An increasing number of illnesses, including cancer and Crohn’s disease, are being connected to mutations in these so-called “junk” DNA regions.
Among the three billion letters that make up our genetic code, scientists have been trying to identify novel sections that could be crucial in the development of disease ever since the Human Genome Project was deemed complete in 2003.
Numerous genome-wide association studies, or GWAS, have been published, finding genetic variations linked to various chronic disorders. This has been made possible by technologies that can analyse entire genome samples quicker and more affordably than ever before.
This has shown to be the easy part, which is frustrating for a lot of geneticists. The much more difficult task is realising their relevance. For instance, whereas GWAS has detected DNA regions linked to inflammatory bowel disease at 215 distinct chromosomal locations, researchers have only been able to determine the precise processes at play for four of these regions.
One of the main obstacles is that a large number of these DNA fragments are located in regions of the genome known as “gene deserts,” which at first glance seemed to contain nothing significant—genetic “junk” that could be ignored. Considering that a large portion of the remaining 98% of the human genome is undefined, less than 2% of it is devoted to encoding the genes that make proteins.
“You will realise that there is a significant correlation that raises your risk of numerous illnesses,” explains James Lee, a scientist-clinician who oversees a study team at the Francis Crick Institute in London. “But when you go and look at that bit of DNA, there’s just nothing there.”
An increasing number of illnesses, including cancer and Crohn’s disease, are being connected to mutations in these so-called “junk” DNA regions.
Among the three billion letters that make up our genetic code, scientists have been trying to identify novel sections that could be crucial in the development of disease ever since the Human Genome Project was deemed complete in 2003.
Numerous genome-wide association studies, or GWAS, have been published, finding genetic variations linked to various chronic disorders. This has been made possible by technologies that can analyse entire genome samples quicker and more affordably than ever before.
This has shown to be the easy part, which is frustrating for a lot of geneticists. The much more difficult task is realising their relevance. For instance, whereas GWAS has detected DNA regions linked to inflammatory bowel disease at 215 distinct chromosomal locations, researchers have only been able to determine the precise processes at play for four of these regions.
One of the main obstacles is that a large number of these DNA fragments are located in regions of the genome known as “gene deserts,” which at first glance seemed to contain nothing significant—genetic “junk” that could be ignored. Considering that a large portion of the remaining 98% of the human genome is undefined, less than 2% of it is devoted to encoding the genes that make proteins.
“You will realise that there is a significant correlation that raises your risk of numerous illnesses,” explains James Lee, a scientist-clinician who oversees a study team at the Francis Crick Institute in London. “But when you go and look at that bit of DNA, there’s just nothing there.”
Gene deserts have long been considered one of the most puzzling areas of medical science, but gradually knowledge concerning their apparent function and cause is being gathered.
A recent study conducted by Lee and associates at the Crick Institute delves into the chr21q22 gene desert. Due to its association with at least five distinct inflammatory disorders, ranging from inflammatory bowel disease (IBD) to ankylosing spondylitis, a kind of spine arthritis, geneticists have been aware of this gene desert for more than ten years. However, figuring out how it works has never been easy.
But for the first time, the researchers at Crick were able to demonstrate that chr21q22 has an enhancer, a section of DNA that may control neighbouring or distant genes and increase the number of proteins those genes produce. This is what Lee calls “a volume dial” behaviour. After more investigation, they discovered that this enhancer is only active in macrophages, which are white blood cells. In macrophages, it can increase the activity of a gene called ETS2, which was previously unknown.
Although macrophages are essential for eliminating dead cells and combating pathogenic microbes, an overabundance of them in the body can cause inflammation or autoimmune disorders by invading afflicted tissues and releasing corrosive substances that target them. The current study showed that almost all of the inflammatory functions of macrophages are enhanced when ETS2 is elevated in them.
“The central orchestrator of inflammation” is how Lee puts it. “We’ve known for a while that there must be something at the top of the pyramid that is telling the macrophages to behave like this,” according to him. But we’ve never been aware of its nature. The most intriguing aspect of this is that should we be able to target it, we may be able to develop a novel treatment for these illnesses.”
However, given their potential to seriously injure humans, why are gene deserts included in our DNA?
By tracing the mutation that causes the sickness in chr21q22 back in time, Lee’s colleagues at Crick’s Ancient Genomics Laboratory were able to demonstrate that it initially appeared in the human genome between 500,000 and one million years ago. This specific mutation in DNA is so old that it was found in the genomes of Neanderthals and some of our ancestors.
It turns out that its primary function was to support the body’s defence against external infections. After all, the ability to quickly activate an increased inflammatory response through ETS2 was very helpful before the development of antibiotics. “Within the first couple of hours of seeing bacteria, it ramps up your macrophage responses,” Lee explains.
Therefore, inhibiting ETS2 may make IBD patients more susceptible to infections in the future. However according to Lee, if its activity is reduced by 25 to 50%, it appears to be able to produce a strong anti-inflammatory impact without running the risk of overly suppressing the patient’s immune system. The researchers demonstrated that MEK inhibitors, a family of cancer medications that can reduce ETS2 signalling, were able to lower inflammation in both macrophages and gut samples from patients with IBD, even though this notion has not yet been tested in clinical trials.
This seems to be a fresh avenue towards an entirely new class of therapy for individuals with IBD. “Some of these MEK inhibitor drugs do have side effects, and what we’re trying to do now is to make them more targeted and safer, so that for lifelong diseases like IBD, we would be able to offer patients a drug that could switch off the inflammatory process and make them a lot better,” Lee explains.
To determine whether modifying ETS2 activity can also aid in reducing the excessive inflammation that appears to be the condition’s primary cause, researchers at the Crick Institute are now focusing on the other four illnesses that have been connected to the chr21q22 gene desert.
“One of the most significant ones is an inflammatory liver disease called primary sclerosing cholangitis,” Lee explains. The fact that it can result in liver failure and necessitate liver transplants makes it a very unpleasant condition. Additionally, it carries a significantly increased risk of developing liver cancer, especially in younger individuals. Additionally, there is now virtually little that can be done for patients—not a single medication has been proven to be effective,” he claims.
From lupus to cancer
Additionally, researchers anticipate that investigating gene deserts may provide important insights into the many mechanisms involved in the genesis of tumours.
For instance, because the human papillomavirus, the primary cause of the disease, embeds itself in the 8q24.21 gene desert, researchers studying cancer have identified this region of the genome as having a role in the development of cervical cancer. In doing so, the virus amplifies the expression of the Myc gene, a recognised cancer driver. Research indicates that ovarian, breast, prostate, and colorectal cancers may be associated with the 8q24.21-Myc link.
According to Richard Houlston of the Institute of Cancer Research in London, gene deserts contain a variety of genetic variations that have been linked to the heritable risk of several prevalent malignancies. Understanding these target genes will open up possibilities for both cancer prevention and medication development.
However, Houlston notes that compared to IBD, it is more difficult to apply this information to the development of novel cancer therapies because tumours are dynamic targets that change over time. “This is the challenge, whereas with something like Crohn’s disease and other bowel conditions, it’s not evolving,” according to him.
Lee is hopeful that the Crick Institute’s study on inflammatory bowel disease (IBD) can serve as a model for future studies aimed at uncovering novel pathways underlying a wide range of inflammatory and autoimmune illnesses. Scientists at the centre are currently looking into more gene deserts that have been linked to illnesses like lupus, a disease where the body’s tissues are damaged by the immune system, causing symptoms including fatigue and skin rashes.
Numerous research institutes worldwide, including the University of Basel in Switzerland, are investigating the potential link between uncommon genetic illnesses and single hereditary mutations found in gene deserts. Scientists at Basel found three years ago that one of these mutations could cause limb deformity in newborns because it regulates a nearby gene.
Lee believes that by comprehending the functions of gene deserts, the infamously ineffective medication development process will eventually be improved. “Making new drugs for these diseases is unsuccessful,” according to him. 90% of medications that enter clinical trials fail because they don’t improve people’s lives; just around 10% of these drugs are approved after the process. However, the likelihood of medicine getting authorised increases three to five times if you are aware that the pathway it is targeting during development is genetically supported.”
