The genetic revolution
Dr Denize Atan
SOCS Lead for Women in Science Consultant Senior Lecturer in Ophthalmology School of Clinical Sciences
F38, Biomedical Sciences Building University of Bristol
We are in the midst of a genetic revolution. Advances such as the Human Genome Project, HapMap, 1000 genomes and innovations in sequencing technology mean that we now know much more about the human DNA sequence and the role of non-coding DNA in regulating which genes are switched on or off, in which cells and at what time during development. We can determine who has inherited certain genetic faults that will inevitably lead to disease but also who has inherited a high genetic risk of future disease.
Eye research has proceeded in these two directions:
a.) To identify genetic variants that increase risk of a disease.
For example, normal variants in the complement factor H gene determine whether an individual is at very high risk of developing age-related macular degeneration. Drs Denize Atan and Amanda Churchill have identified variants in the VEGF gene that are also associated with AMD. There are many variants in other genes that also modify the genetic risk of AMD. In other words, there are several genetic variants that combined together alter risk of AMD. An individual’s genetic risk of AMD is determined by the combination of all of these genetic variants.
Though an individual’s combined genetic risk might be high, there are also environmental risk factors that interact with our genes to actually cause disease. For AMD, these include smoking, high blood pressure, exposure to sunlight, poor diet. This means that if an individual finds they have a high genetic risk of developing AMD in future, they may prevent the onset of disease by making sure they do not smoke, eat a healthy diet, exercise, avoid sun exposure, control their blood pressure etc.
In addition, Dr Atan has identified variants in the TNF and IL10 genes that alter risk and severity of uveitis, an inflammatory disease of the eye that can impair the vision of young working age adults. The treatment of uveitis is with strong immunosuppressive drugs which frequently cause serious side-effects. If we know which individuals are genetically predisposed to severe disease, we can treat them more aggressively from the outset to preserve vision.
The general public are interested in determining their genetic risk and severity of disease as evidenced by the expansion of private companies that offer whole genome DNA sequencing as a commercial service and will report on an individual’s genetic risk for different types of disease. For example, 23andme offer this service for £129 (https://www.23andme.com/en-gb/).
b.) To identify causes of genetic disease.
This research is particularly pertinent in the age of gene therapy. It is not possible to treat a patient with gene therapy if the gene at fault has not been identified first. Combined with imaging technology to diagnose patients with a retinal disorder at an earlier age, early genetic diagnosis means the ability to deliver gene therapy at an earlier stage and while the retina is still developing postnatally so that the effects of the mutation are mitigated. Research by Dr Denize Atan has identified a gene called PRDM8 that is implicated in congenital stationary night blindness – an early onset blinding disorder that could be treated with gene therapy if identified sooner.
In the NHS, genetic screening for inherited retinal diseases is an iterative process (repetitive rounds of analysis). Individuals with a certain pattern of symptoms, signs or syndrome that is thought to be due to an inherited disease will be tested against a panel of the most common genetic mutations to cause that disease. If the first round of tests is negative, patient DNA might be tested against a second panel of less common variants. They might be tested for large DNA deletions or duplications. But if more detailed tests are not available on the NHS, they will be left in the dark about what has caused their disease. Sometimes, doctors send DNA samples to research labs with an interest in a particular disease to test patient DNA for less common mutations, on the presumption that the lab has the funding, interest and good will to do more detailed tests. There is also the 100,000 genomes project that offers DNA sequencing for individuals with rare undiagnosed syndromes and cancer.
As the cost of whole genome sequencing has dramatically reduced in recent years, it is likely to become more cost effective to sequence the whole genome of patients from the outset (e.g. 23and me) rather than the stepwise targeted approach described above. The challenge will be how we process and analyse this data from whole genome sequencing, which is computationally intensive.