Welcome to the 3D genome

When the first draft of the human genome was published in 2001, it was described as a treasure trove of information. But using that information to understand disease demands going far beyond the DNA code. Now, researchers at the Institute are pioneering a new method of mapping our genome’s complex regulatory interactions that could open up new ways to treat genetic diseases and understand ageing.

 

If we think about our genome at all, it’s probably in a linear, two dimensional way: as a string of bead-like genes threaded along a necklace of DNA, a code to be cracked or a blueprint to be read. It turns out, however, that understanding what our genes do – and how tiny changes in our genome can cause genetic diseases – demands different ways of thinking.



The story begins, says Dr Peter Fraser, head of the Nuclear Dynamics research programme, by focusing less on genes – which occupy only 2% of our genome – and putting more thought into the remaining 98%. “This non-coding space between the genes, sequences of DNA that don’t encode for particular proteins, was once viewed as an evolutionary wasteland of junk DNA,” he says.



In fact, these regions are crucial because they regulate our genes by switching them on and off. “There are at least 1 million regulatory elements in the genome. Each of our 22,000 genes uses an average of five of them. But the problem has been understanding how a regulatory element so far away from the gene it controls actually exerts its influence,” Fraser explains.



To understand this, we must add new dimensions to our thinking. “We need to think in 3D because that’s how it is inside the cell,” he says. “DNA is wrapped around proteins and how that bundle

is folded in the nucleus is really important.”



Time matters too, because the folding is dynamic, not fixed, and as the folding patterns change, different genes make contact with regulatory elements in distant regions of DNA. But while this new way of thinking offers a better way of explaining how genes are regulated, how can we unravel such a complex web of changing connections?

For the past 15 years, Fraser and his team have been studying how DNA folds to bring genes and their regulatory elements together. Now, they have developed a pioneering method of mapping these myriad connections, and produced the first ‘pages’ of an atlas they hope will eventually cover every cell type in the human body.



But why is this atlas so important in the quest to understand common genetic diseases – and find new ways to treat them? The answer, he says, is because the atlas allows us to make sense of a vast database of hundreds of thousands of so-called SNPs (pronounced ‘snips’) – single nucleotide polymorphisms – the tiny errors in DNA that are related to genetic diseases such as Crohn’s disease and rheumatoid arthritis.



This database of SNPs has been built up over decades of research using genome-wide association studies – trials comparing the genomes of healthy volunteers with those suffering from a genetic disease.



Sometimes these variations occur in genes, making them malfunction and resulting in genetic diseases. More commonly, however, the error lies in non-coding DNA. Hundreds of thousands of these mistakes have been discovered, but until the atlas, it’s been impossible to explain how such a tiny change, so far from any known relevant gene, could affect a disease.

According to Fraser: “What we’ve found is that these SNPs are in regulatory elements, so by being able to map these onto specific genes, we can identify new potential disease-causing genes.”



Precisely how powerful this mapping could be in combating genetic diseases can be seen from results that Fraser’s team published last year. By mapping the 750,000 connections between regulatory elements and the genes they control in 17 types of white blood cell they were able to identify 2,600 potential disease genes. Only 25% of these disease-associated genes had previously been identified – 75% were new, including genes involved in a range of autoimmune diseases from type 1 diabetes to celiac disease.



As well as helping us understand the genetic basis of disease, the discovery of these potential disease genes also provides the pharmaceutical industry with new targets for novel drugs – or new ways to use (or repurpose) existing drugs.



“The 25% of disease genes we already know about have been very hard fought – one at a time over decades of research. So what we’ve done has really burst the dam,” he says.



As well as white blood cells, the team has mapped the genetic connections in red blood cells and is moving on to map muscle and pancreatic cells. Fraser hopes that these findings will deliver candidate genes relevant to diseases such as certain types of anaemia, type 2 diabetes and muscular dystrophy.



With more than 200 different cell types in the human body, the atlas will be huge. And its impact on our understanding of disease and healthy ageing could be even more significant.



“It’s a big leap,” Fraser says. “There are SNPs in these databases associated with healthier ageing. By mapping those, we may be able to identify more genes involved in ageing. There’s lots of work to be done and lots of genetic diseases we know nothing about. This could potentially crack quite a few.”





This feature was written by Becky Allen for the Annual Research Report 2016