Genes as windows into human biology

Genes as windows into human biology

Which molecular factors underlie human language and how do they explain its origins and evolution? Professor Simon E. Fisher – the co-discoverer of FOXP2, the first gene to have been implicated in this unique aspect of human biology – peers into the genetic ‘black box’ of speech and language.

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Simon E. Fisher is Professor of Language and Genetics at the Donders Institute and director of a new department at the Max Planck Institute for Psycholinguistics. This department was established at the end of 2010 with the goal of using genes to provide insight into the biological basis of speech and language. Prof. Fisher and his colleagues are taking advantage of the latest innovations in molecular methods to discover how our genome helps us learn to speak. ‘We want to reveal the DNA variations that affect our extraordinary ability to communicate in a complex way,’ he explains. ‘This is a novel approach to the enigma of spoken language, but one that can be remarkably effective. We have already gained exciting insights by studying children who mysteriously fail to develop proficiency in this area.’

Despite the extreme complexity of the task, most children learn their native language almost effortlessly, without needing to be formally taught. What role does our genetic makeup play in language learning? ‘Initial clues come from pinpointing susceptibility genes that contribute to language impairments,’ Prof. Fisher says. ‘FOXP2 was the first example of this. We identified the gene in 2001 when I was at Oxford University, and it sparked off a whole new wave of research.’

Family studies

‘In the mid-1990s, when I was a postdoctoral researcher at Oxford,’ he continues, ‘my projects involved gene hunting in families with specific language impairments or reading disabilities. These disorders typically have complex genetic underpinnings involving several – perhaps many – different genes. But then we started working with an unusual family, known as the KE family, which was originally identified by our collaborators in London. Half of the family – 15 people across three generations – were affected by problems which revealed a surprisingly simple pattern of inheritance.’ Prof. Fisher and his colleagues tracked the cause of the disorder to part of chromosome 7 and eventually zeroed in on the mutation responsible, which disrupted FOXP2. ‘Family members who carry this mutation all have severe problems with learning to make sequences of mouth movements that are important for speech, accompanied by further difficulties in language production and understanding. Just a single letter of DNA is affected, a G mutated to an A. That’s enough to change the shape of the protein which FOXP2 encodes in a critical way that prevents it from working properly.’

Could this family be unique – Prof. Fisher and his colleagues wondered – or would mutations of FOXP2 also explain common forms of language impairment? ‘We found that it’s rather rare to have mutations in FOXP2; we now know of several other families which were similarly affected by vulnerability to disruptions of this gene. So most cases of speech and language problems remain unexplained and this is something we really want to tackle in the new department.’ Prof. Fisher is also concerned that language impairments are not sufficiently well understood in society. ‘When an individual has a problem in this area, it can make it difficult to function in the modern world, a world which is increasingly dependent on language. One of our goals is to raise awareness of the impact that these types of disorders have on people’s lives.’

Sequencing whole genomes

Meanwhile, the technology for tracking down genetic causes of disease has made enormous strides with the arrival of next-generation DNA sequencing. ‘It took a large international consortium over a decade and billions of dollars to sequence the first human genome. Now it’s possible to determine the DNA sequence of a person’s entire genome in a matter of days, at a cost of around several hundred euros.’ Prof. Fisher’s department has been collaborating with Professors Joris Veltman and Han Brunner as well as colleagues at the Human Genetics Department of Radboud University Nijmegen on sequencing whole exomes (all the protein-coding parts of the genome, comprising around 20,000 genes) in children and families with language-related impairments. But ‘while the tools for DNA sequencing have advanced dramatically, our ability to interpret genomic data is lagging behind,’ cautions Fisher. ‘Each human individual carries a great many DNA variations, most of which are benign; the big challenge in the future is to figure out which variants are functionally important.’ These issues become even more pertinent as the researchers broaden their focus beyond disorders to consider natural variations in language performance in the general population. ‘We also aim to extend our work to cases of exceptional skills, such as those of simultaneous translators and people who quickly become fluent in numerous languages.’

Peering into the black box

Simon Fisher’s department is not only interested in identifying genomic variants. ‘There’s a vast gap between DNA on the one hand and features of behaviour and cognition on the other. Speech and language are defining features of the human condition – a fundamental part of what makes us human. Yet, we still know very little about how the genome is able to build a language-ready brain and why even our closest primate ‘cousins’ appear unable to match human capabilities in this area.’ Prof. Fisher believes that genes FOXP2 provide unprecedented opportunities to look into the black box and shed light on the biological machinery that supports speech and language. Researchers in the department analyse the relationship between gene variants and function at multiple levels: in human neuron-like cells grown in the laboratory, in neural circuitry from animal models carrying gene disruptions, all the way to human brain structures and functions. Prof. Fisher was one of the initiators, together with Professors Barbara Franke, Peter Hagoort and colleagues who work in the Nijmegen Cognomics programme, which links the advent of personalised genomics to state-of-the-art brain imaging and other cutting-edge techniques used by modern neuroscientists in studies that include thousands of people.

A Darwinian view

Researchers working on another research line in the department ask how language-related genes have changed in the course of evolution and how variants of such genes spread around the world. ‘Again, FOXP2 has proved to be pretty interesting,’ he says. ‘It’s been around for a long time and is in fact one of the oldest genes, which is found in all vertebrates as far as we know. Some years ago – together with Professor Svante Pääbo’s team at the Max Planck Institute for Evolutionary Anthropology in Leipzig – we compared FOXP2 in humans to versions found in other primates. Curiously, there was evidence that the gene underwent accelerated change in the line that led to humans, after splitting from chimpanzees, which suggests its functions might have been tweaked during human evolution.’ Studies in animal models implicate the gene in motor-skill learning and auditory-motor associations. So Simon Fisher thinks that any role that FOXP2 plays in language must have been built on ancient evolutionary functions such as these. ‘It’s a Darwinian view of the emergence of language,’ he says.

Myrna Tinbergen