The European Society
of Human Genetics



Dian Donnai, President of the ESHG

Society President Dian Donnai is Professor of Medical Genetics at the University of Manchester and works in one of the biggest clinical genetics departments in the UK.  She talked to Mary Rice about her work and her vision of the future.

Dian Donnai has been working in clinical genetics for over 30 years.  "When I started in the genetics department at Manchester we had one full time doctor.   I came as a part-time, two days a week assistant, got my feet under the table, and never moved again.    At that time together with the chromosome lab we probably had 15 people; now we have nearly 300."

Clinical genetics has moved from being an obscure, number-crunching discipline to being a real part of medicine, she says.  "We celebrated this last year by changing the name of our department from the Department of Medical Genetics to the Genetic Medicine Department to reflect the fact that these days we focus on the application and relevance of genetics to mainstream medicine."

Contrary to those who say that little has been achieved in genetic medicine in the 10 years since the first human genome sequence was announced, Professor Donnai believes that there has been a considerable amount of progress.   "Of course, in evolutionary terms 10 years is next to nothing.  But during that time the changes have been enormous; we have seen the sheer power of technologies such as next generation sequencing to identify the genetic basis of rare disorders using samples from a handful of patients with the promise of many more discoveries to come from this technology, and a lot has been found out that will help us understand predisposition to complex diseases and the biological pathways involved in disease.   By understanding these complex pathways, for example, an existing drug can be taken off the shelf and considered for other diseases than the one it was intended for.  If the same pathways are disturbed in some way, the chances are that the "old" medication may work in these other diseases.    This is a big step forward from the old days when pharmaceutical companies focused on a particular disease and tried to look for compounds that might help treat that disease alone."

As a physician, Professor Donnai's focus is on the translation of research findings into the clinic particularly for diagnostic and counselling purposes.  "For someone who deals almost entirely with Mendelian genetic disease it's interesting to see that the genes involved are often actually the same genes that genome-wide association studies have identified as variants predisposing to linked common diseases.   I'm sure the two worlds - that of the Mendelian genetic doctors and that of the genome-wide association scientists - are beginning to converge.   There seem to be diseases in the middle that have elements of both, and our better knowledge of copy number variants has fed into this really nicely.   There are variants that in some people seem to cause severe learning disabilities, in other people cause late-onset psychiatric disorders such as schizophrenia, while for some people the same variants can cause epilepsy.    We need to work out whether the copy number variant is a predisposition which then needs something else to happen in one of the genes on the apparently normal chromosomes to combine together to cause the different phenotypes.  Many people are working on this at present."

But all this progress could grind to a halt if the public and health professionals are not properly prepared for it, she says.  "Patients have to be prepared for genetic testing and genetic-based therapy, and there is a big deficit in the genetic knowledge of doctors and nurses in, perhaps, the majority of European countries", she says.  "We need to address things like the educational needs of medical and nursing training, but also to involve the public more in what's going on in genetics.    This is a big challenge, and it's important to find the right way to do it."

Events such as public debates can end up very polarised, with a pro and anti speaker and little in between.   Professor Donnai believes that the best way forward is to put effort into engaging school children with genetics and particularly its potential in medicine.   "These are the professionals and the patients of the future and without preparatory educational and awareness-raising work we will encounter difficulties."

"Some people will perceive personalised medicine, where you have a genetic test to see how you would respond to a certain treatment, as health service rationing.   In fact what we are talking about here is the ability to use powerful drugs that you can be sure won't be unduly toxic in the person you give them to.    In some individuals the drugs may be very toxic, and if you can predict who will react badly you can spare them that harm.   In the old days a lot of people would have been given the powerful drug, a few would react badly to it, and then the drug would be taken off the market, whereas it could have been an extraordinarily good treatment that would have benefited many people.   This new use of genetics to predict response to treatment is alien to many patients and also many health professionals."

"There's a real mountain to climb here, and while I think the stream of technological and medical advances is fantastic, this is worthless if patients and professionals aren't prepared.   In our department we have been working with large numbers of patients for many years - many, many thousands.   Now we know them, we know their families, and we've been following them through generations.   These are the families we can work with in order to try and translate new knowledge in terms of diagnostics and of therapies to modify the progress of illness.   But we are in a privileged situation here - out there in the wider world the gaps in the knowledge of medical genetics and its potential are huge, and we must address them if we are to bring the benefits of our new knowledge to all of those who could benefit from it."

"One thing that has been really good in this respect has been many different countries working together, particularly in Europe, across lots of different initiatives.   Orphanet, for example, based in Paris but now with centres in the majority of European countries, gives access to an incredible amount of information, widely used by patients, professionals, and industry alike.   There are the networks of patient organisations and umbrella organisations in individual countries and across Europe, so there's a real partnership between patients and professionals in terms of developing things together.    And then there's the global nature of genetics that was exemplified in the Human Genome Project, but that also set the standard for big international collaborations that are not just limited to discovery, but can also be in terms of ethics and of standards, for example."
These things are really important and also fascinating, she says.  "That's why I love being in genetics - for the past 30 years I have never been bored, not for one minute.   And I know that I will go on being fascinated by my work for a long time to come."

Sir Alex Jeffreys, ESHG Award Lecturer 2010

Professor Sir Alec Jeffreys FRS is the Royal Society Wolfson Research professor in the Department of Genetics at the University of Leicester, England, UK.   He will be giving the ESHG AWARD Lecture/speaking in the Plenary Session 5 at ESHG 2010 on Tuesday, June 15, 2010 at 14.00 hrs.

He talked to Mary Rice about his view of the future of genetics, and his recent work.

Even in genetics, at the end of the day there's nothing new under the sun, says Alec Jeffreys.  "A paper published recently reviewed the ability of genome-wide association studies to identify loci involved in determining stature, and working how much variation in stature could be predicted from this.   It was about 10-15%.   But well over 100 years ago Francis Galton could do a prediction of about 60% by looking at parent-child regression, so looked at in that way we've gone backwards rather than forwards with GWAS, though I accept that this is not entirely fair!"

Genome-wide surveys, which held out such great hopes at the beginning, has in fact turned out to be a little disappointing, he says.  "One of the great hopes for GWAS was that, in the same way that huge numbers of Mendelian disorders were pinned down at the DNA level and the gene and mutations involved identified, it would be possible to simply extrapolate from single gene disorders to complex multigenic disorders.    That really hasn't happened.   Proponents will argue that it has worked and that all sorts of fascinating genes that predispose to or protect against diabetes or breast cancer, for example, have been identified, but the fact remains that the bulk of the heritability in these conditions cannot be ascribed to loci that have emerged from GWAS, which clearly isn't going to be the answer to everything."

A new approach is needed, he says. "To go further we need to start off with  whole genome sequences on very large cohorts of people and couple this with a lot of bioinformatics linking with information about tissue-specific expression profiling, epigenetics, epigenome scans, etc..   Trying to integrate all this information and tease out its meaning is essentially a systems biology approach, but again there's no guarantee that it will succeed."

He points to recent work on the genomic sequencing of a pair of monozygous twins discordant for multiple sclerosis.  "The great hope was that, if you sequenced the entire genome, maybe you could pick up a mutation that occurred after conception and link it to one of the twins.  But having done the whole genome - or as much of it as can be done and interpreted with existing technology - absolutely nothing came through.  Despite our best intentions, things don't always work out as we hope they will."

A big growth area in genomics in the years to come will be genealogy, he believes.  "I think this will be the field where people will feel most comfortable with accessing their personal genomic information.   I don't believe that most people will want to rummage around in their genome looking for medical information, given the guaranteed certainty that genetic defects will be found.   But everyone is interested in their family history and I can see the time in the not too distant future where having a mouth swab and a personal genome sequence could be a fun Christmas present."

This would involve issues of database regulation and confidentiality that haven't begun to be explored yet, he says, and it would be particularly complicated because in many cases the private databases providing the service would not even be in the country of the person who has provided the DNA sample.  Not to mention the unwelcome discovery of relatives you would rather not have known about.   "But if sequencing got so cheap that everyone could buy into a database, and the entire population were sequenced, then you could put together an entire family tree of that population."

Once again, though, sometimes the old ways of doing things can be just as effective.  "After appearing on a popular UK radio programme I was contacted by someone I had never heard of who thought she might be my cousin.    And she was.  There was no need for any DNA-based genealogy - we could be certain that we were related just by recounting our respective family histories."

Jeffreys will be telling the conference about his personal journey through genetics.   He wants to underline the importance of blue skies research in everything he has done to date, he says, from the discovery of DNA fingerprinting to his recent work on genome instability and genome dynamics.  "In fact this emerged very early on in the DNA fingerprinting story.   Having found that DNA fragments are exceedingly variable, the natural scientific question is -Why?   Trying to answer that question has taken us on a fascinating journey into the world of recombination, recombination hotspots, studies of the evolution of recombination systems,  genome instability and some very recent work to identify master regulators of recombination in the human genome."

"One intriguing thing is that minisatellites are now firmly back in the spotlight thanks to some exciting recent findings from three groups.  A minisatellite  turns out to be a master regulator of recombination hotspots and right at the heart of meiotic recombination, which defines the pattern of DNA diversity in the human genome.  At a very fundamental level, the master regulator is a protein where the key part of the protein is coded by a minisatellite.   So now we have a wonderful world where we have a coding minisatellite coding for a protein that specifies recombination hotspots, some of which generate minisatellites as parasites, maybe one of which could then serve as a regulator or specifier of recombination hotspots.   So you start going round in this amazing circle and getting seriously confused!"

Judging by his past record, we should not expect Jeffreys to be confused for too long.

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