improve our understanding of FOXP2 roles during oncogenesis and provide cues for diagnostic, prognostic and therapeutic analyses.
| S-EPMC5931254 | biostudies-literature
Project description:The forkhead box P2 gene, designated FOXP2, is the first gene implicated in a speech and language disorder. Since its discovery, many studies have been carried out in an attempt to explain the mechanism by which it influences these characteristically human traits. This review presents the story of the discovery of the FOXP2 gene, including early studies of the phenotypic implications of a disruption in the gene. We then discuss recent investigations into the molecular function of the FOXP2 gene, including functional and gene expression studies. We conclude this review by presenting the fascinating results of recent studies of the FOXP2 ortholog in other species that are capable of vocal communication. WIREs Cogn Sci 2013, 4:547-560. doi: 10.1002/wcs.1247 This article is categorized under: Psychology > Language Neuroscience > Genes, Molecules, and Cells.
| S-EPMC3992897 | biostudies-literature
Project description:It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene.of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting an effect of the humanized Foxp2 allele on basal ganglia. In the striatum, a part of the basal ganglia that is affected in humans with a speech deficit due to one non-functional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one non-functional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans. In this particular experiment, we investigate the effects of human Foxp2 (Foxp2hum) and the non-functional Foxp2 allele on striatal gene expression in embryonic, young and adult mice. We determined genome-wide gene expression patterns in striatal biopsies from Foxp2hum/hum, Foxp2wt/ko and Foxp2wt/wt mice using high-density oligonucleotide arrays. The animals were derived from two independent FoxP2 knock-in strains and one knock-out strain. In total 71 animals were used, 29 males and 42 females. The mice ages were E16.5, P15, P18, P21 and P95 when sacrificed. The microarrays were processed in totally six batches.
2010-05-22 | E-GEOD-13588 | biostudies-arrayexpress
Project description:The protein-coding gene FoxP2 (fork head box protein P2) plays a major role in communication and evolutionary changes. The present study carried out a comprehensive codon usage bias analysis in the FoxP2 gene among a diverse group of animals including fishes, birds, reptiles, and mammals. We observed that in the genome of fishes for the FoxP2 gene, codons ending with C or G were most frequently used, while in birds, reptiles, and mammals, codons ending with T or A were most frequently used. A higher ENC value was observed for the FoxP2 gene indicating a lower CUB. Parity role two-bias plots suggested that apart from mutation pressure, other factors such as natural selection might have influenced the CUB. The frequency distribution of the ENC observed and ENC expected ratio revealed that mutation pressure plays a key role in the patterns of codon usage of FoxP2. Besides, correspondence analysis exposed the composition of the nucleobase under mutation bias affects the codon usage of the FoxP2 gene. However, neutrality plots revealed the major role of natural selection over mutation pressure in the CUB of FoxP2. In addition, the codon usage patterns for FoxP2 among the selected genomes suggested that nature has favored nearly all the synonymous codons for encoding the corresponding amino acid. The uniform usage of 12 synonymous codons for FoxP2 was observed among the species of birds. The amino acid usage frequency for FoxP2 revealed that the amino acids Leucine, Glutamine, and Serine were predominant over other amino acids among all the species of fishes, birds, reptiles, and mammals.
| S-EPMC8614651 | biostudies-literature
Project description: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.
| S-EPMC2276350 | biostudies-literature