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The FOXP2 story

28/4/03. By Jane Itzhaki

A single family with speech abnormalities may hold one of the keys to the origin of human culture.

For most of us, learning to speak in our mother tongue is so natural and instinctive that we need no formal instruction. And 'natural' seems to equate, at least in part, to 'in our genes', as studies of identical and non-identical twins to tease out the genetic and environmental components of this trait have shown. These are the genes that set us apart from our closest primate relatives and equip us with the unique combination of physical, articulatory and neurological features necessary for spoken language again.

Dr Simon Fisher, a Royal Society Research Fellow at the Wellcome Trust Centre for Human Genetics in Oxford, was studying for his PhD when he came across Steven Pinker's book, 'The Language Instinct', which speculates on the genetic basis of speech development. He was intrigued by Pinker's ideas.

Now, almost ten years later, he is setting up a research group to look at the molecular basis of speech and language development. His research revolves around a key discovery made in the laboratory of Professor Tony Monaco, director of the centre in Oxford – that of the first gene shown to be necessary for the acquisition of spoken language.

Gene hunting

The trail to the new gene, known as FOXP2, began in 1996 when Professor Monaco was approached by clinicians working at the Institute of Child Health in London who had been treating a unique family with a severe speech and language disorder (the 'KE' family).

Unlike all the other families with speech and language disorders that Professor Monaco's group was studying at the time – in which the disorder is inherited in a complicated way due to the interplay of many different genetic factors – the KE family's disorder was inherited in a simple fashion and as the result of a defect in a single gene.

About half the family, which spans three generations, suffer from the disorder.

"They have trouble controlling fine movements in the lower half of their face, and this gives them problems when making the complicated sounds necessary for speech," explains Dr Fisher. In addition to this problem, they have a variety of problems in both spoken and written language and grammar. "For example," says Dr Fisher, "if you ask them to write down as many words as they can think of beginning with a particular letter, they don't do very well – and that defect is clearly not related to articulation."

Dr Fisher and Cecilia Lai, a colleague in Professor Monaco's laboratory, embarked on the hunt for the defective gene in the KE family and successfully tracked it down with the help of molecular signposts or 'markers' to a region on chromosome 7 containing between 50 and 100 genes. "We went through every candidate gene in the region relating to brain function," says Dr Fisher, "looking through 20 and keeping another 50 or so on the backburner." Then the trawl was cut short by a stroke of luck.

"We were on the look-out for individuals with a speech disorder who had a chromosomal abnormality," explains Dr Fisher, "because there is a history of these being involved in the mapping of single gene disorders such as Duchenne muscular dystrophy."

Quite in's group by a local clinician who noted the strong resemblance between her patient’s speech problems and those of the unrelated KE family. The problems in the patient, known as 'CS', were associated with a chromosomal abnormality in which large segments from the ends of two different chromosomes had swapped around. One of the chromosomes involved was chromosome 7 and the breakpoint appeared to be close to the region implicated in the KE family.

Realising that the gene search in the KE family and in CS had fortuitously converged, the group quickly pressed on with microscopic techniques to narrow down the breakpoint. They alighted on a partially characterised gene, subsequently named FOXP2.

"It was exciting," remarks Dr Fisher, "but we initially sequenced the known half of the gene and the mutation wasn’t in there."

However, once the rest of the gene was pulled out and the sequence completed, the group quickly identified a single base-pair mutation in the sequence of the gene that was specific to affected members of the KE family. The gene responsible for the speech defect in both the KE family and in CS had been caught.

Inside FOXP2

Dr Fisher admits that he was initially sceptical when the group fished out the gene and mutation. "I thought it was going to be difficult to convince people," he says.

But there turned out to be a precedence for mutations in the family of genes to which FOXP2 belongs – the 'forkhead' family of transcription factors. Transcription factors switch on and off other genes in the cell and are key players in directing cell specialisation and pattern formation during development. In fact, the forkhead family acquired its rather unusual name thanks to the bizarre spiked-head structures found in fruit fly embryos, which had mutations in the original forkhead gene.

In humans too, mutations in several genes in the forkhead family have been identified as the cause of certain developmental disorders such as congenital glaucoma and immune deficiency.

The mutation found in FOXP2 in the KE family lies in a critical region of the encoded protein, leaving the cell reliant on just one copy of the normal gene. Though studies in mice indicate that FOXP2 may also be important in the development of the gut, heart and lungs, it seems that these organs can get by with a half-dose of FOXP2 – in the KE family, these organs function normally – whereas the brain appears to be particularly sensitive to lower levels of FOXP2.

The discovery of FOXP2 is a breakthrough for researchers looking for a handle on the molecular components of speech and language development. As Dr Fisher points out, "There aren’t really any convincing molecular biology theories as starting points for speech and language disorders."

His group is embarking on a variety of studies to try and elucidate the role of FOXP2 during development. "We need to have an idea of some of the targets FOXP2 is switching on and off in neural tissue," which in a perfect world would be those already implicated in brain patterning.

Together with collaborators at the Institute of Child Health, he is also looking to see when and where the FOXP2 gene itself is switched on in early brain development during mouse and human embryogenesis. He will be comparing these results with those from in vivo imaging of the brain to see which areas are important for the acquisition of spoken language.

"One of the key questions is whether we can line up the molecular data with regions implicated in adults from imaging," says Dr Fisher. The picture building up is that FOXP2 is only active in specific regions of the brain and is therefore likely to be having its effect by directing the fate of certain types of neurons during development.

Origins

Perhaps one of the most fascinating lines of research opened up by the discovery of FOXP2 is the evolutionary origins of speech and language. "FOXP2 stands out," says Dr Fisher. "It's very unusual from an evolutionary point of view."

With Svante Pääbo's group in Leipzig, he has found that just two amino acids distinguish the FOXP2 protein in humans from the protein in our closest relative, the chimpanzee, and that these amino acids have persisted unchanged in modern humans. FOXP2 appears to have been selected during recent human evolution – sometime within the last 200 000 years.

The estimate of when the human-specific form of FOXP2 became established in the population is intriguing as it is around the time of a population growth of modern humans believed to be driven by the appearance of a more proficient spoken language, probably some 50 000 years ago. Could it be that the tiny changes in the FOXP2 gene helped to set our distant ancestors on the evolutionary trajectory that has led to modern human culture?

Further reading

Dr Simon Fisher research page

Lai et al. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature. 2001 Oct 4;413(6855):519-23. Abstract

Enard W et al. Molecular evolution of FOXP2, a gene involved in speech and language. Nature. 2002 Aug 22;418(6900):869-7. Abstract

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