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Forkhead box protein P2 (FOXP2) is a
protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of functions within organisms, including , , , providing and , and from one location to another. Proteins differ from one another primarily ...

protein
that, in humans, is encoded by the ''FOXP2''
gene In biology, a gene (from ''genos'' "...Wilhelm Johannsen coined the word gene to describe the Mendelian_inheritance#History, Mendelian units of heredity..." (Greek language, Greek) meaning ''generation'' or ''birth'' ) is a basic unit of her ...

gene
. FOXP2 is a member of the
forkhead box FOX (forkhead box) proteins are a family of transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein Proteins are large biomolecules or macromolecules that are comprised o ...
family of
transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid residue (biochemistry), r ...

transcription factors
, proteins that
regulate gene expression
regulate gene expression
by binding to DNA. It is expressed in the brain, heart, lungs and digestive system. ''FOXP2'' is found in many
vertebrates Vertebrates () comprise all species of animal Animals (also called Metazoa) are multicellular eukaryotic organisms that form the Kingdom (biology), biological kingdom Animalia. With few exceptions, animals Heterotroph, consume organic ma ...

vertebrates
, where it plays an important role in mimicry in birds (such as
birdsong (''Turdus merula'') singing, Bogense havn, Funen, Denmark. Bird vocalization includes both bird calls and bird songs. In non-technical use, bird Birds are a group of warm-blooded vertebrates constituting the class (biology), class Aves ...
) and
echolocation
echolocation
in bats. ''FOXP2'' is also required for the proper development of speech and language in humans. In humans, mutations in ''FOXP2'' cause the severe speech and language disorder
developmental verbal dyspraxia Developmental verbal dyspraxia (DVD), also known as childhood apraxia of speech (CAS) and developmental apraxia of speech (DAS), is a condition in which children have problems saying sounds, syllables and words. This is not because of muscle weaknes ...
. Studies of the gene in mice and songbirds indicate that it is necessary for vocal imitation and the related motor learning. Outside the brain, ''FOXP2'' has also been implicated in development of other tissues such as the lung and digestive system. Initially identified in 1998 as the genetic cause of a
speech disorder Speech disorders or speech impairments are a type of communication disorder A communication disorder is any disorder that affects an individual's ability to comprehend, detect, or apply language and speech to engage in discourse effectively with o ...
in a British family designated the
KE family The KE family is a medical name designated for a British people, British family, about half of whom exhibit a severe speech disorder called developmental verbal dyspraxia. It is the first family with speech disorder to be investigated using genetic ...
, ''FOXP2'' was the first gene discovered to be associated with speech and language and was subsequently dubbed "the language gene". However, other genes are necessary for human language development, and a 2018 analysis confirmed that there was no evidence of recent positive
evolutionary selection Natural selection is the differential survival and reproduction of individuals due to differences in phenotype. It is a key mechanism of evolution, the change in the Heredity, heritable Phenotypic trait, traits characteristic of a populatio ...
of ''FOXP2'' in humans.


Structure and function

As a FOX protein, FOXP2 contains a forkhead-box domain. In addition, it contains a
polyglutamine tractA polyglutamine tract or polyQ tract is a portion of a protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functi ...
, a
zinc finger and an antiparallel Beta sheet, β sheet. The zinc ion (green) is coordinated by two histidine residues and two cysteine residues. Image:Zinc finger DNA complex.png, 300px, Cartoon representation of the protein Zif268 (blue) containing three zinc f ...

zinc finger
and a
leucine zipper "Overhead view", or helical wheel diagram, of a leucine zipper, where d represents leucine, arranged with other amino acids on two parallel alpha helices. A leucine zipper (or leucine scissors) is a common three-dimensional structural motif in pro ...

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, 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. ''FOXP2'' is required for proper brain and lung development.
Knockout miceA knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are important ...
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. ''FOXP2'' is expressed in many areas of the brain, including the
basal ganglia The basal ganglia (or basal nuclei) are a group of subcortical The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue Nervous tissue, also called neural tissue, is the main tissue (biology), tissue compon ...

basal ganglia
and inferior
frontal cortex The frontal lobe is the largest of the four major lobes of the brain in mammals, and is located at the front of each cerebral hemisphere (in front of the parietal lobe and the temporal lobe). It is parted from the parietal lobe by a Sulcus (neur ...
, where it is essential for brain maturation and speech and language development. 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 area Broca's area, or the Broca area (, also , ), is a region in the frontal lobe of the dominant Cerebral hemisphere, hemisphere, usually the left, of the Human brain, brain with functions linked to speech production. Language processing in the brain ...
s of female children. The researchers suggested that the gene is more active in "the more communicative sex". The expression of ''FOXP2'' is subject to
post-transcriptional regulation Post-transcriptional regulation is the control of gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-codin ...
, particularly
microRNA A microRNA (abbreviated miRNA) is a small single-stranded non-coding RNA : Ribonucleoproteins are shown in red, non-coding RNAs in blue. Note: in spliceosome is snRNA used A non-coding RNA (ncRNA) is an RNA molecule that is not translated i ...
(miRNA), which binds to multiple miRNA binding-sites in the
neocortex The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian Mammals (from Latin language, Latin , 'breast') are a group of vertebrate animals constituting the class (biology), class ...

neocortex
, causing the repression of the FOXP2 3' untranslated region. 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, but only one of these 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''.


Clinical significance

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. 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. One well identified target is language. Although some research disagrees with this correlation, the majority of research shows that a mutated FOXP2 causes the observed production deficiency. 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. Mutations in FOXP2 are among several (26 genes plus 2 intergenic) loci which correlate to
ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, or excessive activity and impulsivity, which are otherwise not Developmental psychology, appropriate for a person's age. Some indivi ...

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. A 2020
genome-wide association study In genetics Genetics is a branch of biology concerned with the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) Though heredity had been observed for millennia, Gregor Mendel, Moravia, Moravian scientist a ...
(GWAS) implicates
single-nucleotide polymorphisms In genetics Genetics is a branch of biology concerned with the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) Though heredity had been observed for millennia, Gregor Mendel, Moravia, Moravian scientist ...
(SNPs) of FOXP2 in susceptibility to cannabis use disorder.


Language disorder

It is theorized that the translocation of the 7q31.2 region of the FOXP2 gene causes a severe language impairment called
developmental verbal dyspraxia Developmental verbal dyspraxia (DVD), also known as childhood apraxia of speech (CAS) and developmental apraxia of speech (DAS), is a condition in which children have problems saying sounds, syllables and words. This is not because of muscle weaknes ...
(DVD) or childhood apraxia of speech (CAS) So far this type of mutation has only been discovered in three families across the world including the original KE family. A missense mutation causing an arginine-to-histidine substitution (R553H) in the DNA-binding domain is thought to be the abnormality in KE. 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. 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. 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. 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. Additionally, there are more general impairments with the processing of the grammatical and linguistic aspects of speech. 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. Clinically these patients can also have difficulty coughing, sneezing, and/or clearing their throats. 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. 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.


Evolution

The ''FOXP2'' gene is highly conserved in
mammals Mammals (from Latin Latin (, or , ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originally spoken in the area around Rome, known as Latium. Through the power of the R ...
. The human gene differs from that in non-human primates by the substitution of two amino acids, a
threonine Threonine (symbol Thr or T) is an that is used in the of s. It contains an (which is in the protonated −NH form under biological conditions), a (which is in the deprotonated −COO− form under biological conditions), and a side chain con ...

threonine
to
asparagine Asparagine (symbol Asn or N), is an α-amino acid that is Proteinogenic amino acid, used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid gro ...

asparagine
substitution at position 303 (T303N) and an asparagine to
serine Serine (symbol Ser or S) is an α-amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, ...

serine
substitution at position 325 (N325S). In mice it differs from that of humans by three substitutions, and in
zebra finch The zebra finch (''Taeniopygia guttata'') is the most common estrildid finch of Central Australia Central Australia, also known as the Alice Springs Region ( aer, Mparntwe Ampere), is one of the five regions in the Northern Territory of ...

zebra finch
by seven amino acids. One of the two amino acid differences between human and chimps also arose independently in carnivores and bats. Similar ''FOXP2'' proteins can be found in
songbirds A songbird is a bird Birds are a group of warm-blooded vertebrates constituting the class Class or The Class may refer to: Common uses not otherwise categorized * Class (biology), a taxonomic rank * Class (knowledge representatio ...
,
fish Fish are , , -bearing animals that lack with . Included in this definition are the living , s, and and as well as various extinct related groups. Around 99% of living fish species are ray-finned fish, belonging to the class , with over 95 ...

fish
, and
reptiles Reptiles, as most commonly defined, are the animals in the class Class or The Class may refer to: Common uses not otherwise categorized * Class (biology), a taxonomic rank * Class (knowledge representation), a collection of individuals or o ...

reptiles
such as
alligators An alligator is a crocodilia Crocodilia (or Crocodylia, both ) is an order of mostly large, predatory, semiaquatic reptile Reptiles are tetrapod Tetrapods (; from Greek 'four' and 'foot') are four-limbed animals constituting th ...

alligators
. DNA sampling from ''
Homo neanderthalensis Neanderthals (, also Neandertals, ''Homo neanderthalensis'' or ''Homo sapiens neanderthalensis'') are an extinct species In biology Biology is the natural science that studies life and living organisms, including their anatomy, phys ...

Homo neanderthalensis
'' bones indicates that their ''FOXP2'' gene is a little different though largely similar to those of ''
Homo sapiens Humans (''Homo sapiens'') are the most abundant and widespread of , characterized by and large, complex brains. This has enabled the development of advanced , , and . Humans are highly social and tend to live in complex s composed of many ...

Homo sapiens
'' (i.e. humans). See also Previous genetic analysis had suggested that the ''H. sapiens'' FOXP2 gene became fixed in the population around 125,000 years ago. 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. Other researchers offer alternative explanations for how the ''H. sapiens'' version would have appeared in Neanderthals living 43,000 years ago. According to a 2002 study, the ''FOXP2'' gene showed indications of recent
positive selection upThree types of selection In population genetics, directional selection, or positive selection is a mode of natural selection Natural selection is the differential survival and reproduction of individuals due to differences in pheno ...
. Some researchers have speculated that positive selection is crucial for the evolution of language in humans. Others, however, were unable to find a clear association between species with learned vocalizations and similar mutations in ''FOXP2''. 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. Insertion of both human
mutation A red tulip exhibiting a partially yellow petal due to a mutation in its genes In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processe ...
s into mice, whose version of ''FOXP2'' otherwise differs from the human and
chimpanzee The chimpanzee (''Pan troglodytes''), also known simply as chimp, is a species of Hominidae, great ape native to the forest and savannah of tropical Africa. It has four confirmed subspecies and a fifth proposed subspecies. The chimpanzee and t ...
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.


Interactions

FOXP2 is known to regulate '' CNTNAP2'', ''
CTBP1 C-terminal-binding protein 1 also known as CtBP1 is a protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of functions within organisms, including , , , providing and , and from one l ...
'', '' SRPX2'' and '' SCN3A''. FOXP2 downregulates ''CNTNAP2'', a member of the
neurexin Neurexins (NRXN) are a family of presynaptic cell adhesion proteins that have roles in connecting neurons at the synapse. They are located mostly on the presynaptic membrane and contain a single transmembrane protein, transmembrane domain. Th ...
family found in neurons. ''CNTNAP2'' is associated with common forms of language impairment. FOXP2 also downregulates ''SRPX2'', the 'Sushi Repeat-containing Protein X-linked 2'. It directly reduces its expression, by binding to its gene's promoter. SRPX2 is involved in
glutamatergic Glutamatergic means "related to glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid Amino acids are organic compounds that contain amino (–NH2) and Carboxylic acid, carboxyl (–COOH) func ...
synapse formation in the
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting of a ...
and is more highly expressed in childhood. SRPX2 appears to specifically increase the number of glutamatergic synapses in the brain, while leaving inhibitory
GABAergic In molecular biology and physiology, something is GABAergic if it pertains to or affects the neurotransmitter A neurotransmitter is a signaling molecule In biology, cell signaling (cell signalling in British English), or cell-cell communicat ...
synapses unchanged and not affecting
dendritic spine A dendritic spine (or spine) is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical sig ...
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.


In other animals


Chimpanzees

In chimpanzees, FOXP2 differs from the human version by two amino acids. 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. 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. 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.


Mice

In a mouse ''FOXP2''
gene knockoutA gene knockout (abbreviation: KO) is a genetics, genetic technique in which one of an organism's genes is made inoperative ("knocked out" of the organism). However, KO can also refer to the gene that is knocked out or the organism that carries the g ...
s, loss of both copies of the gene causes severe motor impairment related to cerebellar abnormalities and lack of normally elicited when pups are removed from their mothers. 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. Mice that have the R552H point mutation carried by the KE family show cerebellar reduction and abnormal
synaptic plasticity In neuroscience Neuroscience is the science, scientific study of the nervous system. It is a Multidisciplinary approach, multidisciplinary science that combines physiology, anatomy, molecular biology, developmental biology, cytology, computer ...
in striatal and
cerebellar The cerebellum (Latin for "little brain") is a major feature of the hindbrain The hindbrain or rhombencephalon is a developmental categorization of portions of the central nervous system in vertebrates. It includes the medulla, pons, and ce ...
circuits. 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 Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in Cell (biology), cellular organi ...

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. 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 Fifth is the Ordinal number (linguistics), ordinal form of the number 5, five. Fifth or The Fifth may refer to: * Fifth Amendment to the United States Constitution, as in the expression "pleading the Fifth" * Fifth column, a political term * Fifth ...
, and this is consistent with it having greater roles in sensory integration. FOXP2 was also found in the
medial geniculate nucleus The medial geniculate nucleus (MGN) or medial geniculate body (MGB) is part of the auditory thalamus and represents the thalamic relay between the inferior colliculus (IC) and the auditory cortex (AC). It is made up of a number of sub-nuclei that ...
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 The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward system, reward and Motor system, movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts o ...

substantia nigra
,
subthalamic nucleus The subthalamic nucleus is a small lens-shaped nucleus in the brain A brain is an organ (anatomy), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close t ...
and
ventral tegmental area The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline In typography, the mean line is the imagina ...

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 In neurophysiology, long-term depression (LTD) is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus. LTD occurs in many areas of the Central Nervous System, CNS with vary ...
, which is implicated in motor function learning and maintenance. Through
EEG Electroencephalography (EEG) is an electrophysiological monitoring method to record electrical activity on the scalp The scalp is the anatomical area bordered by the human face at the front, and by the neck at the sides and back. Structure ...

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 Schizophrenia is a mental disorder A mental disorder, also called a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may b ...

schizophrenia
,
epilepsy Epilepsy is a group of non-communicable neurological disorder A neurological disorder is any disorder of the nervous system In Biology, biology, the nervous system is a Complex system, highly complex part of an animal that coordinates i ...

epilepsy
,
autism Autism is a developmental disorder Developmental disorders comprise a group of psychiatric conditions originating in childhood that involve serious impairment in different areas. There are several ways of using this term. The most narro ...

autism
,
bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder A mental disorder, also called a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of ...

bipolar disorder
and intellectual disabilities.


Bats

''FOXP2'' has implications in the development of
bat Bats are mammal Mammals (from Latin Latin (, or , ) is a classical language belonging to the Italic branch of the Indo-European languages. Latin was originally spoken in the area around Rome, known as Latium. Through the po ...

bat
. Contrary to apes and mice, ''FOXP2'' is extremely diverse in . Twenty-two sequences of non-bat
eutherian Eutheria (; from Greek , 'good, right' and , 'beast'; ) is the clade A clade (; from grc, , ''klados'', "branch"), also known as a monophyletic group or natural group, is a group of organisms that are monophyly, monophyletic—that is, co ...

eutherian
mammals revealed a total number of 20 nonsynonymous mutations in contrast to half that number of bat sequences, which showed 44 nonsynonymous mutations. All
cetaceans Cetaceans (from la, Cetus (mythology), cetus, lit=whale, from grc, κῆτος, translit=Cetus (mythology), kētos, lit = huge fish, sea monster) are aquatic mammals constituting the infraorder Cetacea (). Key characteristics are their fully aq ...

cetaceans
share three amino acid substitutions, but no differences were found between echolocating
toothed whales The toothed whales (also called odontocetes, systematic name Odontoceti) are a parvorder of cetacea Cetaceans (from la, Cetus (mythology), cetus, lit=whale, from grc, κῆτος, translit=Cetus (mythology), kētos, lit = huge fish, sea mon ...
and non-echolocating baleen cetaceans. Within bats, however, amino acid variation correlated with different echolocating types.


Birds

In
songbird A songbird is a bird Birds are a group of warm-blooded vertebrate Vertebrates () comprise all species of animal Animals (also called Metazoa) are multicellular eukaryotic organisms that form the Kingdom (biology), biologi ...

songbird
s, ''FOXP2'' most likely regulates genes involved in
neuroplasticity Neuroplasticity, also known as neural plasticity, or brain plasticity, is the ability of neural networks#REDIRECT Artificial neural network Artificial neural networks (ANNs), usually simply called neural networks (NNs), are computing syst ...

neuroplasticity
.
Gene knockdown Gene knockdown is an experimental technique by which the expression of one or more of an organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochem ...
of ''FOXP2'' in area X of the
basal ganglia The basal ganglia (or basal nuclei) are a group of subcortical The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue Nervous tissue, also called neural tissue, is the main tissue (biology), tissue compon ...

basal ganglia
in songbirds results in incomplete and inaccurate song imitation. Overexpression of FoxP2 was accomplished through injection of
adeno-associated virus Adeno-associated viruses (AAV) are small virus A virus is a submicroscopic infectious agent In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemi ...
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.Similarly, in adult canaries, higher ''FOXP2'' levels also correlate with song changes. 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. "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. 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. Differences between song-learning and non-song-learning birds have been shown to be caused by differences in ''FOXP2''
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...

gene expression
, rather than differences in the amino acid sequence of the ''FOXP2'' protein.


Zebrafish

In zebrafish, FOXP2 is expressed in the ventral and dorsal thalamus,
telencephalon The cerebrum, telencephalon or endbrain, is the largest part of the brain A brain is an organ Organ may refer to: Biology * Organ (anatomy) An organ is a group of Tissue (biology), tissues with similar functions. Plant life and animal ...

telencephalon
,
diencephalon The diencephalon (or interbrain) is a division of the forebrain In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain (prosencephalon), the midbrain ( ...

diencephalon
where it likely plays a role in nervous system development. The zebrafish FOXP2 gene has an 85% similarity to the human FOX2P ortholog.


History

''FOXP2'' and its gene were discovered as a result of investigations on an English family known as the
KE family The KE family is a medical name designated for a British people, British family, about half of whom exhibit a severe speech disorder called developmental verbal dyspraxia. It is the first family with speech disorder to be investigated using genetic ...
, half of whom (15 individuals across three generations) suffered from a speech and language disorder called
developmental verbal dyspraxia Developmental verbal dyspraxia (DVD), also known as childhood apraxia of speech (CAS) and developmental apraxia of speech (DAS), is a condition in which children have problems saying sounds, syllables and words. This is not because of muscle weaknes ...
. Their case was studied at the Institute of Child Health of University College London. In 1990,
Myrna Gopnik Myrna Lee Gopnik (born 1935) is a Canadians, Canadian linguist. She is a Professor Emerita of Linguistics at McGill University. She is known for her research on the KE family, an English family with several members affected by specific language im ...
, Professor of Linguistics at
McGill University McGill University is a public In public relations Public relations (PR) is the practice of managing and disseminating information from an individual or an organization An organization, or organisation (English in the Commonw ...
, reported that the disorder-affected KE family had severe speech impediment with incomprehensible talk, largely characterized by grammatical deficits. She hypothesized that the basis was not of learning or cognitive disability, but due to genetic factors affecting mainly grammatical ability. (Her hypothesis led to a popularised existence of "grammar gene" and a controversial notion of grammar-specific disorder.) In 1995, the
University of Oxford The University of Oxford is a collegiate university, collegiate research university in Oxford, England. There is evidence of teaching as early as 1096, making it the oldest university in the English-speaking world and the List of oldest universit ...
and the Institute of Child Health researchers found that the disorder was purely genetic. Remarkably, the inheritance of the disorder from one generation to the next was consistent with
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The first ...

autosomal dominant
inheritance, i.e., mutation of only a single gene on an
autosome An autosome is any chromosome that is not a sex chromosome (an allosome). The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosome pairs which may have different structures. The DNA in autosomes is coll ...
(non-
sex chromosome A sex chromosome (also referred to as an allosome, heterotypical chromosome, gonosome, heterochromosome, or idiochromosome) is a chromosome A chromosome is a long DNA molecule with part or all of the genome, genetic material of an organi ...
) acting in a dominant fashion. This is one of the few known examples of
Mendelian Mendelian inheritance is a type of biological inheritance Inheritance is the practice of passing on private property, titles A title is one or more words used before or after a person's name, in certain contexts. It may signify either ...
(monogenic) inheritance for a disorder affecting speech and language skills, which typically have a complex basis involving multiple genetic risk factors. In 1998, Oxford University geneticists
Simon Fisher Simon may refer to: People * Simon (given name) Simon is a common name, from Hebrew language, Hebrew שִׁמְעוֹן ''Simeon, Šimʻôn'', meaning "listen" or "hearing". It is also a classical Greek name, deriving from an adjective meaning ...
,
Anthony Monaco Anthony P. Monaco (born October 10, 1959) is an American geneticist and university administrator. He has been president of Tufts University Tufts University is a Private university, private research university on the border of Medford, Massac ...
, Cecilia S. L. Lai, Jane A. Hurst, and
Faraneh Vargha-Khadem Faraneh Vargha-Khadem (born 1949) is a British cognitive neuroscientist Cognitive neuroscience is the scientific field that is concerned with the study of the Biology, biological processes and aspects that underlie cognition, with a specific f ...
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. The chromosomal region (locus) contained 70 genes. 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 Chromosomal translocation, 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. In 2001, the team identified in CS that the mutation is in the middle of a protein-coding gene. 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 In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid residue (biochemistry), r ...

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. This mutation is due to an amino-acid substitution that inhibits the DNA-binding domain of the ''FOXP2'' protein. Further screening of the gene identified multiple additional cases of ''FOXP2'' disruption, including different point mutations and chromosomal rearrangements, providing evidence that damage to one copy of this gene is sufficient to derail speech and language development.


See also

* Chimpanzee genome project * Evolutionary linguistics * FOX proteins * Olduvai domain * Origin of language * Vocal learning


References


External links


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


* {{DEFAULTSORT:Foxp2 Forkhead transcription factors Evolution of language Genetics concepts Speech and language pathology Genes on human chromosome 7