|Forkhead box P2|
PDB rendering based on 2a07.
|RNA expression pattern|
Forkhead box protein P2 also known as FOXP2 is a protein that in humans is encoded by the FOXP2 gene, located on human chromosome 7 (7q31, at the SPCH1 locus). FOXP2 orthologs have also been identified in all mammals for which complete genome data are available. 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. Versions of FOXP2 exist in similar forms in distantly related vertebrates; functional studies of the gene in mice and in songbirds indicate that it is important for modulating plasticity of neural circuits. Outside the brain FOXP2 has also been implicated in development of other tissues such as the lung and gut. FOXP2 directly regulates a large number of downstream target genes.
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. Two amino-acid substitutions distinguish the human FOXP2 protein from that found in chimpanzees, but only one of these two changes is unique to humans. Evidence from genetically manipulated mice and human neuronal cell models suggests that these changes affect the neural functions of FOXP2.
The human gene was originally identified by Oxford University geneticists Simon Fisher and Anthony Monaco through molecular investigations of an unusual family known as the KE family. Researchers at the Institute of Child Health in London had shown that around half of the family members – fifteen individuals across three generations – suffered from severe speech and language deficits. Remarkably, the transmission of the disorder from one generation to the next was consistent with autosomal dominant inheritance i.e. mutation of only a single gene on an autosome (non-sex chromosome) acting in a dominant fashion. This is one of the few known examples of Mendelian (monogenic) inheritance for a disorder affecting speech and language skills, which typically have a complex basis involving multiple genetic risk factors.
In the mid-1990s Fisher, Monaco and colleagues began to search for the damaged gene in the KE family, performing a genome-wide scan of DNA samples taken from the affected and unaffected members. This scan confirmed autosomal dominant monogenic inheritance and localized the gene responsible to a small section of chromosome 7. The locus was given the official name "SPCH1" (for speech-and-language-disorder-1) by the Human Genome Nomenclature committee. Mapping and sequencing of the chromosomal region was performed with the aid of bacterial artificial chromosome clones. Around this time, the researchers identified an individual who was unrelated to the KE family, but had a similar type of speech and language disorder. In this case the child, known as CS, carried a chromosomal rearrangement (a translocation) in which part of chromosome 7 had become exchanged with part of chromosome 5. The site of breakage of chromosome 7 was located within the SPCH1 region.
The team went on to pinpoint the precise position of the chromosome-7 breakage in case CS, and found that it lay directly in the middle of a protein-coding gene. Using a combination of bioinformatics and RNA analyses they deciphered the full coding region of the gene, discovering that it encoded a novel member of the forkhead-box (FOX) group of transcription factors. As such, it was assigned with the official name of FOXP2. When the researchers sequenced the FOXP2 gene in the KE family they uncovered a heterozygous point mutation that was shared by all the affected individuals, but absent from unaffected members and a large panel of controls from the general population. This mutation yields an amino-acid substitution at a crucial point of the DNA-binding domain of the FOXP2 protein, disrupting its function. Further screening of the gene has since identified multiple additional cases of FOXP2 disruption, including different point mutations and chromosomal rearrangements, providing further evidence that damage to one copy of this gene is sufficient to derail speech and language development.
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. Knockout mice with no functional copies of FOXP2 are runted, display abnormalities in brain regions such as the Purkinje layer, and die an average of 21 days after birth from inadequate lung development.
In human molecular biology, a protein transcription factor FOXP2 is encoded from the Forkhead Box P2 gene region located on chromosome 7 (7q31). The transcriptional targets of FOXP2 range from many areas inside the brain.More specifically, FOXP2 transcribes regions in the human basal ganglia and inferior frontal cortex, which are crucial for brain maturation, lung development, and speech and language development. FOXP2 is also the primary gene that separates Homo sapiens from chimpanzees by the substitution of two amino acids, Threonine to Asparagine and Asparagine to Serine. The substitutions occurred as a result of the separate evolutionary lineages between humans and chimpanzees. There are several abnormalities linked to FOXP2, but the most common mutation results in a modified form of FOXP2. This modified FOXP2 is associated with severe speech impairment known as developmental verbal dyspraxia which is caused by a translocation in the 7q31.2 region [t(5;7)(q22;q31.2)]. Recently, scientists have been using a knockout mouse model to examine FOXP2’s role in brain development and how mutations in the two copies of FOXP2 affect vocalization. Mutations in one copy cause reduced speech and abnormalities in both copies cause major brain and lung developmental issues. Scientists are also running tests on knockout mice to determine exactly how FOXP2 is expressed. A hypothesis suggests that FOXP2 is expressed through post-transcriptional regulation, particularly micro RNA, which binds to multiple miRNA binding-sites in the neocortex, causing the repression of FOXP2 3’UTR.
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. Similarly, in adult canaries higher FOXP2 levels also correlate with song changes. In addition, levels of FOXP2 in adult zebra finches are significantly higher when males direct their song to females than when they sing song in other contexts. Differences between song-learning and non-song-learning birds have been shown to be caused by differences in FOXP2 gene expression, rather than differences in the amino acid sequence of the FOXP2 protein.
Several cases of developmental verbal dyspraxia in humans have been linked to mutations in the FOXP2 gene. 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 "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). Scientists have also looked for associations between FOXP2 and autism and both positive and negative findings have been reported.
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. 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." 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. One of the two amino acid difference between human and chimps also arose independently in carnivores and bats. A recent extraction of DNA from Neanderthal bones indicates that Neanderthals had the same version (allele) of the FOXP2 gene as modern humans. Evidence that the two amino acid substitutions existed so far back in evolutionary history is corroborated by a more recent extraction of DNA from the remains of a related, previously unknown hominid in Denisova Cave. in that, according to University of Wisconsin Professor John Hawk's website, this hominid also shares the two substitutions. Nevertheless, Coop et al. (2008) point out that "modern human contamination ...could produce the observed results". They further point out that the molecular data suggests a more recent origin than 300,000 years ago because "...the selected haplotype appears to have accumulated few mutations since."
Some researchers have speculated that the two amino acid differences between chimps and humans led to the evolution of language in humans. Others, however, have been unable to find a clear association between species with learned vocalizations and similar mutations in FOXP2. 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. 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. However the mutation rate of FOXP2 is slower in the human lineage than in the lineage before the human-chimpanzee split, and proposed that purifying selection would not have relaxed due to deleterious effects. Thus, it was most likely positive selection that drove the two amino acid differences to fixation in humans, suggesting that differences between humans and non-humans are a result of the two amino acid changes.
Li et al. (2007) found that exons 7 and 17 of FoxP2 in bats are highly variable and not as conserved as in other vertebrates. Twenty-two sequences of non-bat eutherian mammals revealed a total number of 20 nonsynonymous mutations in contrast to half that number of bat sequences, which showed 44 nonsynonymous mutations. Interestingly, all cetaceans share three amino acid substitutions, but there are not differences between echolocating and non-echolocating baleen cetaceans. Within bats, however, amino acid variation correlated with different echolocating types. Accelerated evolution in bats is likely due to positive selection on echolocation. Given this hypothesis that a novel FOXP2 sequence can aid echolocation, echolocating and non echolocating cetaceans might be predicted to display differences in their FOXP2 sequences. However, they produce the necessary sounds for echolocation with a complex called a melon (located on the forehead) rather than with the orofacial muscles. Li et al. speculate that because FOXP2 has been tied to orofiacial muscle control in humans its role in bat echolocation may be to increase coordination in these muscles, and that therefore echolocating and non-echolocating cetaceans would not necessarily be expected to show a diverse FOXP2 genotype.
In zebra finch, FoxP2 mRNA expression is observed in structures analogous to FoxP2 rich structures in the human brain including the basal ganglia, cortex (referred to as pallium in birds) and the cerebellum. Notably, FoxP2 is expressed in the song control nucleus Area X, which is a basal ganglia-like nucleus dedicated to singing behaviors. In zebra finch, FoxP2 mRNA shows a developmental increase during sensorimotor learning without any change in other FoxP2 enriched structures. Reinforcing the idea that this increase is tied to sensorimotor learning (as opposed to age per se), the canary – which relearns song every year – shows a similar increase in FoxP2 during late summer and early fall, a time period which corresponds to their yearly sensorimotor learning. Interestingly, blocking this upregulation using lentiviral mediated knockdown in zebra finches impairs song learning and increases variability upon maturation.
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