View source for FOXP2

{{short description|Transcription factor gene of the forkhead box family}}
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{{Use dmy dates|date=August 2021}}
{{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 [[Regulation of gene expression|regulate gene expression]] by [[DNA-binding protein|binding to DNA]]. It is expressed in the brain, heart, lungs and digestive system.<ref name="Fisher_1998">{{cite journal | vauthors = Fisher SE, Vargha-Khadem F, Watkins KE, Monaco AP, Pembrey ME | title = Localisation of a gene implicated in a severe speech and language disorder | journal = Nature Genetics | volume = 18 | issue = 2 | pages = 168–70 | date = February 1998 | pmid = 9462748 | doi = 10.1038/ng0298-168 | hdl-access = free | s2cid = 3190318 | hdl = 11858/00-001M-0000-0012-CBD9-5 }}</ref><ref name="Lai_2000">{{cite journal | vauthors = Lai CS, Fisher SE, Hurst JA, Levy ER, Hodgson S, Fox M, Jeremiah S, Povey S, Jamison DC, Green ED, Vargha-Khadem F, Monaco AP | title = The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder | journal = American Journal of Human Genetics | volume = 67 | issue = 2 | pages = 357–68 | date = August 2000 | pmid = 10880297 | pmc = 1287211 | doi = 10.1086/303011 }}</ref>

''FOXP2'' is found in many [[vertebrates]], where it plays an important role in mimicry in birds (such as [[birdsong]]) and [[Animal echolocation|echolocation]] in bats. ''FOXP2'' is also required for the proper development of speech and language in humans.<ref name="Lai_2001">{{cite journal | vauthors = Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP | title = A forkhead-domain gene is mutated in a severe speech and language disorder | journal = Nature | volume = 413 | issue = 6855 | pages = 519–23 | date = October 2001 | pmid = 11586359 | doi = 10.1038/35097076 | bibcode = 2001Natur.413..519L | hdl = 11858/00-001M-0000-0012-CB9C-F | s2cid = 4421562 | hdl-access = free }}</ref> In humans, mutations in ''FOXP2'' cause the severe speech and language disorder [[developmental verbal dyspraxia]].<ref name="Lai_2001" /><ref name="MacDermot_2005">{{cite journal | vauthors = MacDermot KD, Bonora E, Sykes N, Coupe AM, Lai CS, Vernes SC, Vargha-Khadem F, McKenzie F, Smith RL, Monaco AP, Fisher SE | title = Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits | journal = American Journal of Human Genetics | volume = 76 | issue = 6 | pages = 1074–80 | date = June 2005 | pmid = 15877281 | pmc = 1196445 | doi = 10.1086/430841 }}</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">{{cite journal | vauthors = Groszer M, Keays DA, Deacon RM, de Bono JP, Prasad-Mulcare S, Gaub S, Baum MG, French CA, Nicod J, Coventry JA, Enard W, Fray M, Brown SD, Nolan PM, Pääbo S, Channon KM, Costa RM, Eilers J, Ehret G, Rawlins JN, Fisher SE | title = Impaired synaptic plasticity and motor learning in mice with a point mutation implicated in human speech deficits | journal = Current Biology | volume = 18 | issue = 5 | pages = 354–62 | date = March 2008 | pmid = 18328704 | pmc = 2917768 | doi = 10.1016/j.cub.2008.01.060 | bibcode = 2008CBio...18..354G }}</ref><ref name="Haesler_2007" /><ref name="Fisher_2009">{{cite journal | vauthors = Fisher SE, Scharff C | title = FOXP2 as a molecular window into speech and language | journal = Trends in Genetics | volume = 25 | issue = 4 | pages = 166–77 | date = April 2009 | pmid = 19304338 | doi = 10.1016/j.tig.2009.03.002 | hdl-access = free | hdl = 11858/00-001M-0000-0012-CA31-7 }}</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>{{cite journal | vauthors = Nudel R, Newbury DF | title = FOXP2 | journal = Wiley Interdisciplinary Reviews. Cognitive Science | volume = 4 | issue = 5 | pages = 547–560 | date = September 2013 | pmid = 24765219 | pmc = 3992897 | doi = 10.1002/wcs.1247 }}</ref> and was subsequently dubbed "the language gene".<ref>{{cite web|url=http://human-brain.org/language-gene.html|title=Language gene found| vauthors = Harpaz Y |website=human-brain.org|url-status=dead|archive-url=https://web.archive.org/web/20141025194746/http://human-brain.org/language-gene.html|archive-date=25 October 2014|access-date=31 October 2014}}</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">{{Cite web|url=https://www.the-scientist.com/news-opinion/language-gene-dethroned-64608|title=Language Gene Dethroned|website=The Scientist Magazine®|language=en|access-date=2020-01-28}}</ref>

== Structure and function ==
[[File:Foxp2, ISH, E13.5 mouse, cerebellum-hindbrain.jpg|thumbnail|left|upright=.85|[http://developingmouse.brain-map.org/data/Foxp2/100092348.html?ispopup=true Foxp2] is expressed in the developing cerebellum and the hindbrain of the embryonic day 13.5 mouse. [[Allen Brain Atlas]]es]]

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 binds directly to DNA to control expression 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">{{cite web | title = FOXP2 Gene | work = Genetics Home Reference | publisher = U.S. National Library of Medicine, National Institutes of Health | date = September 2016 | url = https://medlineplus.gov/genetics/gene/foxp2/ }}</ref>

''FOXP2'' is required for proper brain and lung development. [[Knockout mouse|Knockout mice]] with only one functional copy of the ''FOXP2'' gene have significantly reduced vocalizations as pups.<ref name="Shu_2005">{{cite journal | vauthors = Shu W, Cho JY, Jiang Y, Zhang M, Weisz D, Elder GA, Schmeidler J, De Gasperi R, Sosa MA, Rabidou D, Santucci AC, Perl D, Morrisey E, Buxbaum JD | title = Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 27 | pages = 9643–8 | date = July 2005 | pmid = 15983371 | pmc = 1160518 | doi = 10.1073/pnas.0503739102 | doi-access = free | bibcode = 2005PNAS..102.9643S }}</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">{{cite journal | vauthors = Shu W, Lu MM, Zhang Y, Tucker PW, Zhou D, Morrisey EE | title = Foxp2 and Foxp1 cooperatively regulate lung and esophagus development | journal = Development | volume = 134 | issue = 10 | pages = 1991–2000 | date = May 2007 | pmid = 17428829 | doi = 10.1242/dev.02846 | s2cid = 22896384 | doi-access =  }}</ref>

''FOXP2'' is expressed in many areas of the brain,<ref name="Enard_2002">{{cite journal | vauthors = Enard W, Przeworski M, Fisher SE, Lai CS, Wiebe V, Kitano T, Monaco AP, Pääbo S | title = Molecular evolution of FOXP2, a gene involved in speech and language | journal = Nature | volume = 418 | issue = 6900 | pages = 869–72 | date = August 2002 | pmid = 12192408 | doi = 10.1038/nature01025 | url = http://ruccs.rutgers.edu/~karin/550.READINGS/EVOLUTION/Enard2002.pdf | url-status = dead | hdl-access = free | hdl = 11858/00-001M-0000-0012-CB89-A | s2cid = 4416233 | bibcode = 2002Natur.418..869E | archive-url = https://web.archive.org/web/20060830073732/http://ruccs.rutgers.edu/~karin/550.READINGS/EVOLUTION/Enard2002.pdf | archive-date = 30 August 2006 }}</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">{{cite journal | vauthors = Spiteri E, Konopka G, Coppola G, Bomar J, Oldham M, Ou J, Vernes SC, Fisher SE, Ren B, Geschwind DH | title = Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain | journal = American Journal of Human Genetics | volume = 81 | issue = 6 | pages = 1144–57 | date = December 2007 | pmid = 17999357 | pmc = 2276350 | doi = 10.1086/522237 }}</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 area]]s of female children. The researchers suggested that the gene is more active in "the more communicative sex".<ref>{{Cite journal | vauthors = Balter M | title = 'Language Gene' More Active in Young Girls Than Boy | journal = Science | date = February 2013 | page = 360 |url=https://www.science.org/content/article/language-gene-more-active-young-girls-boys }}</ref><ref>{{cite journal | vauthors = Bowers JM, Perez-Pouchoulen M, Edwards NS, McCarthy MM | title = Foxp2 mediates sex differences in ultrasonic vocalization by rat pups and directs order of maternal retrieval | journal = The Journal of Neuroscience | volume = 33 | issue = 8 | pages = 3276–83 | date = February 2013 | pmid = 23426656 | pmc = 3727442 | doi = 10.1523/JNEUROSCI.0425-12.2013 }}</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">{{cite journal | vauthors = Clovis YM, Enard W, Marinaro F, Huttner WB, De Pietri Tonelli D | title = Convergent repression of Foxp2 3'UTR by miR-9 and miR-132 in embryonic mouse neocortex: implications for radial migration of neurons | journal = Development | volume = 139 | issue = 18 | pages = 3332–42 | date = September 2012 | pmid = 22874921 | doi = 10.1242/dev.078063 | doi-access = free }}</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">{{cite journal | vauthors = Enard W, Gehre S, Hammerschmidt K, Hölter SM, Blass T, Somel M, Brückner MK, Schreiweis C, Winter C, Sohr R, Becker L, Wiebe V, Nickel B, Giger T, Müller U, Groszer M, Adler T, Aguilar A, Bolle I, Calzada-Wack J, Dalke C, Ehrhardt N, Favor J, Fuchs H, Gailus-Durner V, Hans W, Hölzlwimmer G, Javaheri A, Kalaydjiev S, Kallnik M, Kling E, Kunder S, Mossbrugger I, Naton B, Racz I, Rathkolb B, Rozman J, Schrewe A, Busch DH, Graw J, Ivandic B, Klingenspor M, Klopstock T, Ollert M, Quintanilla-Martinez L, Schulz H, Wolf E, Wurst W, Zimmer A, Fisher SE, Morgenstern R, Arendt T, de Angelis MH, Fischer J, Schwarz J, Pääbo S | title = A humanized version of Foxp2 affects cortico-basal ganglia circuits in mice | journal = Cell | volume = 137 | issue = 5 | pages = 961–71 | date = May 2009 | pmid = 19490899 | doi = 10.1016/j.cell.2009.03.041 | hdl-access = free | s2cid = 667723 | hdl = 11858/00-001M-0000-000F-F8C5-2 }}</ref> and human neuronal cell models<ref name="Konopka_2009">{{cite journal | vauthors = Konopka G, Bomar JM, Winden K, Coppola G, Jonsson ZO, Gao F, Peng S, Preuss TM, Wohlschlegel JA, Geschwind DH | title = Human-specific transcriptional regulation of CNS development genes by FOXP2 | journal = Nature | volume = 462 | issue = 7270 | pages = 213–7 | date = November 2009 | pmid = 19907493 | pmc = 2778075 | doi = 10.1038/nature08549 | bibcode = 2009Natur.462..213K}}
*{{cite press release |date=November 12, 2009 |title=Why Can't Chimps Speak? Key Differences In How Human And Chimp Versions Of FOXP2 Gene Work |website=ScienceDaily |url=https://www.sciencedaily.com/releases/2009/11/091111130942.htm}}</ref> 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.<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">{{cite journal | vauthors = Gauthier J, Joober R, Mottron L, Laurent S, Fuchs M, De Kimpe V, Rouleau GA | title = Mutation screening of FOXP2 in individuals diagnosed with autistic disorder | journal = American Journal of Medical Genetics. Part A | volume = 118A | issue = 2 | pages = 172–5 | date = April 2003 | pmid = 12655497 | doi = 10.1002/ajmg.a.10105 | s2cid = 39762074 }}</ref> One well identified target is language.<ref name="GHR_FOXP2_disorders">{{cite web |title=FOXP2-related speech and language disorder |url=https://medlineplus.gov/genetics/condition/foxp2-related-speech-and-language-disorder/ | work = Genetics Home Reference | publisher = U.S. National Library of Medicine, National Institutes of Health |access-date=2019-02-26}}</ref> Although some research disagrees with this correlation,<ref>{{cite journal | vauthors = Newbury DF, Bonora E, Lamb JA, Fisher SE, Lai CS, Baird G, Jannoun L, Slonims V, Stott CM, Merricks MJ, Bolton PF, Bailey AJ, Monaco AP | title = FOXP2 is not a major susceptibility gene for autism or specific language impairment | journal = American Journal of Human Genetics | volume = 70 | issue = 5 | pages = 1318–27 | date = May 2002 | pmid = 11894222 | pmc = 447606 | doi = 10.1086/339931 }}</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">{{cite journal | vauthors = Lennon PA, Cooper ML, Peiffer DA, Gunderson KL, Patel A, Peters S, Cheung SW, Bacino CA | title = Deletion of 7q31.1 supports involvement of FOXP2 in language impairment: clinical report and review | journal = American Journal of Medical Genetics. Part A | volume = 143A | issue = 8 | pages = 791–8 | date = April 2007 | pmid = 17330859 | doi = 10.1002/ajmg.a.31632 | s2cid = 22021740 }}</ref><ref name="Gauthier_2003" /><ref>{{Cite journal | vauthors = Rossell S, Tan E, Bozaoglu K, Neill E, Sumner P, Carruthers S, Van Rheenen T, Thomas E, Gurvich C |date=2017|title=Is language Impairment in Schizophrenia related to Language Genes? |journal=European Neuropsychopharmacology |volume=27 |pages=S459–S460 |doi=10.1016/j.euroneuro.2016.09.532 |s2cid=54316143}}</ref><ref name="Reuter_2017">{{cite journal | vauthors = Reuter MS, Riess A, Moog U, Briggs TA, Chandler KE, Rauch A, Stampfer M, Steindl K, Gläser D, Joset P, Krumbiegel M, Rabe H, Schulte-Mattler U, Bauer P, Beck-Wödl S, Kohlhase J, Reis A, Zweier C | title = FOXP2 variants in 14 individuals with developmental speech and language disorders broaden the mutational and clinical spectrum | journal = Journal of Medical Genetics | volume = 54 | issue = 1 | pages = 64–72 | date = January 2017 | pmid = 27572252 | doi = 10.1136/jmedgenet-2016-104094 | s2cid = 24589445 }}</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>{{cite journal | vauthors = Liégeois F, Baldeweg T, Connelly A, Gadian DG, Mishkin M, Vargha-Khadem F | title = Language fMRI abnormalities associated with FOXP2 gene mutation | journal = Nature Neuroscience | volume = 6 | issue = 11 | pages = 1230–7 | date = November 2003 | pmid = 14555953 | doi = 10.1038/nn1138 | url = https://www.nature.com/articles/nn1138 | s2cid = 31003547 | url-access = subscription }}</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">{{cite journal | vauthors = Demontis D, Walters RK, Martin J, Mattheisen M, Als TD, Agerbo E, Baldursson G, Belliveau R, Bybjerg-Grauholm J, Bækvad-Hansen M, Cerrato F, Chambert K, Churchhouse C, Dumont A, Eriksson N, Gandal M, Goldstein JI, Grasby KL, Grove J, Gudmundsson OO, Hansen CS, Hauberg ME, Hollegaard MV, Howrigan DP, Huang H, Maller JB, Martin AR, Martin NG, Moran J, Pallesen J, Palmer DS, Pedersen CB, Pedersen MG, Poterba T, Poulsen JB, Ripke S, Robinson EB, Satterstrom FK, Stefansson H, Stevens C, Turley P, Walters GB, Won H, Wright MJ, Andreassen OA, Asherson P, Burton CL, Boomsma DI, Cormand B, Dalsgaard S, Franke B, Gelernter J, Geschwind D, Hakonarson H, Haavik J, Kranzler HR, Kuntsi J, Langley K, Lesch KP, Middeldorp C, Reif A, Rohde LA, Roussos P, Schachar R, Sklar P, Sonuga-Barke EJ, Sullivan PF, Thapar A, Tung JY, Waldman ID, Medland SE, Stefansson K, Nordentoft M, Hougaard DM, Werge T, Mors O, Mortensen PB, Daly MJ, Faraone SV, Børglum AD, Neale BM | title = Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder | journal = Nature Genetics | volume = 51 | issue = 1 | pages = 63–75 | date = January 2019 | pmid = 30478444 | pmc = 6481311 | doi = 10.1038/s41588-018-0269-7 }}</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">{{cite journal | vauthors = Johnson EC, Demontis D, Thorgeirsson TE, Walters RK, Polimanti R, Hatoum AS, Sanchez-Roige S, Paul SE, Wendt FR, Clarke TK, Lai D, Reginsson GW, Zhou H, He J, Baranger DA, Gudbjartsson DF, Wedow R, Adkins DE, Adkins AE, Alexander J, Bacanu SA, Bigdeli TB, Boden J, Brown SA, Bucholz KK, Bybjerg-Grauholm J, Corley RP, Degenhardt L, Dick DM, Domingue BW, Fox L, Goate AM, Gordon SD, Hack LM, Hancock DB, Hartz SM, Hickie IB, Hougaard DM, Krauter K, Lind PA, McClintick JN, McQueen MB, Meyers JL, Montgomery GW, Mors O, Mortensen PB, Nordentoft M, Pearson JF, Peterson RE, Reynolds MD, Rice JP, Runarsdottir V, Saccone NL, Sherva R, Silberg JL, Tarter RE, Tyrfingsson T, Wall TL, Webb BT, Werge T, Wetherill L, Wright MJ, Zellers S, Adams MJ, Bierut LJ, Boardman JD, Copeland WE, Farrer LA, Foroud TM, Gillespie NA, Grucza RA, Harris KM, Heath AC, Hesselbrock V, Hewitt JK, Hopfer CJ, Horwood J, Iacono WG, Johnson EO, Kendler KS, Kennedy MA, Kranzler HR, Madden PA, Maes HH, Maher BS, Martin NG, McGue M, McIntosh AM, Medland SE, Nelson EC, Porjesz B, Riley BP, Stallings MC, Vanyukov MM, Vrieze S, Davis LK, Bogdan R, Gelernter J, Edenberg HJ, Stefansson K, Børglum AD, Agrawal A | title = A large-scale genome-wide association study meta-analysis of cannabis use disorder | journal = The Lancet. Psychiatry | volume = 7 | issue = 12 | pages = 1032–1045 | date = December 2020 | pmid = 33096046 | pmc = 7674631 | doi = 10.1016/S2215-0366(20)30339-4 | doi-access = free }}</ref>

=== 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]] (DVD)<ref name="GHR_FOXP2_disorders"/> or childhood apraxia of speech (CAS)<ref>{{cite journal | vauthors = Morgan A, Fisher SE, Scheffer I, Hildebrand M | title = FOXP2-Related Speech and Language Disorders | journal = GenReviews | date = 23 June 2016 | pmid = 27336128 | publisher = University of Washington | veditors = Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A }}</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>{{cite journal | vauthors = Vargha-Khadem F, Gadian DG, Copp A, Mishkin M | title = FOXP2 and the neuroanatomy of speech and language | journal = Nature Reviews. Neuroscience | volume = 6 | issue = 2 | pages = 131–8 | date = February 2005 | pmid = 15685218 | doi = 10.1038/nrn1605 | s2cid = 2504002 }}</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>{{cite book | vauthors = Friederici AD | author-link = Angela D. Friederici | title = 'Language in the Brain | date = 2016 | publisher = The MIT Press | location = Cambridge, MA | isbn = 978-0-262-03692-4 | page = 222 }}</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>{{cite book | vauthors = Berwick RC, Chomsky N | date = 2016 | title = Why Only Us? | isbn = 978-0-262-53349-2 | publisher = The MIT Press | location = Cambridge, MA | page = 76 }}</ref>

== Evolution ==
[[Image: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 ([[exon]]s).|thumb|right|upright=1.25]]

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">{{cite journal | vauthors = Preuss TM | title = Human brain evolution: from gene discovery to phenotype discovery | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = Suppl 1 | pages = 10709–16 | date = June 2012 | pmid = 22723367 | pmc = 3386880 | doi = 10.1073/pnas.1201894109 | bibcode = 2012PNAS..10910709P | doi-access = free }}</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">{{cite journal | vauthors = Teramitsu I, Kudo LC, London SE, Geschwind DH, White SA | author-link5 = Stephanie A. White | title = Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction | journal = The Journal of Neuroscience | volume = 24 | issue = 13 | pages = 3152–63 | date = March 2004 | pmid = 15056695 | doi = 10.1523/JNEUROSCI.5589-03.2004 | url = https://www.jneurosci.org/content/24/13/3152 | pmc = 6730014 }}</ref><ref name="Haesler_2004">{{cite journal | vauthors = Haesler S, Wada K, Nshdejan A, Morrisey EE, Lints T, Jarvis ED, Scharff C | title = FoxP2 expression in avian vocal learners and non-learners | journal = The Journal of Neuroscience | volume = 24 | issue = 13 | pages = 3164–75 | date = March 2004 | pmid = 15056696 | pmc = 6730012 | doi = 10.1523/JNEUROSCI.4369-03.2004 }}</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">{{cite journal | vauthors = Webb DM, Zhang J | title = FoxP2 in song-learning birds and vocal-learning mammals | journal = The Journal of Heredity | volume = 96 | issue = 3 | pages = 212–6 | year = 2005 | pmid = 15618302 | doi = 10.1093/jhered/esi025 | doi-access =  }}</ref><ref name="Scharff_2005">{{cite journal | vauthors = Scharff C, Haesler S | title = An evolutionary perspective on FoxP2: strictly for the birds? | journal = Current Opinion in Neurobiology | volume = 15 | issue = 6 | pages = 694–703 | date = December 2005 | pmid = 16266802 | doi = 10.1016/j.conb.2005.10.004 | s2cid = 11350165 }}</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">{{cite news | vauthors = Zimmer C |author-link=Carl Zimmer |title=Humans Interbred With Hominins on Multiple Occasions, Study Finds |url=https://www.nytimes.com/2016/03/22/science/neanderthals-interbred-with-humans-denisovans.html |date=17 March 2016 |work=[[The New York Times]] |access-date=17 March 2016 }}</ref><ref name="Krause_2007">{{cite journal | vauthors = 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 | title = The derived FOXP2 variant of modern humans was shared with Neandertals | journal = Current Biology | volume = 17 | issue = 21 | pages = 1908–12 | date = November 2007 | pmid = 17949978 | doi = 10.1016/j.cub.2007.10.008 | bibcode = 2007CBio...17.1908K | hdl = 11858/00-001M-0000-000F-FED3-1 | s2cid = 9518208 | hdl-access = free }}
*{{cite news |author=Nicholas Wade |date=19 October 2007 |title=Neanderthals Had Important Speech Gene, DNA Evidence Shows |newspaper=The New York Times |url=https://www.nytimes.com/2007/10/19/science/19speech-web.html |url-access=subscription}}
See also {{cite journal | vauthors = Benítez-Burraco A, Longa VM, Lorenzo G, Uriagereka J | title = Also sprach Neanderthalis... Or Did She? | journal = Biolinguistics | volume = 2 | issue = 2–3 | pages = 225–232 | date=November 2008| doi = 10.5964/bioling.8643 | s2cid = 60864520 | url = https://www.biolinguistics.eu/index.php/biolinguistics/article/view/50/67| doi-access = free }}</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">{{cite journal | vauthors = Benítez-Burraco A, Longa VM, Lorenzo G, Uriagereka J | title = Also sprach Neanderthalis... Or Did She? | journal = Biolinguistics | volume = 2 | issue = 2–3 | pages = 225–232 | date=November 2008| doi = 10.5964/bioling.8643 | s2cid = 60864520 | url = https://www.biolinguistics.eu/index.php/biolinguistics/article/view/50/67| doi-access = free }}</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>{{cite journal | vauthors = Toda M, Okubo S, Ikigai H, Suzuki T, Suzuki Y, Hara Y, Shimamura T | title = The protective activity of tea catechins against experimental infection by Vibrio cholerae O1 | journal = Microbiology and Immunology | volume = 36 | issue = 9 | pages = 999–1001 | year = 1992 | pmid = 1461156 | doi = 10.1111/j.1348-0421.1992.tb02103.x | s2cid = 34400234 | doi-access = free }}</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">{{cite journal | vauthors = Atkinson EG, Audesse AJ, Palacios JA, Bobo DM, Webb AE, Ramachandran S, Henn BM | title = No Evidence for Recent Selection at FOXP2 among Diverse Human Populations | journal = Cell | volume = 174 | issue = 6 | pages = 1424–1435.e15 | date = September 2018 | pmid = 30078708 | pmc = 6128738 | doi = 10.1016/j.cell.2018.06.048 }}</ref><ref name=":1" /> Insertion of both human [[mutation]]s into mice, whose version of ''FOXP2'' otherwise differs from the human and [[Common chimpanzee|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"/>

== Interactions ==
FOXP2 is known to regulate ''[[CNTNAP2]]'', ''[[CTBP1]]'',<ref name="Li_2004">{{cite journal | vauthors = Li S, Weidenfeld J, Morrisey EE | title = Transcriptional and DNA binding activity of the Foxp1/2/4 family is modulated by heterotypic and homotypic protein interactions | journal = Molecular and Cellular Biology | volume = 24 | issue = 2 | pages = 809–22 | date = January 2004 | pmid = 14701752 | pmc = 343786 | doi = 10.1128/MCB.24.2.809-822.2004 }}</ref> ''[[SRPX2]]'' and ''[[SCN3A]]''.<ref>{{cite journal | vauthors = Smith RS, Kenny CJ, Ganesh V, Jang A, Borges-Monroy R, Partlow JN, Hill RS, Shin T, Chen AY, Doan RN, Anttonen AK, Ignatius J, Medne L, Bönnemann CG, Hecht JL, Salonen O, Barkovich AJ, Poduri A, Wilke M, de Wit MC, Mancini GM, Sztriha L, Im K, Amrom D, Andermann E, Paetau R, Lehesjoki AE, Walsh CA, Lehtinen MK | title = Sodium Channel SCN3A (Na<sub>V</sub>1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development | journal = Neuron | volume = 99 | issue = 5 | pages = 905–913.e7 | date = September 2018 | pmid = 30146301 | pmc = 6226006 | doi = 10.1016/j.neuron.2018.07.052 }}</ref><ref name="Spiteri_2007" /><ref name="Vernes_207">{{cite journal | vauthors = Vernes SC, Spiteri E, Nicod J, Groszer M, Taylor JM, Davies KE, Geschwind DH, Fisher SE | title = High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech and language disorders | journal = American Journal of Human Genetics | volume = 81 | issue = 6 | pages = 1232–50 | date = December 2007 | pmid = 17999362 | pmc = 2276341 | doi = 10.1086/522238 }}</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">{{cite journal | vauthors = Vernes SC, Newbury DF, Abrahams BS, Winchester L, Nicod J, Groszer M, Alarcón M, Oliver PL, Davies KE, Geschwind DH, Monaco AP, Fisher SE | title = A functional genetic link between distinct developmental language disorders | journal = The New England Journal of Medicine | volume = 359 | issue = 22 | pages = 2337–45 | date = November 2008 | pmid = 18987363 | pmc = 2756409 | doi = 10.1056/NEJMoa0802828 }}</ref>

FOXP2 also downregulates  ''SRPX2'', the 'Sushi Repeat-containing Protein X-linked 2'.<ref name=":02"/><ref>{{cite news|url=https://www.science.org/content/article/language-gene-has-partner|title='Language Gene' Has a Partner| vauthors = Pennisi E |author-link=Elizabeth Pennisi|date=31 October 2013|work=Science|access-date=30 October 2014|ref=pennisi}}</ref> It directly reduces its expression, by binding to its gene's [[Promoter (genetics)|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">{{cite journal | vauthors = Sia GM, Clem RL, Huganir RL | title = The human language-associated gene SRPX2 regulates synapse formation and vocalization in mice | journal = Science | volume = 342 | issue = 6161 | pages = 987–91 | date = November 2013 | pmid = 24179158 | pmc = 3903157 | doi = 10.1126/science.1245079 | bibcode = 2013Sci...342..987S }}</ref>

== In other animals ==

=== <span id="Chimpanzees compared with humans"></span>Chimpanzees ===
In chimpanzees, FOXP2 differs from the human version by two amino acids.<ref>{{Cite journal | vauthors = Smith K |date=2009-11-11|title=Evolution of a single gene linked to language|journal=Nature|doi=10.1038/news.2009.1079|issn=1744-7933}}</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>{{Cite news|date=2009-11-11|title=Why can't chimps talk? It's more than just genes|work=Reuters|url=https://www.reuters.com/article/us-humans-speech-idUSTRE5AA3J920091111|access-date=2019-02-21}}</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" />

=== Mice ===
In a mouse ''FOXP2'' [[gene knockout]]s, loss of both copies of the gene causes severe motor impairment related to cerebellar abnormalities and lack of [[ultrasound|ultrasonic]] [[Animal communication|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">{{cite journal | vauthors = Holy TE, Guo Z | title = Ultrasonic songs of male mice | journal = PLOS Biology | volume = 3 | issue = 12 | pages = e386 | date = December 2005 | pmid = 16248680 | pmc = 1275525 | doi = 10.1371/journal.pbio.0030386 | doi-access = free }}</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-thalamo-cortical loop|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 [[Cerebral cortex#Layer VI|sixth layer]] of the cortex than in the [[Cerebral cortex#Layer V|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 [[Dopamine receptor D1|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">{{cite journal | vauthors = French CA, Fisher SE | title = What can mice tell us about Foxp2 function? | journal = Current Opinion in Neurobiology | volume = 28 | pages = 72–9 | date = October 2014 | pmid = 25048596 | doi = 10.1016/j.conb.2014.07.003 | hdl-access = free | s2cid = 17848265 | hdl = 11858/00-001M-0000-0019-F62D-4 }}</ref>

=== Bats ===
''FOXP2'' has implications in the development of [[bat]] [[animal echolocation|echolocation]].<ref name="Preuss_2012"/><ref name="Li_2007">{{cite journal | vauthors = Li G, Wang J, Rossiter SJ, Jones G, Zhang S | title = Accelerated FoxP2 evolution in echolocating bats | journal = PLOS ONE | volume = 2 | issue = 9 | pages = e900 | date = September 2007 | pmid = 17878935 | pmc = 1976393 | doi = 10.1371/journal.pone.0000900 | veditors = Ellegren H | doi-access = free | bibcode = 2007PLoSO...2..900L }}</ref><ref name="Wilbrecht_2003">{{cite journal | vauthors = Wilbrecht L, Nottebohm F | title = Vocal learning in birds and humans | journal = Mental Retardation and Developmental Disabilities Research Reviews | volume = 9 | issue = 3 | pages = 135–48 | year = 2003 | pmid = 12953292 | doi = 10.1002/mrdd.10073 }}</ref> Contrary to apes and mice, ''FOXP2'' is extremely diverse in [[Microbat|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" /> There is also evidence of ongoing intraspecific selection in at least one species of bat, in response to environmental changes.<ref>{{cite journal | vauthors = Auteri GG, Knowles LL | title = Decimated little brown bats show potential for adaptive change | journal = Scientific Reports | volume = 10 | issue = 1 | pages = 3023 | date = February 2020 | pmid = 32080246 | doi = 10.1038/s41598-020-59797-4 | pmc = 7033193 }}</ref>

=== Birds ===
In [[songbird]]s, ''FOXP2'' most likely regulates genes involved in [[neuroplasticity]].<ref name="Haesler_2007">{{cite journal | vauthors = Haesler S, Rochefort C, Georgi B, Licznerski P, Osten P, Scharff C | title = Incomplete and inaccurate vocal imitation after knockdown of FoxP2 in songbird basal ganglia nucleus Area X | journal = PLOS Biology | volume = 5 | issue = 12 | pages = e321 | date = December 2007 | pmid = 18052609 | pmc = 2100148 | doi = 10.1371/journal.pbio.0050321 | doi-access = free }}</ref><ref name="Teramitsu_2006">{{cite journal | vauthors = Teramitsu I, White SA | author-link2 = Stephanie A. White | title = FoxP2 regulation during undirected singing in adult songbirds | journal = The Journal of Neuroscience | volume = 26 | issue = 28 | pages = 7390–4 | date = July 2006 | pmid = 16837586 | doi = 10.1523/JNEUROSCI.1662-06.2006 | url = https://doi.org/10.1523/JNEUROSCI.1662-06.2006 | pmc = 2683919 }}</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>{{cite journal | vauthors = Heston JB, White SA | author-link2 = Stephanie A. White | title = Behavior-linked FoxP2 regulation enables zebra finch vocal learning | journal = The Journal of Neuroscience | volume = 35 | issue = 7 | pages = 2885–94 | date = February 2015 | pmid = 25698728 | doi = 10.1523/JNEUROSCI.3715-14.2015 | url = https://doi.org/10.1523/JNEUROSCI.3715-14.2015 | pmc = 4331621 }}</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>{{cite journal | vauthors = Jarvis ED, Scharff C, Grossman MR, Ramos JA, Nottebohm F | title = For whom the bird sings: context-dependent gene expression | journal = Neuron | volume = 21 | issue = 4 | pages = 775–88 | date = October 1998 | pmid = 9808464 | doi = 10.1016/s0896-6273(00)80594-2 | s2cid = 13893471 | doi-access = free }}</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.

=== Zebrafish ===
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">{{cite journal | vauthors = Bonkowsky JL, Chien CB | title = Molecular cloning and developmental expression of foxP2 in zebrafish | journal = Developmental Dynamics | volume = 234 | issue = 3 | pages = 740–6 | date = November 2005 | pmid = 16028276 | doi = 10.1002/dvdy.20504 | s2cid = 24771138 | doi-access = free }}</ref>

== History ==
''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 [[UCL Institute of Child Health|Institute of Child Health of University College London]].<ref name = "Hurst_1990">{{cite journal | vauthors = Hurst JA, Baraitser M, Auger E, Graham F, Norell S | title = An extended family with a dominantly inherited speech disorder | journal = Developmental Medicine and Child Neurology | volume = 32 | issue = 4 | pages = 352–5 | date = April 1990 | pmid = 2332125 | doi = 10.1111/j.1469-8749.1990.tb16948.x | s2cid = 2654363 }}</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>{{cite journal | vauthors = Gopnik M | title = Genetic basis of grammar defect | journal = Nature | volume = 347 | issue = 6288 | pages = 26 | date = September 1990 | pmid = 2395458 | doi = 10.1038/347026a0 | s2cid = 4323390 | doi-access = free | bibcode = 1990Natur.347...26G }}</ref> She hypothesized that the basis was not of learning or cognitive disability, but due to genetic factors affecting mainly grammatical ability.<ref>{{cite journal | vauthors = Gopnik M | title = Feature-blind grammar and dysphagia | journal = Nature | volume = 344 | issue = 6268 | pages = 715 | date = April 1990 | pmid = 2330028 | doi = 10.1038/344715a0 | s2cid = 4360334 | bibcode = 1990Natur.344..715G | doi-access = free }}</ref> (Her hypothesis led to a popularised existence of "grammar gene" and a controversial notion of grammar-specific disorder.<ref>{{cite book| vauthors = Cowie F |title=What's Within?: Nativism Reconsidered|year=1999|publisher=Oxford University Press|location=New York, US|isbn=978-0-19-515978-3|pages=290–291|url=https://books.google.com/books?id=xb1pvz1JhQYC}}</ref><ref>{{cite book| vauthors = Jenkins L |title=Biolinguistics: Exploring the Biology of Language|year=2000|publisher=Cambridge University Press|location=Cambridge, UK|isbn=978-0-521-00391-9|pages=98–99|edition=Revised|url=https://books.google.com/books?id=Z2AN2f6GPFQC}}</ref>) In 1995, the [[University of Oxford]] and the Institute of Child Health researchers found that the disorder was purely genetic.<ref>{{cite journal | vauthors = Vargha-Khadem F, Watkins K, Alcock K, Fletcher P, Passingham R | title = Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 3 | pages = 930–3 | date = January 1995 | pmid = 7846081 | pmc = 42734 | doi = 10.1073/pnas.92.3.930 | doi-access = free | bibcode = 1995PNAS...92..930V }}</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">{{cite journal | vauthors = Fisher SE, Lai CS, Monaco AP | title = Deciphering the genetic basis of speech and language disorders | journal = Annual Review of Neuroscience | volume = 26 | pages = 57–80 | year = 2003 | pmid = 12524432 | doi = 10.1146/annurev.neuro.26.041002.131144 | hdl-access = free | s2cid = 1276712 | hdl = 11858/00-001M-0000-0012-CB7E-4 }}</ref>

[[File:FOXP2 location.png|thumb|left|The ''FOXP2'' gene is located on the long (q) arm of [[Chromosome 7 (human)|chromosome 7]], at position 31.]]
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>{{cite web|title=Genes that are essential for speech|url=https://thebrain.mcgill.ca/flash/d/d_10/d_10_m/d_10_m_lan/d_10_m_lan.html|website=The Brain from Top to Bottom|access-date=31 October 2014}}</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 [[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.<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">{{cite journal | vauthors = Vernes SC, Nicod J, Elahi FM, Coventry JA, Kenny N, Coupe AM, Bird LE, Davies KE, Fisher SE | title = Functional genetic analysis of mutations implicated in a human speech and language disorder | journal = Human Molecular Genetics | volume = 15 | issue = 21 | pages = 3154–67 | date = November 2006 | pmid = 16984964 | doi = 10.1093/hmg/ddl392 | doi-access = free | hdl = 11858/00-001M-0000-0012-CB23-C | hdl-access = free }}</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">{{cite journal | vauthors = Feuk L, Kalervo A, Lipsanen-Nyman M, Skaug J, Nakabayashi K, Finucane B, Hartung D, Innes M, Kerem B, Nowaczyk MJ, Rivlin J, Roberts W, Senman L, Summers A, Szatmari P, Wong V, Vincent JB, Zeesman S, Osborne LR, Cardy JO, Kere J, Scherer SW, Hannula-Jouppi K | title = Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia | journal = American Journal of Human Genetics | volume = 79 | issue = 5 | pages = 965–72 | date = November 2006 | pmid = 17033973 | pmc = 1698557 | doi = 10.1086/508902 }}</ref> 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 ==
{{Reflist}}

== External links ==
{{Commons category|FOXP2}}
* [https://www.ncbi.nlm.nih.gov/gene/93986 Gene information at NCBI]
* [https://medlineplus.gov/genetics/gene/foxp2/ Gene information at Genetic Home Reference]
* [https://www.mpi.nl/departments/language-and-genetics Language and Genetics Research] at the [[Max Planck Institute for Psycholinguistics]]
* [https://web.archive.org/web/20091116190757/http://genome.wellcome.ac.uk/doc_WTD020797.html The FOXP2 story]
* [https://scienceblogs.com/notrocketscience/2009/11/11/revisiting-foxp2-and-the-origins-of-language/ Revisiting FOXP2 and the origins of language]
* [http://www.evolutionpages.com/FOXP2_language.htm FOXP2 and the Evolution of Language]
* {{FactorBook|FOXP2}}

{{PDB_Gallery|geneid=93986}}
{{Transcription factors|g3}}
{{Animal communication}}

{{DEFAULTSORT:Foxp2}}
[[Category:Forkhead transcription factors]]
[[Category:Evolution of language]]
[[Category:Genetics concepts]]
[[Category:Speech and language pathology]]
[[Category:Genes on human chromosome 7]]
[[Category:Human embryology]]