The idea that the information contained in your personal DNA sequence could be used to develop treatments that are specifically tailored to you is a hot topic in medical research, but how likely is it that this will ever become a reality? A recent collaborative study, involving scientists from the WIMM and many others across Oxford, set out to answer this question: and their findings were published in Nature Genetics earlier this month. Martin Larke looks into what they found.
In 2003, the completion of the Human Genome Project (HGP) was announced, and was viewed by some as arguably one of greatest scientific achievements of all time.
When the project was instigated, it was believed that once we had the complete sequence of our DNA (known as the reference genome, containing all the instructions required to make a human) we could rapidly identify differences or changes (mutations) found within the genomes of patients suffering from different genetic diseases.
In turn, this would allow the development of new diagnostic tests and ultimately the dawn of personalised medicine where drugs could be designed specifically to an individual based on their genetic makeup, resulting in more targeted and therefore hopefully more effective ways to treat disease.
However, at times the project had been considered impossible given that the complete human DNA sequence or genome is a chain made up of 3 billion chemical molecules, otherwise known as the letters A, C, G and T or nucleotides.
Even at the peak of the project an individual DNA sequencing machine could only read or sequence around 300 letters an hour. This meant that using only one machine, it would take over 1000 years to read through a single copy of the genome!
However, by working together and sharing resources and expertise, the scientific community was eventually able to complete this task in a mere 20 years – but at an estimated cost of £1.7 billion pounds, a sum clearly prohibitive to routinely sequence the DNA of patients suffering from genetic conditions.
But in the decade that followed the publication of the first draft sequence of the human genome, the technology used to sequence DNA advanced at a phenomenal pace. Now, the entire genome of a human being can be sequenced in just four and a half hours at a cost of around £640 – an astounding increase in speed and reduction in cost.
But can this technology actually be used to help diagnose and treat patients? This was the question that a team of scientists from across Oxford set out to answer, and their findings were published in Nature Genetics earlier this month.
Funded by the MRC, the Wellcome Trust and the NIHR Oxford BRC (amongst others) the team of researchers – including many scientists at the WIMM – sought to pinpoint factors which influence the success of genome sequencing in identifying changes to the DNA that are actually linked to human diseases.
DNA samples from a total of 217 individuals were sequenced, comprising 156 patients with a range of genetic disorders, and some of their family members. Mutations not present in the reference genome were identified, generating a long list of over 30 potential disease-causing mutations per person.
The scientists compared this candidate list to other sequences generated from unaffected family members, and also across the whole group of 217 samples. In this way, mutations that were common to everyone could be identified. These common mutations are not likely to be associated with disease, as they are present in many people and not just the patient with the disease.
The list of mutations was also filtered in terms of potential ‘biological significance’. This process involved identifying mutations that had already been linked to a disease, were present in genes known to be involved in important biological processes or were in areas of the genome known to act as switches controlling when genes are turned on or off.
After these considerations scientists were confident that they had identified a disease-causing mutation in 21% of all cases (33/156) and in a specific subset of cases where an individual had a mutation not carried by either of their parents the success rate increased to 57% (8/14).
To be confident that the mutations identified actually caused the diseases in question, scientists looked for evidence such as mutations in the same place in the genome in other people with the same disease, or mutations in similar places in the genome in related disorders, or by testing the mutations in experiments in the lab.
The filtering steps employed by the team of researchers demonstrated that with the right approach, genome sequencing could be used to at least narrow down the list of potential changes to the DNA that could be linked to a given disease.
This then provides scientists and clinicians with a shortlist of mutations to investigate in further tests, hopefully leading to a greater understanding of the underlying cause of the disease, and allowing the development of better, more specific, therapies.
This study highlights that genome sequencing is a powerful tool capable of identifying mutations that cause genetic disease – but it also shows that this approach is only possible through the combined efforts of doctors, scientists, patients, their families and, of course, with generous financial support.
Although many barriers remain to be overcome before personalised genetic testing becomes a routine diagnostic approach, it seems the dawn of a new era of medicine is upon us. Watch this space…
Post edited by Paolo Piazza, Aimee Fenwick and Bryony Graham.