Genes and disease: a molecular jigsaw puzzle

The promise of the human genome project was that once we knew the sequence of 3 billion DNA ‘letters’ that encode a human being, we would be able to find the variant ‘spellings’ underlying a huge range of common and rare diseases. Recent years have seen a flourishing of technologies that enable researchers to interrogate the DNA of patients fast and accurately, and of databases that catalogue variation in human genes. Numerous variants have been found that map to particular conditions more often than not. Discovering how those variants lead to disease, and using that knowledge to develop treatments, has proved much more difficult. But scientists at the Wellcome Trust Centre for Human Genetics (WTCHG) are making steps in the right direction.

It was a particular triumph for George Ebers, Action Research Professor in the Department of Clinical Neurology, when he and his colleagues published a paper in February showing how genes and environment might conspire to cause multiple sclerosis. MS is a relatively common disease of the nervous system that affects adults (women more often than men), particularly those of white Northern European descent. It develops when the body’s immune system attacks the insulating layer that surrounds nerve fibres in the brain and spinal cord, eventually destroying their capacity to transmit signals. Those with an affected family member have a much higher risk of developing the disease, suggesting a genetic cause, but there are also clear links to the environment. It is more common the nearer you live to either pole: the rate in Scotland, for example, is three times the rate in England and Wales. The geographical distribution suggests that exposure to sunlight might be a factor. Without sunlight on the skin, the body cannot make vitamin D, an essential nutrient lacking in many people’s diet.

Professor Ebers and his colleagues have been using a large database of DNA from thousands of families with MS, the Canadian Collaborative Study on Genetic Susceptibility to Multiple Sclerosis, to ask a variety of questions about its genetic and environmental causes. Like others, they have found that most of the genetic risk associated with MS is carried by a cluster of genetic variants in the region on chromosome 6 known as the major histocompatibility complex (MHC), which plays an important role in enabling the immune system to tell the tissues of its own body from foreign invaders. Professor Ebers set out to discover whether vitamin D might be influencing the activity of some of these variants. ‘It was the obvious candidate, and no one had really looked before’, he says. They found that vitamin D binds to a short DNA sequence that affects the activity of a gene variant common in Europe that carries a threefold increase in the risk of MS. People with variants of the same gene that were not associated with MS did not have the same switch sequence. ‘We’ve shown that the main environmental risk candidate – vitamin D – and the main gene region are directly linked and interact’, says Professor Ebers. Other findings suggest that vitamin D supplements might be an effective means of preventing MS, an effect that could be sustained through succeeding generations.

Professor Anthony Monaco of the Neurodevelopmental and Neurological Disorders Group at WTCHG is taking a similar approach to a very different condition. Autism is a developmental disorder that occurs early in childhood and is strongly genetically determined: in 90 per cent of identical twin pairs where one twin is affected with autism, the other will be also have an autistic spectrum disorder. Because it is so heritable, Professor Monaco initially believed that he would soon discover a small number of gene variants with large effects. But even with access to DNA from an international collection of 3,000 families with an autistic member, it has not turned out to be that easy. ‘We now think there are multiple genes involved’, he says. ‘They won’t all be involved in each individual, but overall there could be hundreds of genes.’

Each one of these could supply a small piece of the puzzle of what has gone wrong in the brains of children with autism, and in April Professor Monaco and his colleagues fitted another piece. Taking a closer look at a region on chromosome 7 that had previously been linked to autism, they found a new set of variants in a gene called Dock4 that were associated with increased risk. Although variants in Dock4 have only a small overall effect on autism susceptibility, they contribute to a picture of autism as a problem in the formation of connections in the brain early in development. Like several other candidate genes, Dock4 plays a role in making the initial contacts that establish the brain’s network of synapses. ‘That does give us a focus for looking at the biological basis of the condition’, says Monaco.’

Other genes that have been linked to autism appear to play a similar developmental role. But the link between gene and disease may not be straightforward. ‘The outcome may be influenced by other genetic or environmental factors’, he says. ‘It’s complex to make a brain – if you make a perturbation early on, the outcome can be quite different.’

Many of the variants that have been discovered in children with autism are not simply variant spellings but editing errors known as copy number variations. These occur when chromosomes exchange material and leave the cell with one or three copies of a gene (or part of a gene) instead of the usual two. Professor Monaco and his colleagues are currently working to develop tests for copy number variations that might contribute to the clinical care of autistic children. ‘If you found a copy number variation that was important in a child with some autistic traits, you’d know that there was a connection you could use in counselling’, he says. ‘It’s never going to be an absolute genetic diagnosis. But you could put a risk figure on it for younger siblings, and watch them carefully in case there was a need for early intervention.’

Both Professor Monaco and Professor Ebers agree that international collaboration has been vital to their work. ‘We could never have achieved the number of samples that we have unless a large group of individuals decided to work together’, says Monaco. For this kind of jigsaw puzzle, the larger the table-top, the better.