Former Lister Fellow Darren Monckton is Professor of Human Genetics at the University of Glasgow. His research focuses on DNA repeats in inherited illnesses, with the aim of understanding how instability in DNA contributes to disease and ageing. Darren received the Lister Prize, then called a Lister Fellowship, in 1998 and was a Lister Fellow from 1998 to 2003. We caught up with him to learn more about his research.
Q: Tell us more about your lab’s work
A: Our goal is to understand what drives the disease process in a related group of inherited disorders including Huntington disease and myotonic dystrophy type 1, the most common form of inherited muscular dystrophy. There are at least 50 diseases with the same underlying genetic pathology, an expansion of simple sequence repeats. That means a short sequence of nucleotides – usually three at a time – are repeated in the person’s DNA.
Q: So DNA repeats cause illness?
A: It’s normal for a person to have some repeats of sequences within their genes. For the general population, there might be 30 repeats in the gene. But someone affected by one of these conditions might inherit between 40 and 60 repeats, which is the range typical for Huntington disease. For myotonic dystrophy type 1 it could range from 50 repeats to several thousand.
We’ve known for a long time that the more repeats a person inherits, the more severe their disease and the earlier they start to get symptoms. We also knew that the symptoms become worse at an earlier age in successive generations of a family – a phenomenon known as anticipation. That happens because the repeats are unstable, and nearly always change in length when they are inherited, usually getting larger.
Q: What research methods do you use to study repeats?
A: When I started my Lister Fellowship, one of the primary questions my group had was why these repeats were unstable and what was driving this phenomenon of anticipation. We looked at how the repeats are transmitted within families, but this was limited by the number of children somebody had. Instead, we started to look directly at sperm DNA, since genetically speaking each sperm represents a child the person could have had.
Q: So these repeats don’t just increase when they are inherited?
When we researched the reproductive cells, we analysed blood samples at the same time as a kind of control. We found that repeats were unstable in blood too – it wasn’t just the sperm cells. In fact, the blood tissue was even more biased towards expanding the repeats. Over the last 20 years, we’ve discovered that this process is really important in driving disease.
These mutations multiply during a person’s lifetime, and that is key to how the disease develops. For instance, Huntington patients only inherit 40 or 50 repeats, but it requires around 150 repeats for the cells to become really sick. Having 40 repeats is the starting number required to get there during the person’s lifetime. That may explain why many of the diseases we study are late onset.
The increases happen at a different rate in different tissues. Some of the most susceptible cells, the striatal neurons, can acquire as many as 1,000 repeats during a lifetime.
Q: What causes genetic sequences to be repeated during someone’s lifespan?
When these repeats were first identified, it was assumed that the changes must be happening when the cell divides, and the DNA is replicated. That is a key point for mistakes to be made, so the body has very good DNA repair mechanisms such as the DNA mismatch repair system. It seemed likely that this repair system was being overwhelmed by the number of repeats.
However, our research shows that these assumptions are completely wrong – the repeats continue to grow even in cells that aren’t dividing. That explains why we see a lot of repeats in the types of cells that don’t divide much after early development, like neurons.
In fact, instead of protecting against repeats, malfunctioning mismatch repair mechanisms are actually generating the expansions. So, we are now looking closely at that phenomenon, quantifying it in humans, then using a human genetics approach, cell lines and animal models to try and get an insight into the molecular mechanisms that drive the increase.
Q: So the repair mechanism actually makes the damage worse?
A: Yes, and the data at a population level bears that out. We know that two people with the same number of repeats at birth won’t have exactly the same disease course. One reason will be environmental things like diet and exercise, but another is the millions of genetic differences between them overall.
When we investigate those other parts of the genetic landscape to see what has an impact on repeats – protecting against expansions or accelerating the problem – it’s exactly the DNA repair genes we have been studying. Natural variants in those DNA repair genes modify the rate of expansions, and consequently onset and progression of the symptoms.
Q: What are the implications of your research for treating patients?
A: If you could stop the repeats getting bigger, that would potentially be therapeutically beneficial, so we are identifying the key protein players in the mismatch repair mechanism to see which ones are the most promising therapeutic targets. We are also trying to develop biomarkers so that when drugs reach trial stage, we can show directly that they are having an impact on expansions.
We think the underlying mechanisms are shared by many disorders, so a drug that can prevent Huntington disease could work equally well in many other conditions, so it’s really exciting.
Q: Where did the Lister Prize fit into your research journey?
I started working in this area in 1993, and I won the Lister Fellowship in 1998. It took a long time to build up the body of evidence needed to show what was happening, and a lot of hard work in the lab. The big advances in DNA sequencing technology have definitely helped a lot. The Lister award came at an important time when I was just developing my independence. I was in a temporary position at the time, and the Fellowship enabled me to negotiate to make that position permanent. It also meant we could do more research in the lab and explore new ideas. Having that pool of money available meant we could ask different questions, establish new techniques and take our research in some new and exciting directions.
Learn more about Darren’s work
