HGP is 10: more than just genes

In the last of a series of articles marking the 10th anniversary of the first draft human genome, OxSciBlog talks to Professor George Ebers about what we know now about the genetics involved in multiple sclerosis.

Since the sequencing of the human genome, our understanding has greatly increased of the subtle interplay between our genes, our lifestyles, and all that we encounter and are exposed to as we grow up and develop.

We know more about the interactions between our genes, the intricate control systems within the body that switch them on and off, and have some evidence of the way outside factors can link to our genes and make us more susceptible to some conditions.

The idea that we are at the mercy of our genes, that all we are is hard-written into our DNA – if it ever truly held sway – has long gone. It is clear that genetic and lifestyle or ‘environmental’ factors are both important in many complex diseases, from heart disease to obesity and mental health conditions.

Multiple sclerosis, the complex and devastating neurological disease which leads to progressive loss of function in the nervous system, is one condition which offers a clear illustration of this.

Genes linked to MS
Professor George Ebers of the Department for Clinical Neurology says: ‘The sequencing of the human genome has provided a vital tool for understanding the interactions between genes and the environment, how “nature” and “nurture” are bound up together, in many human diseases such as multiple sclerosis.

Over the past 15 years and more, George Ebers has amassed a large database of genetic and lifestyle information from Canadian patients with multiple sclerosis and their families. This has proved to be very powerful in answering many questions about MS.

It’s been known for a long time that multiple sclerosis is associated with the major histocompatibility complex (MHC), a big player in the human immune system. Work by George Ebers and colleagues, though, has demonstrated that the picture is more complicated than originally thought.

They pinpointed the single strongest genetic effect in MS to a variation in one gene called HLA-DRB1 that is involved in the MHC. This is a highly variable genetic region, but one variant that may be present, called HLA-DRB1*15, is strongly linked to susceptibility to the condition.

Unfortunately it’s not quite as simple as having one or two copies of this genetic variant increases your risk of MS by a certain amount. Other variations present in this tight cluster of genes appear to modify further a person’s risk of developing MS. They could increase or decrease the risk associated with HLA-DRB1*15. Further genetic variations in this region appear to affect the severity of the condition where it develops.

It’s a complex picture of genes influencing the effects of other genes – a phenomenon called epistasis. You can’t just consider the effects of each gene individually in isolation.

Getting more sun
But there’s yet more to it than just genes. Where you live in the world has an effect. The further you are from the equator, the greater is your risk of MS. That is, there are more cases in Edinburgh than Marseilles and more in Sydney than North Queensland.

The evidence is accruing that the amount of sunlight people get influences the number of cases of MS that are seen. Sunlight helps the body produce vitamin D, and those populations with lower levels of the vitamin do have more cases of MS. This and other potential health benefits has led to suggestions in Scotland (where rates of MS are the highest in the world) of widely distributing vitamin D supplements.

The group has also identified a modest ‘month of birth effect’, where babies born in May have slightly higher risk of MS than those born in November. One possible reason? Mothers who are pregnant over winter months see less sun and have lower vitamin D levels.

Last year, George Ebers, Julian Knight and colleagues made a direct connection between these observations and the genetics of MS. They showed that vitamin D binds to a section of DNA next to the important genetic region for MS – HLA-DRB1 – and alters the amount of protein that’s produced from the gene.

Here is a route by which genes and the environment (the amount of sunlight a person experiences and their vitamin D levels) interact, and where they are both known to influence MS risk. How this process increases MS risk is unknown, but the finding suddenly allows new studies to investigate.

Enter epigenetics
However, George Ebers thinks this is only one way in which genes and environmental factors interact in multiple sclerosis. ‘Epigenetics – an emerging field that moves beyond the sequence of the DNA code alone to consider other changes in the chemical and physical structure of our genes – is turning out to be the most important of these gene-environment interactions,’ he says.

There are a number of processes occurring on a DNA molecule that can switch genes on and off, controlling their effect. These modifications can be added or removed, so can be temporary, and do not involve changes in DNA sequence. Jane Mellor has described many of these processes previously on OxSciBlog and the effects they can have in disease, in growth and development and across generations.

Epigenetics adds yet another level of complexity, and geneticists are increasingly moving away from considering DNA sequence alone to include these additional chemical markers on the DNA.

Epigenetics is likely to be behind what are some otherwise surprising observations in multiple sclerosis. Data from George’s Canadian study has revealed that mothers tend to contribute more to disease development than fathers. Comparing where nieces and nephews are affected and where there’s also an uncle or aunt with the condition shows this effect. The parent connecting the niece/nephew through the family tree to the uncle/aunt is found to be more likely the mother than the father.

His team are now looking at how the genetic region important for MS might be chemically modified, and how these epigenetic markers get passed down the generations. Such epigenetic changes to the DNA might occur in response to environmental factors to predispose people to disease, perhaps they could occur in the womb for example. Even more confusingly, the genetic trait mysteriously disappears after two or three generations. An article by Michael Gross in a recent issue of Oxford Today explains it like this:

'These epigenetic markers can remain on a gene long enough to be passed on to the next generation or two, but they don't last forever. Studying large families in North America descended from one European and one Native American parent - which is of particular interest, as the MS susceptibility trait is virtually unheard of among Native Americans - Ebers' group found that the disease hit two generations with the predicted pattern, but then disappeared in the third.

Ebers says his group has now shown three ways in which the environment interacts with the genes to influence MS risk. 'Firstly, gene expression in the main genetic region for MS risk is regulated by vitamin D. Secondly, the month of birth effect maps to the same genetic region, and finally we have shown that epigenetic modifications determining MS risk take place in this same region.'

These findings, says Ebers, confirm that the 'genetic cause' that scientists were hunting for so long, really reflects environment-gene interaction, an epigenetic pattern that is passed on for one or two generations but then tends to disappear. 'Multiple sclerosis is the first common disorder with an important epigenetic mechanism', Ebers concludes.'

To investigate the epigenetic changes that are having an effect on MS will be a challenge, however. New experimental techniques will be required to identify and pinpoint those extra chemical or structural modifications to the DNA that are important in disease, says George Ebers.

‘We can recognise clues from genetic epidemiological studies that epigenetics is playing a role in disease, and it is possible to identify disease-specific epigenetic markers. But the pressing challenge in this field is to come up with efficient and reliable sequencing methods for detecting the key epigenetic changes.’

He is confident this will happen. ‘We can expect many new insights from epigenetics in the coming years, in areas from cancer to multiple sclerosis, continuing to build on the knowledge we have gained from the human genomics studies of the last ten years,’ George Ebers says.

‘My hopes are very high and I believe the understanding of epigenetics will represent and embody the most important contributions genetics has to offer. Epigenetics is the interface between genetics and the environment and its understanding holds the key to preventing many common diseases.'