Research Area:	Genetics and Genomics
Technology Exchange:	Bioinformatics, Cell sorting, Chromosome mapping, ES cell / homologous recombination, Immunohistochemistry, In situ hybridisation, Protein interaction, Transcript profiling, Microscopy (Confocal) and Transgenesis
Keywords:	speech and language, FOXP2 gene, functional genomics, human evolution, neurons and central nervous system

We are pioneering new ways of uncovering brain pathways that are important for speech and language development. Our research strategy is based on the idea that genes implicated in language disorders can provide "molecular windows" into neural mechanisms contributing to human communication. People who carry abnormalities in a gene known as FOXP2 have difficulties with learning and producing the complicated sequences of mouth movements needed for speech, accompanied by impaired language and grammar. The FOXP2 gene encodes a conserved regulatory protein that switches on and off other genes in the developing and mature brain. FOXP2 appears to help regulate a subset of neuronal circuits in a wide range of non-speaking vertebrates, but its role may have been modified during human evolution. The discovery of FOXP2 represented the first time that a gene has been clearly linked to speech and language development.
Taking FOXP2 as a starting point, complementary approaches for uncovering the origins and bases of speech and language pathways are underway. These include identification and study of people who have speech/language deficits as a consequence of FOXP2 mutation, investigations of gene function in neurons grown in the laboratory, and exploration of the ways that this gene impacts on the development of the mammalian central nervous system. State-of-the-art functional genomic techniques (including high-throughput gene expression profiling and chromatin-immunoprecipitation) are used to identify other elements of the pathways that FOXP2 regulates in living cells. Our research also benefits from a strong multidisciplinary remit, integrating data from diverse fields including psychology, neuroscience, genetics, developmental biology and evolutionary anthropology.

There are no collaborations listed for this principal investigator.

Fisher SE, Francks C, Marlow AJ, MacPhie IL, Newbury DF, Cardon LR, Ishikawa-Brush Y, Richardson AJ, Talcott JB, Gayán J, Olson RK, Pennington BF, Smith SD, DeFries JC, Stein JF, Monaco AP. 2002. Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia. Nature genetics, 30 (1), pp. 86-91. Read abstract | View on PubMed

Developmental dyslexia is defined as a specific and significant impairment in reading ability that cannot be explained by deficits in intelligence, learning opportunity, motivation or sensory acuity. It is one of the most frequently diagnosed disorders in childhood, representing a major educational and social problem. It is well established that dyslexia is a significantly heritable trait with a neurobiological basis. The etiological mechanisms remain elusive, however, despite being the focus of intensive multidisciplinary research. All attempts to map quantitative-trait loci (QTLs) influencing dyslexia susceptibility have targeted specific chromosomal regions, so that inferences regarding genetic etiology have been made on the basis of very limited information. Here we present the first two complete QTL-based genome-wide scans for this trait, in large samples of families from the United Kingdom and United States. Using single-point analysis, linkage to marker D18S53 was independently identified as being one of the most significant results of the genome in each scan (P< or =0.0004 for single word-reading ability in each family sample). Multipoint analysis gave increased evidence of 18p11.2 linkage for single-word reading, yielding top empirical P values of 0.00001 (UK) and 0.0004 (US). Measures related to phonological and orthographic processing also showed linkage at this locus. We replicated linkage to 18p11.2 in a third independent sample of families (from the UK), in which the strongest evidence came from a phoneme-awareness measure (most significant P value=0.00004). A combined analysis of all UK families confirmed that this newly discovered 18p QTL is probably a general risk factor for dyslexia, influencing several reading-related processes. This is the first report of QTL-based genome-wide scanning for a human cognitive trait. Hide abstract

Fisher SE, Francks C, McCracken JT, McGough JJ, Marlow AJ, MacPhie IL, Newbury DF, Crawford LR, Palmer CG, Woodward JA, Del'Homme M, Cantwell DP, Nelson SF, Monaco AP, Smalley SL. 2002. A genomewide scan for loci involved in attention-deficit/hyperactivity disorder. American journal of human genetics, 70 (5), pp. 1183-96. Read abstract | View on PubMed

Attention deficit/hyperactivity disorder (ADHD) is a common heritable disorder with a childhood onset. Molecular genetic studies of ADHD have previously focused on examining the roles of specific candidate genes, primarily those involved in dopaminergic pathways. We have performed the first systematic genomewide linkage scan for loci influencing ADHD in 126 affected sib pairs, using a approximately 10-cM grid of microsatellite markers. Allele-sharing linkage methods enabled us to exclude any loci with a lambda(s) of > or =3 from 96% of the genome and those with a lambda(s) of > or =2.5 from 91%, indicating that there is unlikely to be a major gene involved in ADHD susceptibility in our sample. Under a strict diagnostic scheme we could exclude all screened regions of the X chromosome for a locus-specific lambda(s) of >/=2 in brother-brother pairs, demonstrating that the excess of affected males with ADHD is probably not attributable to a major X-linked effect. Qualitative trait maximum LOD score analyses pointed to a number of chromosomal sites that may contain genetic risk factors of moderate effect. None exceeded genomewide significance thresholds, but LOD scores were >1.5 for regions on 5p12, 10q26, 12q23, and 16p13. Quantitative-trait analysis of ADHD symptom counts implicated a region on 12p13 (maximum LOD 2.6) that also yielded a LOD >1 when qualitative methods were used. A survey of regions containing 36 genes that have been proposed as candidates for ADHD indicated that 29 of these genes, including DRD4 and DAT1, could be excluded for a lambda(s) of 2. Only three of the candidates-DRD5, 5HTT, and CALCYON-coincided with sites of positive linkage identified by our screen. Two of the regions highlighted in the present study, 2q24 and 16p13, coincided with the top linkage peaks reported by a recent genome-scan study of autistic sib pairs. Hide abstract

Fisher SE, DeFries JC. 2002. Developmental dyslexia: genetic dissection of a complex cognitive trait. Nature reviews. Neuroscience, 3 (10), pp. 767-80. View on PubMed

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), pp. 519-23. Read abstract | View on PubMed

Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or neurological impairment and despite adequate intelligence and opportunity. Although studies of twins consistently indicate that a significant genetic component is involved, most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait. Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5). We also identified an unrelated individual, CS, in whom speech and language impairment is associated with a chromosomal translocation involving the SPCH1 interval. Here we show that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS. In addition, we identify a point mutation in affected members of the KE family that alters an invariant amino-acid residue in the forkhead domain. Our findings suggest that FOXP2 is involved in the developmental process that culminates in speech and language. Hide abstract

Lai CS, Gerrelli D, Monaco AP, Fisher SE, Copp AJ. 2003. FOXP2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder. Brain : a journal of neurology, 126 (Pt 11), pp. 2455-62. Read abstract | View on PubMed

Disruption of FOXP2, a gene encoding a forkhead-domain transcription factor, causes a severe developmental disorder of verbal communication, involving profound articulation deficits, accompanied by linguistic and grammatical impairments. Investigation of the neural basis of this disorder has been limited previously to neuroimaging of affected children and adults. The discovery of the gene responsible, FOXP2, offers a unique opportunity to explore the relevant neural mechanisms from a molecular perspective. In the present study, we have determined the detailed spatial and temporal expression pattern of FOXP2 mRNA in the developing brain of mouse and human. We find expression in several structures including the cortical plate, basal ganglia, thalamus, inferior olives and cerebellum. These data support a role for FOXP2 in the development of corticostriatal and olivocerebellar circuits involved in motor control. We find intriguing concordance between regions of early expression and later sites of pathology suggested by neuroimaging. Moreover, the homologous pattern of FOXP2/Foxp2 expression in human and mouse argues for a role for this gene in development of motor-related circuits throughout mammalian species. Overall, this study provides support for the hypothesis that impairments in sequencing of movement and procedural learning might be central to the FOXP2-related speech and language disorder. Hide abstract

MacDermot KD, Bonora E, Sykes N, Coupe AM, Lai CS, Vernes SC, Vargha-Khadem F, McKenzie F, Smith RL, Monaco AP, Fisher SE. 2005. Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. American journal of human genetics, 76 (6), pp. 1074-80. Read abstract | View on PubMed

FOXP2, the first gene to have been implicated in a developmental communication disorder, offers a unique entry point into neuromolecular mechanisms influencing human speech and language acquisition. In multiple members of the well-studied KE family, a heterozygous missense mutation in FOXP2 causes problems in sequencing muscle movements required for articulating speech (developmental verbal dyspraxia), accompanied by wider deficits in linguistic and grammatical processing. Chromosomal rearrangements involving this locus have also been identified. Analyses of FOXP2 coding sequence in typical forms of specific language impairment (SLI), autism, and dyslexia have not uncovered any etiological variants. However, no previous study has performed mutation screening of children with a primary diagnosis of verbal dyspraxia, the most overt feature of the disorder in affected members of the KE family. Here, we report investigations of the entire coding region of FOXP2, including alternatively spliced exons, in 49 probands affected with verbal dyspraxia. We detected variants that alter FOXP2 protein sequence in three probands. One such variant is a heterozygous nonsense mutation that yields a dramatically truncated protein product and cosegregates with speech and language difficulties in the proband, his affected sibling, and their mother. Our discovery of the first nonsense mutation in FOXP2 now opens the door for detailed investigations of neurodevelopment in people carrying different etiological variants of the gene. This endeavor will be crucial for gaining insight into the role of FOXP2 in human cognition. Hide abstract

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), pp. 869-72. Read abstract | View on PubMed

Language is a uniquely human trait likely to have been a prerequisite for the development of human culture. The ability to develop articulate speech relies on capabilities, such as fine control of the larynx and mouth, that are absent in chimpanzees and other great apes. FOXP2 is the first gene relevant to the human ability to develop language. A point mutation in FOXP2 co-segregates with a disorder in a family in which half of the members have severe articulation difficulties accompanied by linguistic and grammatical impairment. This gene is disrupted by translocation in an unrelated individual who has a similar disorder. Thus, two functional copies of FOXP2 seem to be required for acquisition of normal spoken language. We sequenced the complementary DNAs that encode the FOXP2 protein in the chimpanzee, gorilla, orang-utan, rhesus macaque and mouse, and compared them with the human cDNA. We also investigated intraspecific variation of the human FOXP2 gene. Here we show that human FOXP2 contains changes in amino-acid coding and a pattern of nucleotide polymorphism, which strongly suggest that this gene has been the target of selection during recent human evolution. Hide abstract

Fisher SE, Marcus GF. 2006. The eloquent ape: genes, brains and the evolution of language. Nature reviews. Genetics, 7 (1), pp. 9-20. Read abstract | View on PubMed

The human capacity to acquire complex language seems to be without parallel in the natural world. The origins of this remarkable trait have long resisted adequate explanation, but advances in fields that range from molecular genetics to cognitive neuroscience offer new promise. Here we synthesize recent developments in linguistics, psychology and neuroimaging with progress in comparative genomics, gene-expression profiling and studies of developmental disorders. We argue that language should be viewed not as a wholesale innovation, but as a complex reconfiguration of ancestral systems that have been adapted in evolutionarily novel ways. Hide abstract