FOXP2

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File:FOXP2 location.png
FOXP2 gene is located on the long (q) arm of chromosome 7 at position 31.

Forkhead box protein P2 (FOXP2) is a protein that, in humans, is encoded by the FOXP2 gene, also known as CAGH44, SPCH1 or TNRC10, and is required for proper development of speech and language.[1] The gene is shared with many vertebrates, where it generally plays a role in communication (for instance, the development of bird song).

Initially identified as the genetic factor of speech disorder in KE family, FOXP2 is the first gene discovered associated with speech and language.[2] The gene is located on chromosome 7 (7q31, at the SPCH1 locus) and is expressed in fetal and adult brain, heart, lung and gut.[3][4] FOXP2 orthologs[5] have also been identified in other 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. The gene is more active in females than in males, to which could be attributed better language learning in females.[6]

In humans, mutations of FOXP2 cause a severe speech and language disorder.[1][7] Versions of FOXP2 exist in similar forms in distantly related vertebrates; functional studies of the gene in mice[8] and in songbirds[9] indicate that it is important for modulating plasticity of neural circuits.[10] Outside the brain FOXP2 has also been implicated in development of other tissues such as the lung and gut.[11]

FOXP2 is popularly dubbed the "language gene", but this is only partly correct since there are other genes involved in language development.[12] It directly regulates a number of other genes, including CNTNAP2, CTBP1, and SRPX2.[13][14]

Two amino acid substitutions distinguish the human FOXP2 protein from that found in chimpanzees,[15] but only one of these changes is unique to humans.[11] Evidence from genetically manipulated mice[16] and human neuronal cell models[17] suggests that these changes affect the neural functions of FOXP2.

Discovery

FOXP2 and its gene were discovered as a result of investigations on an English family known as the KE family, half of whom (fifteen individuals across three generations) suffered from a speech and language disorder called developmental verbal dyspraxia. Their case was studied at the Institute of Child Health of University College London.[18] 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.[19] She hypothesized that the basis was not of learning or cognitive disability, but due to genetic factors affecting mainly grammatical ability.[20] (Her hypothesis led to a popularised existence of "grammar gene" and a controversial notion of grammar-specific disorder.[21][22]) In 1995, the University of Oxford and the Institute of Child Health researchers found that the disorder was purely genetic.[23] 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.[24]

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.[3] The chromosomal region (locus) contained 70 genes.[25] 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.[4] 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.[4]

In 2001, the team identified in CS that the mutation is in the middle of a protein-coding gene.[1] 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.[1] This mutation is due to an amino-acid substitution that inhibits the DNA-binding domain of the FOXP2 protein.[26] Further screening of the gene identified multiple additional cases of FOXP2 disruption, including different point mutations[7] and chromosomal rearrangements,[27] providing evidence that damage to one copy of this gene is sufficient to derail speech and language development.

Function

File:Foxp2, ISH, E13.5 mouse, cerebellum-hindbrain.jpg
Foxp2 is expressed in the developing cerebellum and the hindbrain of the embryonic day 13.5 mouse. Allen Brain Atlases

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.[28] 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.[11]

FOXP2 is expressed in many areas of the brain[15] including the basal ganglia and inferior frontal cortex where it is essential for brain maturation and speech and language development.[13]

A knockout mouse model has been used to examine FOXP2's role in brain development and how mutations in the two copies of FOXP2 affect vocalization. Mutations in one copy result in reduced speech while abnormalities in both copies cause major brain and lung developmental issues.[11]

The expression of FOXP2 is subject to post-transcriptional regulation, particularly micro RNA, which binds to multiple miRNA binding-sites in the neocortex, causing the repression of FOXP2 3’UTR.[29]

Clinical significance

There are several abnormalities linked to FOXP2. The most common mutation results in severe speech impairment known as developmental verbal dyspraxia (DVD) which is caused by a translocation in the 7q31.2 region [t(5;7)(q22;q31.2)].[1][4] A missense mutation causing an arginine-to-histidine substitution (R553H) in the DNA-binding domain is thought to be the abnormality in KE.[30] 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.[7] R553H and R328X mutations also affected nuclear localization, DNA-binding, and the transactivation (increased gene expression) properties of FOXP2.[31][32] Although DVD associated with FOXP2 disruptions are thought to be rare (~2% by one estimate),[7] genetic links from FOXP2 to disease usually relate to speech or language problems.

Several cases of developmental verbal dyspraxia in humans have been linked to mutations in the FOXP2 gene.[27][33][34][35] Such individuals have little or no cognitive handicap 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).[36] Scientists have also looked for associations between FOXP2 and autism, and both positive and negative findings have been reported.[37][38]

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 examples, the impairments include difficulties in comprehension. 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.

Evolution

File:BrowserFoxp2.jpg
Human FOXP2 gene and evolutionary conservation is shown in a multiple alignment (at bottom of figure) in this image from the UCSC Genome Browser. Note that conservation tends to cluster around coding regions (exons).

The FOXP2 gene is highly conserved in mammals.[39] 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).[30] In mice it differs from that of humans by three substitutions, and in zebra finch by seven amino acids.[15][40][41] One of the two amino acid differences between human and chimps also arose independently in carnivores and bats.[11][42] Similar FOXP2 proteins can be found in songbirds, fish, and reptiles such as alligators.[43][44]

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). [45][46]

The FOXP2 gene showed indications of recent positive selection.[39][47] Some researchers have speculated that positive selection is crucial for the evolution of language in humans.[15] Others, however, have been unable to find a clear association between species with learned vocalizations and similar mutations in FOXP2.[43][44] Recent data from a large sample of globally distributed genomes showed no evidence of positive selection, suggesting that the original signal of positive selection may be driven by sample composition.[48] 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.[16]

However, FOXP2 is extremely diverse in echolocating bats.[49] 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.[42] All cetaceans share three amino acid substitutions, but no differences were found between echolocating toothed whales and non-echolocating baleen cetaceans.[42] Within bats, however, amino acid variation correlated with different echolocating types.[42]

Interactions

FOXP2 interacts with a regulatory gene CTBP1.[50] It also downregulates CNTNAP2 gene, a member of the neurexin family found in neurons. The target gene is associated with common forms of language impairment.[51] It regulates the repeat-containing protein X-linked 2 (SRPX2), which is an epilepsy and language-associated gene in humans, and sound-controlling gene in mice.[52]

Mice

In a mouse FOXP2 knockout study, loss of both copies of the gene caused severe motor impairment related to cerebellar abnormalities and lack of ultrasonic vocalisations normally elicited when pups are removed from their mothers.[28] 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.[53] Mice that have the R552H point mutation carried by the KE family show cerebellar reduction and abnormal synaptic plasticity in striatal and cerebellar circuits.[8]

Birds

In songbirds, FOXP2 most likely regulates genes involved in neuroplasticity.[9][54] Gene knockdown of FOXP2 in Area X of the basal ganglia in songbirds results in incomplete and inaccurate song imitation.[9] 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.[55] Similarly, in adult canaries higher FOXP2 levels also correlate with song changes.[41]

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.[54] “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.[56] 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.[57]

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.

FOXP2 also has possible implications in the development of bat echolocation.[30][42][58]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP (2001). "A forkhead-domain gene is mutated in a severe speech and language disorder". Nature. 413 (6855): 519–23. doi:10.1038/35097076. PMID 11586359.
  2. ↑ Nudel R, Newbury DF (2013). "FOXP2". Wiley Interdiscip Rev Cogn Sci. 4 (5): 547–560. doi:10.1002/wcs.1247. PMC 3992897. PMID 24765219.
  3. ↑ 3.0 3.1 Fisher SE, Vargha-Khadem F, Watkins KE, Monaco AP, Pembrey ME (1998). "Localisation of a gene implicated in a severe speech and language disorder". Nat. Genet. 18 (2): 168–70. doi:10.1038/ng0298-168. PMID 9462748.
  4. ↑ 4.0 4.1 4.2 4.3 Lai CS, Fisher SE, Hurst JA, Levy ER, Hodgson S, Fox M, et al. (2000). "The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder". Am. J. Hum. Genet. 67 (2): 357–68. doi:10.1086/303011. PMC 1287211. PMID 10880297.
  5. ↑ "OrthoMaM phylogenetic marker: FOXP2 coding sequence".
  6. ↑ Pennisi E (31 October 2013). "'Language Gene' Has a Partner". Science. Retrieved 30 October 2014.
  7. ↑ 7.0 7.1 7.2 7.3 MacDermot KD, Bonora E, Sykes N, Coupe AM, Lai CS, Vernes SC, et al. (2005). "Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits". Am. J. Hum. Genet. 76 (6): 1074–80. doi:10.1086/430841. PMC 1196445. PMID 15877281.
  8. ↑ 8.0 8.1 Groszer M, Keays DA, Deacon RM, de Bono JP, Prasad-Mulcare S, Gaub S, et al. (2008). "Impaired synaptic plasticity and motor learning in mice with a point mutation implicated in human speech deficits". Curr. Biol. 18 (5): 354–62. doi:10.1016/j.cub.2008.01.060. PMC 2917768. PMID 18328704.
  9. ↑ 9.0 9.1 9.2 Haesler S, Rochefort C, Georgi B, Licznerski P, Osten P, Scharff C (December 2007). "Incomplete and inaccurate vocal imitation after knockdown of FoxP2 in songbird basal ganglia nucleus Area X". PLoS Biology. 5 (12): e321. doi:10.1371/journal.pbio.0050321. PMC 2100148. PMID 18052609.
  10. ↑ Fisher SE, Scharff C (2009). "FOXP2 as a molecular window into speech and language". Trends Genet. 25 (4): 166–77. doi:10.1016/j.tig.2009.03.002. PMID 19304338.
  11. ↑ 11.0 11.1 11.2 11.3 11.4 Shu W, Lu MM, Zhang Y, Tucker PW, Zhou D, Morrisey EE (2007). "Foxp2 and Foxp1 cooperatively regulate lung and esophagus development". Development. 134 (10): 1991–2000. doi:10.1242/dev.02846. PMID 17428829.
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  13. ↑ 13.0 13.1 Spiteri E, Konopka G, Coppola G, Bomar J, Oldham M, Ou J, et al. (2007). "Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain". Am. J. Hum. Genet. 81 (6): 1144–57. doi:10.1086/522237. PMC 2276350. PMID 17999357.
  14. ↑ Vernes SC, Spiteri E, Nicod J, Groszer M, Taylor JM, Davies KE, et al. (2007). "High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech and language disorders". Am. J. Hum. Genet. 81 (6): 1232–50. doi:10.1086/522238. PMC 2276341. PMID 17999362.
  15. ↑ 15.0 15.1 15.2 15.3 Enard W, Przeworski M, Fisher SE, Lai CS, Wiebe V, Kitano T, Monaco AP, Pääbo S (2002). "Molecular evolution of FOXP2, a gene involved in speech and language". Nature. 418 (6900): 869–72. doi:10.1038/nature01025. PMID 12192408.
  16. ↑ 16.0 16.1 Enard W, Gehre S, Hammerschmidt K, Hölter SM, Blass T, Somel M, et al. (2009). "A humanized version of Foxp2 affects cortico-basal ganglia circuits in mice". Cell. 137 (5): 961–71. doi:10.1016/j.cell.2009.03.041. PMID 19490899.
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  32. ↑ Tanabe Y, Fujita E, Momoi T (2011). "FOXP2 promotes the nuclear translocation of POT1, but FOXP2(R553H), mutation related to speech-language disorder, partially prevents it". Biochem. Biophys. Res. Commun. 410 (3): 593–6. doi:10.1016/j.bbrc.2011.06.032. PMID 21684252.
  33. ↑ Shriberg LD, Ballard KJ, Tomblin JB, Duffy JR, Odell KH, Williams CA (2006). "Speech, prosody, and voice characteristics of a mother and daughter with a 7;13 translocation affecting FOXP2". J. Speech Lang. Hear. Res. 49 (3): 500–25. doi:10.1044/1092-4388(2006/038). PMID 16787893.
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  35. ↑ Vargha-Khadem F, Gadian DG, Copp A, Mishkin M (2005). "FOXP2 and the neuroanatomy of speech and language". Nat. Rev. Neurosci. 6 (2): 131–8. doi:10.1038/nrn1605. PMID 15685218.
  36. ↑ Carroll SB (2005). "Evolution at two levels: on genes and form". PLoS Biol. 3 (7): e245. doi:10.1371/journal.pbio.0030245. PMC 1174822. PMID 16000021.
  37. ↑ Scherer SW, Cheung J, MacDonald JR, Osborne LR, Nakabayashi K, Herbrick JA, et al. (2003). "Human chromosome 7: DNA sequence and biology". Science. 300 (5620): 767–72. doi:10.1126/science.1083423. PMC 2882961. PMID 12690205.
  38. ↑ Newbury DF, Bonora E, Lamb JA, Fisher SE, Lai CS, Baird G, et al. (2002). "FOXP2 is not a major susceptibility gene for autism or specific language impairment". Am. J. Hum. Genet. 70 (5): 1318–27. doi:10.1086/339931. PMC 447606. PMID 11894222.
  39. ↑ 39.0 39.1 Enard W, Przeworski M, Fisher SE, Lai CS, Wiebe V, Kitano T, Monaco AP, Pääbo S (2002). "Molecular evolution of FOXP2, a gene involved in speech and language" (PDF). Nature. 418 (6900): 869–72. doi:10.1038/nature01025. PMID 12192408. Archived from the original (PDF) on 30 August 2006.
  40. ↑ Teramitsu I, Kudo LC, London SE, Geschwind DH, White SA (2004). "Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction". J. Neurosci. 24 (13): 3152–63. doi:10.1523/JNEUROSCI.5589-03.2004. PMID 15056695.
  41. ↑ 41.0 41.1 Haesler S, Wada K, Nshdejan A, Morrisey EE, Lints T, Jarvis ED, Scharff C (2004). "FoxP2 expression in avian vocal learners and non-learners". J. Neurosci. 24 (13): 3164–75. doi:10.1523/JNEUROSCI.4369-03.2004. PMID 15056696.
  42. ↑ 42.0 42.1 42.2 42.3 42.4 Li G, Wang J, Rossiter SJ, Jones G, Zhang S (2007). Ellegren H, ed. "Accelerated FoxP2 evolution in echolocating bats". PLoS ONE. 2 (9): e900. doi:10.1371/journal.pone.0000900. PMC 1976393. PMID 17878935.
  43. ↑ 43.0 43.1 Webb DM, Zhang J (2005). "FoxP2 in song-learning birds and vocal-learning mammals". J. Hered. 96 (3): 212–6. doi:10.1093/jhered/esi025. PMID 15618302.
  44. ↑ 44.0 44.1 Scharff C, Haesler S (2005). "An evolutionary perspective on FoxP2: strictly for the birds?". Curr. Opin. Neurobiol. 15 (6): 694–703. doi:10.1016/j.conb.2005.10.004. PMID 16266802.
  45. ↑ Zimmer, Carl (17 March 2016). "Humans Interbred With Hominins on Multiple Occasions, Study Finds". The New York Times. Retrieved 17 March 2016.
  46. ↑ Krause J, Lalueza-Fox C, Orlando L, Enard W, Green RE, Burbano HA, Hublin JJ, Hänni C, Fortea J, de la Rasilla M, Bertranpetit J, Rosas A, Pääbo S (2007). "The derived FOXP2 variant of modern humans was shared with Neandertals". Curr. Biol. 17 (21): 1908–12. doi:10.1016/j.cub.2007.10.008. PMID 17949978. Lay summary – The New York Times (19 October 2007). See also Benítez-Burraco A, Longa VM, Lorenzo G, Uriagereka J (November 2008). "Also sprach Neanderthalis... Or Did She?". Biolinguistics. 2 (2): 225–232.
  47. ↑ Toda M, Okubo S, Ikigai H, Suzuki T, Suzuki Y, Hara Y, Shimamura T (1992). "The protective activity of tea catechins against experimental infection by Vibrio cholerae O1". Microbiol. Immunol. 36 (9): 999–1001. doi:10.1111/j.1348-0421.1992.tb02103.x. PMID 1461156.
  48. ↑ Atkinson EG, Audesse AJ, Palacios JA, Bobo DM, Webb AE, Ramachandran S, et al. (2018). "No Evidence for Recent Selection at FOXP2 among Diverse Human Populations". Cell. doi:10.1016/j.cell.2018.06.048. PMID 30078708.
  49. ↑ Li G, Wang J, Rossiter SJ, Jones G, Zhang S (2007). "Accelerated FoxP2 evolution in echolocating bats". PLoS ONE. 2 (9): e900. doi:10.1371/journal.pone.0000900. PMC 1976393. PMID 17878935.
  50. ↑ Li S, Weidenfeld J, Morrisey EE (2004). "Transcriptional and DNA binding activity of the Foxp1/2/4 family is modulated by heterotypic and homotypic protein interactions". Mol. Cell. Biol. 24 (2): 809–22. doi:10.1128/MCB.24.2.809-822.2004. PMC 343786. PMID 14701752.
  51. ↑ Vernes SC, Newbury DF, Abrahams BS, Winchester L, Nicod J, Groszer M, et al. (2008). "A functional genetic link between distinct developmental language disorders". N. Engl. J. Med. 359 (22): 2337–45. doi:10.1056/NEJMoa0802828. PMC 2756409. PMID 18987363.
  52. ↑ Sia GM, Clem RL, Huganir RL (2013). "The human language-associated gene SRPX2 regulates synapse formation and vocalization in mice". Science. 342 (6161): 987–91. doi:10.1126/science.1245079. PMC 3903157. PMID 24179158.
  53. ↑ Holy TE, Guo Z (2005). "Ultrasonic songs of male mice". PLoS Biol. 3 (12): e386. doi:10.1371/journal.pbio.0030386. PMC 1275525. PMID 16248680.
  54. ↑ 54.0 54.1 Teramitsu I, White SA (July 2006). "FoxP2 regulation during undirected singing in adult songbirds". The Journal of Neuroscience. 26 (28): 7390–4. doi:10.1523/JNEUROSCI.1662-06.2006. PMC 2683919. PMID 16837586.
  55. ↑ Heston JB, White SA (February 2015). "Behavior-linked FoxP2 regulation enables zebra finch vocal learning". The Journal of Neuroscience. 35 (7): 2885–94. doi:10.1523/JNEUROSCI.3715-14.2015. PMC 4331621. PMID 25698728.
  56. ↑ Jarvis ED, Scharff C, Grossman MR, Ramos JA, Nottebohm F (October 1998). "For whom the bird sings: context-dependent gene expression". Neuron. 21 (4): 775–88. doi:10.1016/s0896-6273(00)80594-2. PMID 9808464.
  57. ↑ Teramitsu I, White SA (July 2006). "FoxP2 regulation during undirected singing in adult songbirds". The Journal of Neuroscience. 26 (28): 7390–4. doi:10.1523/JNEUROSCI.1662-06.2006. PMC 2683919. PMID 16837586.
  58. ↑ Wilbrecht L, Nottebohm F (2003). "Vocal learning in birds and humans". Ment Retard Dev Disabil Res Rev. 9 (3): 135–48. doi:10.1002/mrdd.10073. PMID 12953292.

External links

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