FOXP2

FOXP2 ("forkhead box P2") is a gene that is implicated in the development of language skills,cite journal |author=Lai C, Fisher S, Hurst J, Levy E, Hodgson S, Fox M, Jeremiah S, Povey S, Jamison D, Green E, Vargha-Khadem F, Monaco A |title=The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder |journal=Am J Hum Genet |volume=67 |issue=2 |pages=357–68 |year=2000 |pmid=10880297 |doi=10.1086/303011] including grammatical competence.

Introduction

FOXP2 is a member of the large FOX family of transcription factors. Information from known human mutations and mouse studies suggest that FOXP2 regulates genes involved in the development of tissues such as brain, lung, and gut. The exact identity of the genes FOXP2 regulates is still not known, however.

FOXP2 and human disease

Several cases of developmental verbal dyspraxia in humans have been linked to mutations in the FOXP2 genecite journal |author=Vargha-Khadem F, Gadian DG, Copp A, Mishkin M |title=FOXP2 and the neuroanatomy of speech and language |journal=Nature Reviews Neuroscience |volume=6 |pages=131–137 |year=2005 |pmid=15685218 |doi=10.1038/nrn1605] . Individuals have little or no cognitive handicaps but are unable to correctly perform the coordinated movements required for speech. fMRI analysis of these individuals performing silent verb generation and spoken word repetition tasks showed underactivation of Broca's area and the putamen, brain centers thought to be involved in language tasks. Because of this, FOXP2 has been dubbed the "speech and 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).cite journal | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1174822 | title = Evolution at Two Levels: On Genes and Form | journal = PLoS Biol. | date = 2005 July | volume = 3 | issue = 7 | pages = e245 | doi = 10.1371/journal.pbio.0030245 | author = Sean B Carroll | pmid = 16000021] Scientists have also looked for associations between FOXP2 and autism and both positive and negative findings have been reported cite journal |author=Scherer SW, et al.|title=Human chromosome 7: DNA sequence and biology|journal=Science|volume=300|pages=767–772 | year=2003 |pmid=12690205 |doi=10.1126/science.1083423] cite journal |author=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=Am J Hum Genet |volume=70 |issue=5 |pages=1318–27 |year=2002 |pmid=11894222 |doi=10.1086/339931] .

There is some evidence that the linguistic impairments associated with a mutation of the FOXP2 gene are not simply the result of a fundamental deficit in motor control. For example:

* the 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.

Function

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 pupscite journal
author=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 = Proc Natl Acad Sci U S A
volume=102 |issue=27 |pages=9643–8 |year=2005 |pmid=15983371
doi=10.1073/pnas.0503739102] .Knockout mice with no functional copies of FOXP2 are runted, display abnormalities in brain regions such as the Purkinje layer, and die 21 days after birth from inadequate lung development.cite journal
author = 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
year=2007
pmid=17428829
doi = 10.1242/dev.02846]

Different studies of FOXP2 in songbirds suggest that FOXP2 may regulate genes involved in neuroplasticity: During song learning FOXP2 is upregulated in brain regions critical for song learning in young zebra finches.
Knockdown of FOXP2 in Area X of the basal ganglia of these birds results in incomplete and inaccurate song imitation. [Cite journal
author = Sebastian Haesler, Christelle Rochefort, Benjamin Georgi, Pawel Licznerski, Pavel Osten, Constance Scharff
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
doi = 10.1371/journal.pbio.0050321
year = 2007] Similarly, in adult canaries higher FoxP2 levels also correlate with song changes.cite journal
author=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 = Journal of Neuroscience
volume = 24
issue = 24
pages = 3164–3175
year = 2004
pmid =15056696
doi=10.1523/JNEUROSCI.4369-03.2004] In addition, levels of FOXP2 in adult zebra finches are significantly lower when males direct their song to females than when they sing song in other contexts.cite journal
author = I. Teramitsu and S. A. White
title = FoxP2 regulation during undirected singing in adult songbirds
journal = Journal of Neuroscience
volume=26
issue=28
pages=7390–7294
year=2006
pmid=16837586
doi = 10.1523/JNEUROSCI.1662-06.2006] Differences between birds which are learning songs and those which are not 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 has also been implicated in the development of bat echolocation. [Citation | last1 = Li | first1 = Gang | last2 = Wang | first2 = Jinhong | last3 = Rossiter | first3 = Stephen J. | last4 = Jones | first4 = Gareth | last5 = Zhang | first5 = Shuyi
title = Accelerated FoxP2 Evolution in Echolocating Bats
year = 2007
url = http://www.plosone.org/article/fetchArticle.action?articleURI=info:doi/10.1371/journal.pone.0000900 | accessdate = 2007-09-19
doi = 10.1371/journal.pone.0000900 | accessdate = 2007-09-19] A recent extraction of DNA from Neanderthal bones indicates that Neanderthals had the same version (allele) of the FOXP2 gene that is known to play a role in human language. [Cite journal
title = The Derived FOXP2 Variant of Modern Humans Was Shared with Neandertals
author = Johannes Krause, Carles Lalueza-Fox, Ludovic Orlando, Wolfgang Enard, Richard E. Green, Hernán A. Burbano, Jean-Jacques Hublin, Catherine Hänni, Javier Fortea, Marco de la Rasilla, Jaume Bertranpetit, Antonio Rosas and Svante Pääbo
journal = Current Biology
volume = 17
issue = 21
date = 2007-11-6
pages = 1908–1912
doi = 10.1016/j.cub.2007.10.008 News article:
* Cite news
url= http://www.nytimes.com/2007/10/19/science/19speech-web.html?ref=world
title = Neanderthals Had Important Speech Gene, DNA Evidence Shows
publisher = New York Times
date = 2007-10-19]

Evolution

The FOXP2 protein sequence is highly conserved. Similar FOXP2 proteins can be found in songbirds, fish, and reptiles such as alligators.cite journal |author=Webb DM, Zhang J |title=FoxP2 in song-learning birds and vocal-learning mammals |journal=J Hered. |volume=96 |issue=3 |pages=212–6 |year=2005 |pmid=15618302 |doi=10.1093/jhered/esi025] cite journal |author=Scharff C, Haesler S |title=An evolutionary perspective on FoxP2: strictly for the birds? |journal=Curr Opin Neurobiol |volume=15 |issue=6 |pages=694–703 |year=2004 |pmid=16266802 |doi=10.1016/j.conb.2005.10.004] Aside from a polyglutamine tract, human FOXP2 differs from chimp FOXP2 by only two amino acids, mouse FOXP2 by only 3 amino acids, and zebra finch FOXP2 by only 7 amino acids.cite journal |author=Enard W, Przeworski M, Fisher S, Lai C, Wiebe V, Kitano T, Monaco A, Pääbo S |title=Molecular evolution of FOXP2, a gene involved in speech and language |journal=Nature |volume=418 |issue=6900 |pages=869–72 |year=2002 |pmid=12192408 |doi=10.1038/nature01025] cite journal |author=Teramitsu I, Kudo LC, London SE, Geschwind DH, White SA |title=Parallel FoxP1 and FoxP2 expression in songbird and human brain predicts functional interaction |journal=J Neurosci. |volume=24 |issue=13 |pages=3152–63 |year=2004 |pmid=15056695 |doi=10.1523/JNEUROSCI.5589-03.2004] cite journal |author=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=J Neurosci. |issue=24 |pages=3164–75 |year=2004 |pmid=15056696 |volume=24 |doi=10.1523/JNEUROSCI.4369-03.2004] Some researchers have speculated that the two amino acid differences between chimps and humans led to the evolution of language in humans.cite journal |author=Enard W, Przeworski M, Fisher S, Lai C, Wiebe V, Kitano T, Monaco A, Pääbo S |title=Molecular evolution of FOXP2, a gene involved in speech and language |journal=Nature |volume=418 |issue=6900 |pages=869–72 |year=2002 |pmid=12192408 |doi=10.1038/nature01025] Others, however, have been unable to find a clear association between species with learned vocalizations and similar mutations in FOXP2.cite journal |author=Webb DM, Zhang J |title=FoxP2 in song-learning birds and vocal-learning mammals |journal=J Hered. |volume=96 |issue=3 |pages=212–6 |year=2005 |pmid=15618302 |doi=10.1093/jhered/esi025] cite journal |author=Scharff C, Haesler S |title=An evolutionary perspective on FoxP2: strictly for the birds? |journal=Curr Opin Neurobiol |volume=15 |issue=6 |pages=694–703 |year=2004 |pmid=16266802 |doi=10.1016/j.conb.2005.10.004] Both human mutations occur in an exon with no known function. It is also likely, based on general observations of development and songbird results, that any difference between humans and non-humans would be due to regulatory sequence divergence (affecting where and when FOXP2 is expressed) rather than the two amino acid differences mentioned above.

History

The search for the gene was initially started as a result of the investigations into the KE (or K) family. Certain members of this family suffered from an inherited speech and language disorder and living members stretched back three generations. Closer inspection of the family revealed the disorder to be autosomal dominant.

A scan was performed of the genome of the affected and some of the unaffected family members. This initial scan limited the affected region to a spot on chromosome 7, which the team called "SPCH1". Sequencing of this region was done with the aid of bacterial artificial chromosome clones. At this point, another individual was located who had a similar disorder but was unrelated to the family. The genome of this individual was mapped and it was discovered that there was a break in chromosome 7.

Further investigation discovered a point mutation in this chromosome. Sequenced and analysed, this is now referred to as the FOXP2 gene.

See also

* FOX proteins
* FOXP1
* dyspraxia
* Broca's area
* Evolution of Homo sapiens
* Human evolutionary genetics
* Human Genome Project
* Chimpanzee genome project
* Origin of language
* Vocal learning

References

External links

* [http://www.well.ox.ac.uk/~simon/FOXP2/index.shtml The FOXP2 gene in neurological development] at University of Oxford
* Essay on [http://www.evolutionpages.com/FOXP2_language.htm FOXP2 and the Evolution of Language]

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