FOXP2
Template:Short description Template:Cs1 config Template:Use dmy dates Template:Infobox gene
Forkhead box protein P2 (FOXP2) is a protein that, in humans, is encoded by the FOXP2 gene. FOXP2 is a member of the forkhead box family of transcription factors, proteins that regulate gene expression by binding to DNA. It is expressed in the brain, heart, lungs and digestive system.<ref name="Fisher_1998">Template:Cite journal</ref><ref name="Lai_2000">Template:Cite journal</ref>
FOXP2 is found in many vertebrates, where it plays an important role in mimicry in birds (such as birdsong) and echolocation in bats. FOXP2 is also required for the proper development of speech and language in humans.<ref name="Lai_2001">Template:Cite journal</ref> In humans, mutations in FOXP2 cause the severe speech and language disorder developmental verbal dyspraxia.<ref name="Lai_2001" /><ref name="MacDermot_2005">Template:Cite journal</ref> Studies of the gene in mice and songbirds indicate that it is necessary for vocal imitation and the related motor learning.<ref name="Groszer 2008">Template:Cite journal</ref><ref name="Haesler_2007" /><ref name="Fisher_2009">Template:Cite journal</ref> Outside the brain, FOXP2 has also been implicated in development of other tissues such as the lung and digestive system.<ref name="Shu_2007" />
Initially identified in 1998 as the genetic cause of a speech disorder in a British family designated the KE family, FOXP2 was the first gene discovered to be associated with speech and language<ref>Template:Cite journal</ref> and was subsequently dubbed "the language gene".<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> However, other genes are necessary for human language development, and a 2018 analysis confirmed that there was no evidence of recent positive evolutionary selection of FOXP2 in humans.<ref name="Atkinson_2018" /><ref name=":1">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Structure and functionEdit
As a FOX protein, FOXP2 contains a forkhead-box domain. In addition, it contains a polyglutamine tract, a zinc finger and a leucine zipper. The protein attaches to the DNA of other proteins and controls their activity through the forkhead-box domain. Only a few targeted genes have been identified, however researchers believe that there could be up to hundreds of other genes targeted by the FOXP2 gene. The forkhead box P2 protein is active in the brain and other tissues before and after birth, and many studies show that it is paramount for the growth of nerve cells and transmission between them. The FOXP2 gene is also involved in synaptic plasticity, making it imperative for learning and memory.<ref name = "GHR_FOXP2">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref name="Shu_2005">Template:Cite journal</ref> 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.<ref name="Shu_2007">Template:Cite journal</ref>
FOXP2 is expressed in many areas of the brain,<ref name="Enard_2002">Template:Cite journal</ref> including the basal ganglia and inferior frontal cortex, where it is essential for brain maturation and speech and language development.<ref name="Spiteri_2007">Template:Cite journal</ref> In mice, the gene was found to be twice as highly expressed in male pups than female pups, which correlated with an almost double increase in the number of vocalisations the male pups made when separated from mothers. Conversely, in human children aged 4–5, the gene was found to be 30% more expressed in the Broca's areas of female children. The researchers suggested that the gene is more active in "the more communicative sex".<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
The expression of FOXP2 is subject to post-transcriptional regulation, particularly microRNA (miRNA), causing the repression of the FOXP2 3' untranslated region.<ref name="Clovis_2012">Template:Cite journal</ref>
Three amino acid substitutions distinguish the human FOXP2 protein from that found in mice, while two amino acid substitutions distinguish the human FOXP2 protein from that found in chimpanzees,<ref name="Enard_2002" /> but only one of these changes is unique to humans.<ref name="Shu_2007" /> Evidence from genetically manipulated mice<ref name="Enard_2009">Template:Cite journal</ref> and human neuronal cell models<ref name="Konopka_2009">Template:Cite journal
- Template:Cite press release</ref> suggests that these changes affect the neural functions of FOXP2.
Clinical significanceEdit
The FOXP2 gene has been implicated in several cognitive functions including; general brain development, language, and synaptic plasticity. The FOXP2 gene region acts as a transcription factor for the forkhead box P2 protein. Transcription factors affect other regions, and the forkhead box P2 protein has been suggested to also act as a transcription factor for hundreds of genes. This prolific involvement opens the possibility that the FOXP2 gene is much more extensive than originally thought.<ref name="GHR_FOXP2" /> Other targets of transcription have been researched without correlation to FOXP2. Specifically, FOXP2 has been investigated in correlation with autism and dyslexia, however with no mutation was discovered as the cause.<ref name="Gauthier_2003">Template:Cite journal</ref><ref name="MacDermot_2005" /> One well identified target is language.<ref name="GHR_FOXP2_disorders">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Although some research disagrees with this correlation,<ref>Template:Cite journal</ref> the majority of research shows that a mutated FOXP2 causes the observed production deficiency.<ref name="GHR_FOXP2" /><ref name="GHR_FOXP2_disorders"/><ref name="Lennon_2007">Template:Cite journal</ref><ref name="Gauthier_2003" /><ref>Template:Cite journal</ref><ref name="Reuter_2017">Template:Cite journal</ref>
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. Brain imaging of affected individuals indicates functional abnormalities in language-related cortical and basal ganglia regions, demonstrating that the problems extend beyond the motor system.<ref>Template:Cite journal</ref>
Mutations in FOXP2 are among several (26 genes plus 2 intergenic) loci which correlate to ADHD diagnosis in adults – clinical ADHD is an umbrella label for a heterogeneous group of genetic and neurological phenomena which may result from FOXP2 mutations or other causes.<ref name="Demontis 2018">Template:Cite journal</ref>
A 2020 genome-wide association study (GWAS) implicates single-nucleotide polymorphisms (SNPs) of FOXP2 in susceptibility to cannabis use disorder.<ref name="Johnson_2020">Template:Cite journal</ref>
Language disorderEdit
It is theorized that the translocation of the 7q31.2 region of the FOXP2 gene causes a severe language impairment called developmental verbal dyspraxia (DVD)<ref name="GHR_FOXP2_disorders"/> or childhood apraxia of speech (CAS)<ref>Template:Cite journal</ref> So far this type of mutation has only been discovered in three families across the world including the original KE family.<ref name="Reuter_2017"/> A missense mutation causing an arginine-to-histidine substitution (R553H) in the DNA-binding domain is thought to be the abnormality in KE.<ref name="Preuss_2012" /> This would cause a normally basic residue to be fairly acidic and highly reactive at the body's pH. A heterozygous nonsense mutation, R328X variant, produces a truncated protein involved in speech and language difficulties in one KE individual and two of their close family members. R553H and R328X mutations also affected nuclear localization, DNA-binding, and the transactivation (increased gene expression) properties of FOXP2.<ref name="MacDermot_2005" />
These individuals present with deletions, translocations, and missense mutations. When tasked with repetition and verb generation, these individuals with DVD/CAS had decreased activation in the putamen and Broca's area in fMRI studies. These areas are commonly known as areas of language function.<ref>Template:Cite journal</ref> This is one of the primary reasons that FOXP2 is known as a language gene. They have delayed onset of speech, difficulty with articulation including slurred speech, stuttering, and poor pronunciation, as well as dyspraxia.<ref name="Reuter_2017"/> It is believed that a major part of this speech deficit comes from an inability to coordinate the movements necessary to produce normal speech including mouth and tongue shaping.<ref name="GHR_FOXP2_disorders" /> Additionally, there are more general impairments with the processing of the grammatical and linguistic aspects of speech.<ref name="MacDermot_2005" /> These findings suggest that the effects of FOXP2 are not limited to motor control, as they include comprehension among other cognitive language functions. General mild motor and cognitive deficits are noted across the board.<ref name="Lennon_2007"/> Clinically these patients can also have difficulty coughing, sneezing, or clearing their throats.<ref name="GHR_FOXP2_disorders" />
While FOXP2 has been proposed to play a critical role in the development of speech and language, this view has been challenged by the fact that the gene is also expressed in other mammals as well as birds and fish that do not speak.<ref>Template:Cite book</ref> It has also been proposed that the FOXP2 transcription-factor is not so much a hypothetical 'language gene' but rather part of a regulatory machinery related to externalization of speech.<ref>Template:Cite book</ref>
EvolutionEdit
The FOXP2 gene is highly conserved in mammals.<ref name="Enard_2002" /> The human gene differs from that in non-human primates by the substitution of two amino acids, a threonine to asparagine substitution at position 303 (T303N) and an asparagine to serine substitution at position 325 (N325S).<ref name="Preuss_2012">Template:Cite journal</ref> In mice it differs from that of humans by three substitutions, and in zebra finch by seven amino acids.<ref name="Enard_2002"/><ref name="Teramitsu_2004">Template:Cite journal</ref><ref name="Haesler_2004">Template:Cite journal</ref> One of the two amino acid differences between human and chimps also arose independently in carnivores and bats.<ref name="Shu_2007"/><ref name="Li_2007" /> Similar FOXP2 proteins can be found in songbirds, fish, and reptiles such as alligators.<ref name="Webb_2005">Template:Cite journal</ref><ref name="Scharff_2005">Template:Cite journal</ref>
DNA sampling from Homo neanderthalensis bones indicates that their FOXP2 gene is a little different though largely similar to those of Homo sapiens (i.e. humans).<ref name="NYT-20160317">Template:Cite news</ref><ref name="Krause_2007">Template:Cite journal
See also Template:Cite journal</ref> Previous genetic analysis had suggested that the H. sapiens FOXP2 gene became fixed in the population around 125,000 years ago.<ref name="Sprach_2008">Template:Cite journal</ref> Some researchers consider the Neanderthal findings to indicate that the gene instead swept through the population over 260,000 years ago, before our most recent common ancestor with the Neanderthals.<ref name="Sprach_2008"/> Other researchers offer alternative explanations for how the H. sapiens version would have appeared in Neanderthals living 43,000 years ago.<ref name="Sprach_2008"/>
According to a 2002 study, the FOXP2 gene showed indications of recent positive selection.<ref name="Enard_2002"/><ref>Template:Cite journal</ref> Some researchers have speculated that positive selection is crucial for the evolution of language in humans.<ref name="Enard_2002"/> Others, however, were unable to find a clear association between species with learned vocalizations and similar mutations in FOXP2.<ref name="Webb_2005"/><ref name="Scharff_2005"/> A 2018 analysis of a large sample of globally distributed genomes confirmed there was no evidence of positive selection, suggesting that the original signal of positive selection may be driven by sample composition.<ref name="Atkinson_2018">Template:Cite journal</ref><ref name=":1" /> 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, and a decrease in maze learning time. A reduction in dopamine levels and changes in the morphology of certain nerve cells are also observed.<ref name="Enard_2009"/>
InteractionsEdit
FOXP2 is known to regulate CNTNAP2, CTBP1,<ref name="Li_2004">Template:Cite journal</ref> SRPX2 and SCN3A.<ref>Template:Cite journal</ref><ref name="Spiteri_2007" /><ref name="Vernes_207">Template:Cite journal</ref>
FOXP2 downregulates CNTNAP2, a member of the neurexin family found in neurons. CNTNAP2 is associated with common forms of language impairment.<ref name="Vernes_2008">Template:Cite journal</ref>
FOXP2 also downregulates SRPX2, the 'Sushi Repeat-containing Protein X-linked 2'.<ref name=":02"/><ref>Template:Cite news</ref> It directly reduces its expression, by binding to its gene's promoter. SRPX2 is involved in glutamatergic synapse formation in the cerebral cortex and is more highly expressed in childhood. SRPX2 appears to specifically increase the number of glutamatergic synapses in the brain, while leaving inhibitory GABAergic synapses unchanged and not affecting dendritic spine length or shape. On the other hand, FOXP2's activity does reduce dendritic spine length and shape, in addition to number, indicating it has other regulatory roles in dendritic morphology.<ref name=":02">Template:Cite journal</ref>
In other animalsEdit
ChimpanzeesEdit
In chimpanzees, FOXP2 differs from the human version by two amino acids.<ref>Template:Cite journal</ref> A study in Germany sequenced FOXP2's complementary DNA in chimps and other species to compare it with human complementary DNA in order to find the specific changes in the sequence.<ref name="Enard_2002" /> FOXP2 was found to be functionally different in humans compared to chimps. Since FOXP2 was also found to have an effect on other genes, its effects on other genes is also being studied.<ref>Template:Cite news</ref> Researchers deduced that there could also be further clinical applications in the direction of these studies in regards to illnesses that show effects on human language ability.<ref name="Konopka_2009" />
MiceEdit
In a mouse FOXP2 gene knockouts, loss of both copies of the gene causes severe motor impairment related to cerebellar abnormalities and lack of ultrasonic vocalisations normally elicited when pups are removed from their mothers.<ref name="Shu_2005"/> These vocalizations have important communicative roles in mother–offspring interactions. Loss of one copy was associated with impairment of ultrasonic vocalisations and a modest developmental delay. Male mice on encountering female mice produce complex ultrasonic vocalisations that have characteristics of song.<ref name="Holy_2005">Template:Cite journal</ref> Mice that have the R552H point mutation carried by the KE family show cerebellar reduction and abnormal synaptic plasticity in striatal and cerebellar circuits.<ref name="Groszer 2008"/>
Humanized FOXP2 mice display altered cortico-basal ganglia circuits. The human allele of the FOXP2 gene was transferred into the mouse embryos through homologous recombination to create humanized FOXP2 mice. The human variant of FOXP2 also had an effect on the exploratory behavior of the mice. In comparison to knockout mice with one non-functional copy of FOXP2, the humanized mouse model showed opposite effects when testing its effect on the levels of dopamine, plasticity of synapses, patterns of expression in the striatum and behavior that was exploratory in nature.<ref name="Enard_2009" />
When FOXP2 expression was altered in mice, it affected many different processes including the learning motor skills and the plasticity of synapses. Additionally, FOXP2 is found more in the sixth layer of the cortex than in the fifth, and this is consistent with it having greater roles in sensory integration. FOXP2 was also found in the medial geniculate nucleus of the mouse brain, which is the processing area that auditory inputs must go through in the thalamus. It was found that its mutations play a role in delaying the development of language learning. It was also found to be highly expressed in the Purkinje cells and cerebellar nuclei of the cortico-cerebellar circuits. High FOXP2 expression has also been shown in the spiny neurons that express type 1 dopamine receptors in the striatum, substantia nigra, subthalamic nucleus and ventral tegmental area. The negative effects of the mutations of FOXP2 in these brain regions on motor abilities were shown in mice through tasks in lab studies. When analyzing the brain circuitry in these cases, scientists found greater levels of dopamine and decreased lengths of dendrites, which caused defects in long-term depression, which is implicated in motor function learning and maintenance. Through EEG studies, it was also found that these mice had increased levels of activity in their striatum, which contributed to these results. There is further evidence for mutations of targets of the FOXP2 gene shown to have roles in schizophrenia, epilepsy, autism, bipolar disorder and intellectual disabilities.<ref name="French_2014">Template:Cite journal</ref>
BatsEdit
FOXP2 has implications in the development of bat echolocation.<ref name="Preuss_2012"/><ref name="Li_2007">Template:Cite journal</ref><ref name="Wilbrecht_2003">Template:Cite journal</ref> Contrary to apes and mice, FOXP2 is extremely diverse in echolocating bats.<ref name="Li_2007" /> 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.<ref name="Li_2007" /> All cetaceans share three amino acid substitutions, but no differences were found between echolocating toothed whales and non-echolocating baleen cetaceans.<ref name="Li_2007" /> Within bats, however, amino acid variation correlated with different echolocating types.<ref name="Li_2007" />
BirdsEdit
In songbirds, FOXP2 most likely regulates genes involved in neuroplasticity.<ref name="Haesler_2007">Template:Cite journal</ref><ref name="Teramitsu_2006">Template:Cite journal</ref> Gene knockdown of FOXP2 in area X of the basal ganglia in songbirds results in incomplete and inaccurate song imitation.<ref name="Haesler_2007" /> Overexpression of FOXP2 was accomplished through injection of adeno-associated virus serotype 1 (AAV1) into area X of the brain. This overexpression produced similar effects to that of knockdown; juvenile zebra finch birds were unable to accurately imitate their tutors.<ref>Template:Cite journal</ref> Similarly, in adult canaries, higher FOXP2 levels also correlate with song changes.<ref name="Haesler_2004"/>
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.<ref name="Teramitsu_2006"/> "Directed" singing refers to when a male is singing to a female usually for a courtship display. "Undirected" singing occurs when for example, a male sings when other males are present or is alone.<ref>Template:Cite journal</ref> Studies have found that FoxP2 levels vary depending on the social context. When the birds were singing undirected song, there was a decrease of FoxP2 expression in Area X. This downregulation was not observed and FoxP2 levels remained stable in birds singing directed song.<ref name="Teramitsu_2006"/>
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.
ZebrafishEdit
In zebrafish, FOXP2 is expressed in the ventral and dorsal thalamus, telencephalon, diencephalon where it likely plays a role in nervous system development. The zebrafish FOXP2 gene has an 85% similarity to the human FOX2P ortholog.<ref name="Bonkowsky_2005">Template:Cite journal</ref>
HistoryEdit
FOXP2 and its gene were discovered as a result of investigations on an English family known as the KE family, half of whom (15 individuals across three generations) had a speech and language disorder called developmental verbal dyspraxia. Their case was studied at the Institute of Child Health of University College London.<ref name = "Hurst_1990">Template:Cite journal</ref> In 1990, Myrna Gopnik, Professor of Linguistics at McGill University, reported that the disorder-affected KE family had severe speech impediment with incomprehensible talk, largely characterized by grammatical deficits.<ref>Template:Cite journal</ref> She hypothesized that the basis was not of learning or cognitive disability, but due to genetic factors affecting mainly grammatical ability.<ref>Template:Cite journal</ref> (Her hypothesis led to a popularised existence of "grammar gene" and a controversial notion of grammar-specific disorder.<ref>Template:Cite book</ref><ref>Template:Cite book</ref>) In 1995, the University of Oxford and the Institute of Child Health researchers found that the disorder was purely genetic.<ref>Template:Cite journal</ref> Remarkably, the inheritance 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.<ref name = "Fisher_2003">Template:Cite journal</ref>
In 1998, Oxford University geneticists Simon Fisher, Anthony Monaco, Cecilia S. L. Lai, Jane A. Hurst, and Faraneh Vargha-Khadem identified an autosomal dominant monogenic inheritance that is localized on a small region of chromosome 7 from DNA samples taken from the affected and unaffected members.<ref name="Fisher_1998"/> The chromosomal region (locus) contained 70 genes.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="Lai_2000"/> 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.<ref name="Lai_2000"/>
In 2001, the team identified in CS that the mutation is in the middle of a protein-coding gene.<ref name="Lai_2001"/> Using a combination of bioinformatics and RNA analyses, they discovered that the gene codes for a novel protein belonging to 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 found a heterozygous point mutation shared by all the affected individuals, but not in unaffected members of the family and other people.<ref name="Lai_2001"/> This mutation is due to an amino-acid substitution that inhibits the DNA-binding domain of the FOXP2 protein.<ref name = "Vernes_2006">Template:Cite journal</ref> Further screening of the gene identified multiple additional cases of FOXP2 disruption, including different point mutations<ref name="MacDermot_2005"/> and chromosomal rearrangements,<ref name="Feuk_2006">Template:Cite journal</ref> providing evidence that damage to one copy of this gene is sufficient to derail speech and language development.
See alsoEdit
- Chimpanzee genome project
- Evolutionary linguistics
- FOX proteins
- Olduvai domain
- Origin of language
- Vocal learning
ReferencesEdit
External linksEdit
- Gene information at NCBI
- Gene information at Genetic Home Reference
- Language and Genetics Research at the Max Planck Institute for Psycholinguistics
- The FOXP2 story
- Revisiting FOXP2 and the origins of language
- FOXP2 and the Evolution of Language
- Template:FactorBook
Template:PDB Gallery Template:Transcription factors Template:Animal communication