By Sharon Kingman

BioWorld International Correspondent

LONDON ¿ A doorway into the molecular pathways that control our ability to talk and express our thoughts has opened, with the identification of a gene that plays an important role in speech and language.

Anthony Monaco, director of the Wellcome Trust Centre for Human Genetics at the University of Oxford in the UK, told BioWorld International that the FOXP2 gene is the first to be conclusively linked to an aspect of human cognition. ¿This discovery is an important landmark for the field of cognitive genetics because it is our first entry point into the brain developmental pathway which culminates in speech and language,¿ he said.

Monaco, together with colleagues in Oxford and at the Institute of Child Health in London, report their finding in a letter to Nature titled ¿A forkhead-domain gene is mutated in a severe speech and language disorder.¿

Commenting on the paper in a News and Views article titled ¿Talk of genetics and vice versa,¿ Steven Pinker, at the Massachusetts Institute of Technology in Cambridge, Mass., noted that Charles Darwin himself speculated that the ability to speak is inherited. In 1871, Darwin wrote: ¿Man has an instinctive tendency to speak, as we see in the babble of our young children, while no child has an instinctive tendency to bake, brew or write.¿ Pinker added: ¿Darwin¿s observation has just been supported in a way he could not have dreamed of, with the discovery . . . of a gene that is mutated in a disorder of speech and language.¿

The search for the gene reported in the Nature letter, which has Cecilia S.L. Lai and Simon E. Fisher of the Wellcome Trust Centre as its joint first authors, came about as a result of studying the KE family, many of whose members are unable to speak normally. Those affected find it difficult to use the correct grammar, and struggle to learn language skills that most people pick up without effort. They also have problems in producing the fine motor movements of the tongue, lips and mouth that are required in order to produce speech. People unfamiliar with the family find it difficult to understand what they are saying.

The KE family, whose members include three generations, were identified by the geneticist Jane Hurst, one of the authors of the Nature letter, and described by her in a paper published in 1990. In 1997, she and the Oxford group began to collaborate on a project to track down the gene.

¿We could see that the condition was caused by a single gene, which was quite amazing, because every single affected member of the family had a very small region of chromosome 7 in common,¿ Monaco said.

By 1998 they had narrowed down the region responsible to a segment of DNA about 6 or 7 megabases long. The Human Genome Project had sequenced the area and the team could see that it included about 70 genes. They made a ¿hit list¿ of which ones to study first, based on what they knew of these genes, such as whether they were expressed in the brain.

One year later, they had sequenced 10 of these genes in affected members of the KE family. They had found no mutations ¿ and there were still 60 genes to go.

At this point, Hurst saw a new patient in her clinic who she realized had a very similar phenotype to the affected members of the KE family. She ordered a check on this young boy¿s chromosomes, which identified a translocation on chromosome 7.

Monaco said, ¿We mapped the disrupted region at the molecular level and it mapped to the critical interval of the KE family.¿ The gene, they found, was called FOXP2 (also known as SPCH1). From its characteristics, it was clear that it was a member of the family known as forkhead transcription factors. Transcription factors are proteins that bind to DNA to turn other genes on and off.

Further analysis showed that the KE family had a point mutation in FOXP2 that changed an amino acid at a point where the transcription factor should bind to DNA.

Monaco and his colleagues now plan to find out more about what the FOXP2 gene product does. They are studying exactly where in the brain it is expressed during fetal development.

¿We have no idea what genes it acts on,¿ Monaco said. ¿The forkhead transcription factor family has been implicated in many other developmental disorders in mouse and humans affecting different organs. In almost every case, the disorder develops when one gene is lost, so that protein levels fall to 50 percent of normal, so clearly having the right amount of protein is crucial to development.¿

They intend to study knockout mice that lack the gene, as well as heterozygote animals, which mimic the human heterozygote condition. They are also intrigued to compare the FOXP2 gene in humans with that of nonhuman primates. ¿Since humans are the only species to have language,¿ Monaco said, ¿we want to see if the gene evolved faster when it reached humans.¿