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Forkhead box protein P2 also known as FOXP2 is a protein that in humans is encoded by the FOXP2 gene[1], located on human chromosome 7 (7q31, at the SPCH1 locus).[2][3] The FOXP2 protein contains a forkhead-box DNA-binding domain, making it a member of the FOX group of transcription factors, involved in regulation of gene expression. In addition to this characteristic forkhead-box domain, the protein contains a polyglutamine tract, a zinc finger and a leucine zipper. In humans, mutations of FOXP2 cause a severe speech and language disorder.[1][4] Versions of FOXP2 exist in similar forms in distantly related vertebrates; functional studies of the gene in mice[5] and in songbirds[6] indicate that it is important for modulating plasticity of neural circuits.[7] Outside the brain FOXP2 has also been implicated in development of other tissues such as the lung and gut.[8] FOXP2 directly regulates a large number of downstream target genes.[9][10] One particular target that is directly downregulated by FOXP2 in human neurons is the CNTNAP2 gene, a member of the neurexin family; variants in this target gene have been associated with common forms of language impairment. [11] Two amino-acid substitutions distinguish the human FOXP2 protein from that found in chimpanzees.[12] Evidence from genetically manipulated mice[13] and human neuronal cell models[14] suggests that these changes affect the neural functions of FOXP2.
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FOXP2 is required for proper brain and lung development. Knockout mice with only one functional copy of the FOXP2 gene have significantly reduced vocalizations as pups[15]. Knockout mice with no functional copies of FOXP2 are runted, display abnormalities in brain regions such as the Purkinje layer, and die 21 days after birth from inadequate lung development.[8]
Different studies of FOXP2 in songbirds suggest that FOXP2 may regulate genes involved in neuroplasticity: During song learning FOXP2 is upregulated in brain regions critical for song learning in young zebra finches. Knockdown of FOXP2 in Area X of the basal ganglia of these birds results in incomplete and inaccurate song imitation.[16] Similarly, in adult canaries higher FOXP2 levels also correlate with song changes.[17] In addition, levels of FOXP2 in adult zebra finches are significantly lower when males direct their song to females than when they sing song in other contexts.[18] Differences between birds which are learning songs and those which are not have been shown to be caused by differences in FOXP2 gene expression, rather than differences in the amino acid sequence of the FOXP2 protein.[19]
FOXP2 has also been implicated in the development of bat echolocation.[20]
Several cases of developmental verbal dyspraxia in humans have been linked to mutations in the FOXP2 gene.[21] Such individuals have little or no cognitive handicaps but are unable to correctly perform the coordinated movements required for speech. fMRI analysis of these individuals performing silent verb generation and spoken word repetition tasks showed underactivation of Broca's area and the putamen, brain centers thought to be involved in language tasks. Because of this, FOXP2 has been dubbed the "speech and language gene." People with this mutation also experience symptoms not related to language (not surprisingly, as FOXP2 is known to affect development in other parts of the body as well).[19] Scientists have also looked for associations between FOXP2 and autism and both positive and negative findings have been reported.[22][23]
There is some evidence that the linguistic impairments associated with a mutation of the FOXP2 gene are not simply the result of a fundamental deficit in motor control. For example:
The FOXP2 protein sequence is generally thought to be highly conserved. Similar FOXP2 proteins can be found in songbirds, fish, and reptiles such as alligators.[24][25] However, recent studies in bats (chiroptera) has prompted some researchers to conclude that FoxP2 is not well conserved in non-human mammals and write: "We found that contrary to previous reports, FoxP2 is not highly conserved across all nonhuman mammals but is extremely diverse in echolocating bats."[26] Aside from a polyglutamine tract, human FOXP2 differs from chimp FOXP2 by only two amino acids, mouse FOXP2 by only 3 amino acids, and zebra finch FOXP2 by only 7 amino acids.[12][27][28] A recent extraction of DNA from Neanderthal bones indicates that Neanderthals had the same version (allele) of the FOXP2 gene as modern humans.[29]
Some researchers have speculated that the two amino acid differences between chimps and humans led to the evolution of language in humans.[12] Others, however, have been unable to find a clear association between species with learned vocalizations and similar mutations in FOXP2.[24][25] Insertion of both human mutations into mice, whose version of FOXP2 otherwise differs from the human and chimpanzee versions in only one additional base pair, causes changes in vocalizations as well as other behavioral changes, such as a reduction in exploratory tendencies; a reduction in dopamine levels and changes in the morphology of certain nerve cells are also observed.[13] It may also be, based on general observations of development and songbird results, that any difference between humans and non-humans would be due to regulatory sequence divergence (affecting where and when FOXP2 is expressed) rather than the two amino acid differences mentioned above.[19]
The search for the gene was initially started as a result of the investigations into the KE family. Certain members of this family suffered from an inherited speech and language disorder and living members stretched back three generations. Closer inspection of the family revealed the disorder to be autosomal dominant.
A scan was performed of the genome of the affected and some of the unaffected family members. This initial scan limited the affected region to a spot on chromosome 7, which the team called "SPCH1". Sequencing of this region was done with the aid of bacterial artificial chromosome clones. At this point, another individual was located who had a similar disorder but was unrelated to the family. The genome of this individual was mapped and it was discovered that there was a break in chromosome 7.
Further investigation discovered a point mutation in this chromosome. Sequenced and analysed, this is now referred to as the FOXP2 gene.
FOXP2 has been shown to interact with CTBP1.[30]
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   | Molecular evolution of language: Biological selection for mutated FOXP2 - Molecular evolution of language :The Scientist [15/8/2002] |
| | Molecular evolution of FOXP2, a gene involved in speech and language - The page you requested is no longer here [error 404] |
| | FOXP2 and the Evolution of Language - FOXP2 and the Evolution of Language |
| | Accelerated FoxP2 Evolution in Echolocating Bats - PLoS ONE: Accelerated FoxP2 Evolution in Echolocating Bats |
| | Neanderthals Had Important Speech Gene, DNA Evidence Shows - The New York Times > Log In |
| | From Squeak to Syntax: Language's Incremental Evolution - The New York Times > Log In |
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