A talk by Professor Peter Donnelly, University of Oxford

Published May 2012

Genetics in the past 20 years has had a huge impact on the study and treatment of human disease. “As genetics and human diseases go there’s a spectrum; at one end diseases where genetics is all the story – those diseases are thankfully rare, they are usually serious and they have the property that if you inherit in some cases one and in some cases two chains or mutative copies of the gene in question you get sick. Examples you’ve probably heard of are cystic fibrosis, Huntington's disease, there are many, many more, and while they are individually rare it’s suggested that perhaps one per cent of children born each year will be affected at some state in their life by genetic disorders.”

For many of these inherited disorders the genes involved - whose changes underlie the condition - have been identified. Over the last few years, with improvements in our ability to measure and analyse DNA, there’s been a resurgence in discoveries for these rare but serious conditions. The cost of reading a DNA sequence has gone down by a factor of a hundred million in the last 20 years and in the last four by a factor of 10,000. Changes in technology have led to advances in informatics and statistics giving scientists the ability to extract information from large amounts of genomic data.

Our genetic information is encoded in DNA, which we think of as an instruction manual. In the Caucasian population one of the most common examples of a genetic disorder is cystic fibrosis, which affects one in about two and a half thousand people. The identification of the gene involved in 1989 was one of the big early successes in genetics, and in some sense, says Prof Donnelly, can be seen as the start of the modern age in human genetics.

The next big genetic breakthrough occurred in the mid 1990s with the discovery of two genes involved in familial forms of breast cancer: BRCA1 and BRCA2. Individuals who carry a particular kind of mutation in BRCA1 have an elevated risk of breast cancer at 80 per cent as opposed to ten per cent in the average woman.

“Identification of the gene has been important for women in families that carry breast cancer much more than you’d expect. Those women now have the option of deciding whether to be tested for the genes or not. If they choose to be tested there’s a 50/50 chance they won’t carry the mutation. If they do carry the mutation there are tough decisions but there are various things that can be done surgically and otherwise to substantially reduce their disease risk. It has made a big difference to patients potentially at high risk,” says Prof Donnelly.

The Human Genome Project's mapping of the entirety of the DNA that a human carries was another great success in genetics. Human DNA is made up of about three billion letters in the DNA code and they are organised into 23 pairs of chromosomes. Although it may be tempting to think that humans are the most sophisticated creatures on the planet, and must need more DNA to encapsulate that sophistication, it’s not totally true. A salamander has about ten times as much DNA as a human being. A chimpanzee DNA agrees with humans in 99 places out of a hundred.

The complete version of the Human Genome Project was announced in 2003. In the years since, scientists and journalists have speculated about whether the project had fulfilled its aims, if we have gained as much knowledge as we might have expected, and where the future of genetics lies. Professor Donnelly has his own view: “I think the human genome project and the human genome sequence has been hugely important in a sense for indirect reasons rather more than direct reasons. We learned some important biology from knowing the genome sequence but I think that the best way to think about it is that the genome sequence is like a map.”

“Our genomes are huge, vast and largely unexplored territories. Having the sequence enables us in a sense to put co-ordinates down. We know where we are and where this bit of information in our DNA is in relation to others. Trying to do human genetics before [that] is hard to imagine... it was like trying to be an explorer of one of the more exotic parts of the earth in the days when there were no maps.” It’s that ability to know where things are in the genome that has led to more breakthroughs.

Comparing the DNA sequences between two individuals – or more precisely between one copy of the human chromosome and another copy of the human chromosome – will reveal almost identical sequences. They will agree at about 999 places out of a thousand. However, one difference in a thousand amongst three billion pieces of information in our DNA is still a lot of difference. A lot of the current focus in research and in Professor Donnelly’s own work is on understanding the consequences of these differences for medically relevant traits.

How do particular differences in DNA change someone’s susceptibility to a disease? We know for common human diseases such as heart disease, diabetes, arthritis and many of the cancers and mental health disorders that genetics plays a part. “Some of the explanation for the way in which people’s susceptibility to disease differs amongst individuals is due to their DNA," says Prof Donnelly, "We also know that genetics is only part of the story, that some of those differences are due to external factors - the environment, things like lifestyle and so on... and until recently, although there’s been a huge amount of research effort to try and understand how genetic differences are related to differences in susceptibility to disease, there hadn’t been much progress.”

In 2005 things altered with the discovery that changes in DNA sequence on a particular chromosome affected susceptibility to age-related macular degeneration (a medical condition which usually affects older adults and results in a loss of vision). Further discoveries emerged in the following years. Now there are over 1,500 variants associated reliably with more than 200 diseases. Each one of these has in it a clue to the biology of the particular disease.

Genetics has been important in developing a whole new thinking about the disease process. Rather than taking the previous ‘top down’ approach of starting with the symptoms and working down, instead scientists can now look across the genome in an unbiased way and try to find positions where there are genetic variations that matter for that disease. If we know how a change in DNA translates into biological differences, we know some aspect of the process that leads to people developing a disease.

Professor Donnelly is optimistic that over time scientists will be able to harness that extra biological information to develop cures and treatments. Already genetics is used in personalised medicine to determine whether a person may gain from a particular cancer treatment or suffer side-effects known to crop up in people with one particular genetic variation. Genetics is impacting in a major way on healthcare – all thanks to the genetic revolution.

Peter Donnelly is Director of the Wellcome Trust Centre for Human Genetics and Professor of Statistical Science at the University of Oxford. He has played central roles in a number of major collaborations, including the International HapMap Project, the successor to the Human Genome Project, which studied the patterns of genetic variation in global populations, and the Wellcome Trust Case Control Consortia, which he chairs.

These UK-wide consortia represent some of the largest studies of the genetics of common human diseases ever undertaken, analysing genetic data from more than 80,000 people and using that data to study 25 common diseases and conditions.

In 2007 Prof Donnelly moved within Oxford to take up the Directorship of the Wellcome Trust Centre for Human Genetics, a research centre of around 400 scientists working to understand the genetic basis of common human diseases. He has received a number of academic awards for his work, and is a Fellow of the Royal Society and of the Academy of Medical Sciences.