he relationship between genes and language is generally accepted to be complex and multifarious. XXX Waffle?? link to title… maybe add a linker here to previous chapters…
Whilst twin studies have demonstrated that genes play a significant role in language development in humans (Bishop et al 1995), the majority of families displaying such language disorders also show complex patterns of inheritance and so conventional linkage analysis is not a useful research strategy. One rare exception is the three-generation large KE family, who have been a source of scientific interest since they were brought to attention in the 1980’s, given finding an autosomal dominant gene relating to language disorders could point the way in researching language evolution. Behavioural studies highlighted the most striking feature of the language disorder as verbal dyspraxia caused somewhat by orofacial dyspraxia, anatomically reflected in the partial immobility of the affect member’s lower face and mouth. Furthermore, the disorder is not restricted purely to function and extends to both expressive and receptive language abilities, in addition to below average verbal and non-verbal intelligence (Vargha-Khadem et al (1995)). Initial reports suggested that the disorder was genetic, but it was not until Fisher et al (1998) initiated a genome-wide search for linkage within the family that the abnormal gene (SPCH1) was localised to chromosome band 7q31, and further research allowed Lai and Fisher et al (2001) to name FOXP2 as the gene implicated. The gene encodes FOXP2 protein, part of which is a transcription factor involved in regulating a number of other genes including SRPX2, CTBP1, and CTNAP2 (Spiteri et al (2007), Vernes et al (2007)). Investigations led to detection of a missense mutation of G to A in exon 14, resulting in an arginine-to-histidine substitution in the forkhead DNA binding domain of FOXP2, disrupting the binding properties and rendering it dysfunctional (Lai (2001). Further subjects with language disorders have been studied. One subject, CS, also had verbal dyspraxia. It was found CS had a chromosomal translocation with a single breakpoint that was mapped to a single clone inside SPCH1, thus providing additional evidence for the involvement of FOXP2 in language disorders (Lai et al (2000)). These studies demonstrate that two functional copies of FOXP2 seem to be required for the acquisition of spoken language, implying it has a role in language development, and this was further supported by functional studies… 1** …
Functional studies on affected and unaffected KE family members revealed, using positron emission tomography (PET) and magnetic resonance imaging (MRI), that the left supplementary motor area (SMA), the left subjacent cingulate cortex, and the left preSMA/cingulate cortex were less active in those affected. Also highlighted were several overactive areas, including the head and tail of the left caudate nucleus, the left premotor cortex with a ventral extension into Broca’s area, and a left ventral prefrontal area. (6**) The research continued and further MRI showed affected members have more grey matter bilaterally in the angular gyrus, and less grey matter in the preSMA/cingulate cortex, left Broca’s area, and bilateral caudate nuclei. In the affected, the caudate nuclei bilaterally had lower volumes in the affected, though notably this is on a group level rather than the individual level. 2 … maybe bit about why it affects mouth movement
Whilst it is evident FOXP2 has a role in language, this research alone cannot explain the evolution of complex language uniquely in man, nor does it mean that it is the only gene of interest. Animal studies have shown FOXP2 is highly conserved across different species, so FOXP2 itself is not unique in man (Zhang et al (2002)), suggesting it plays an important role regardless of if it is in language or not. However the presence of FOXP2 in species which utilise vocal communication, including man, can be studied and compared to those species with little or no vocal communication. This includes cross species sequence comparison, neuroimaging, humanisation studies, and behavioural testing.…etctec…>XXX
Given the presence of FOXP2 in many species, a cross species comparison provides information about the level of sequence conservation. Enard et al (2002) sequenced the cDNAs in the chimpanzee, gorilla, orangutan, rhesus macque and mouse that encoded FOXP2, and compared them with human cDNA. It was found that the lengths of the polyglutamine stretches varied in the different taxa, but Newbury et al (2002) suggested, through genotyping members of a family with a significant language impairment, that that minor changes in length may not significantly alter the function of the protein. Disregarding the polyglutamine stretches, it was found that in comparison to the human FOXP2, the mouse FOXP2 orthologue differs at only three amino-acid positions. The rhesus macque, gorilla and chimpanzee FOXP2 proteins all differ at two of those three positions (T303N and N325S) and are all identical to each other. The orang-utan was the most different, carrying two differences from the mouse and three from humans (+++3). Furthermore, Enard et al compared the predicted protein structures and whilst the mouse and chimpanzee proteins were essentially identical, it was proposed that the amino acid change of asparagine-to-serine at position 325 in the human FOXP2 causes both a minor change in predicted secondary structure and creates a potential target site for phosphorylation by protein kinase C. Given that phosphorylation of transcription factors can be an important mechanism mediating transcriptional regulation (Whitmarsh (2000)), perhaps this is evidence in favour of functional consequences of this amino acid variation within humans, possibly affecting protein function related to fine orofacial movements (Enard (2002)). This links closely with the disrupted orofacial movements displayed in the phenotype of the KE family. However, this research alone is not enough to warrant any level of causal relationship between this mutation and language in humans, nor does it prove there are functional consequences to the mutations. Interestingly, the same substitution has occurred independently in bat species (Li et al 2007), meaning that it cannot account for any functions of FOXP2 specific to humans alone. Additionally if either human specific amino acid change was responsible for vocal communication we would expect to find one or both in other taxa of vocal learning mammals, but research has proved neither is present in the whale (Zhang (2002)) or the dolphin (Webb et al, 2005), and so no definite relationship between FOXP2 and vocal learning in the human can be concluded.
Given the evidence that FOXP2 is implicated in the acquisition of spoken language in humans, and that there are human specific amino acid changes in exon 7, several studies have investigated the pattern of expression of FOXP2 in other species.
High degree of conservation in expression patterns in …. suggest it may have a more general role, which is clearly vital given the level of conservation of FOXP2 across species. As a result, perhaps functional studies can give more info about effect of human AA substitutions in other animals (humanisation studies). (enard)