What are the mysterious genetic deserts in our DNA that scientists associate with diseases such as cancer and Crohn’s?

“You’ll say, ‘Oh, there’s a significant association here and it increases the risk of lots of different diseases,'” says James Lee, a clinical scientist who leads a research group at the Francis Crick Institute in London. “But when you look at that piece of DNA, there’s nothing.”

For many years, Genetic deserts have been one of the most puzzling areas of medicine.but scientists are slowly gathering information about their apparent purpose and why they exist.

Recently, Lee and colleagues at the Crick Institute published new research on a particular gene desert known as chr21q22. Geneticists have known about this gene desert for more than a decade, because it is associated with at least five different inflammatory diseases, from inflammatory bowel disease (IBD) to a form of spinal arthritis known as ankylosing spondylitis. However, its function has always been elusive.

For the first time, Crick scientists have been able to show that chr21q22 contains an enhancera segment of DNA that can regulate nearby or distant genes, being able to increase the amount of proteins they produce.

Lee refers to this behavior as “a volume dial.” As they studied further, they discovered that this enhancer is only active in macrophages, white blood cells, where it can increase the activity of a previously little-known gene, ETS2.

Although macrophages play a vital role in removing dead cells or fighting off harmful microorganisms, when the body produces too many of them, they can wreak havoc in inflammatory or autoimmune diseases by flooding affected tissues and secreting harmful chemicals that attack them. The new study has shown that when ETS2 is enhanced in macrophages, almost all of their inflammatory functions are enhanced.

Lee describes it as “the central driver of inflammation.” “We’ve known for a long time that there must be something at the top of the pyramid that tells macrophages to behave like this,” he says. “But we never knew what it was. The exciting thing is that if we can target it somehow, we might have a new way to treat these diseases.”

But if genetic deserts are capable of causing us so much harm, why are they in our DNA?

Tracing back in time, Lee’s colleagues from the Crick’s Ancient Genomics Laboratory They were able to show that the disease-causing mutation in the chr21q22 region first entered the human genome between 500,000 years ago. and a million years ago. This particular change in DNA is so old that it was even present in the genomes of Neanderthals and some ancestors of Homo sapiens.

It turns out that its original function was to help the body fight off foreign pathogens. Before antibiotics were invented, it was very useful to be able to trigger a greater inflammatory response through the ETS2 gene. “In the first few hours after a bacteria appears, the macrophage response goes into overdrive,” Lee explains.

Blocking ETS2 entirely could therefore leave IBD patients vulnerable to future infections. However, Lee says that when its activity is reduced by 25% to 50%, it has a profound anti-inflammatory effect, without the risk of overly immunosuppressing the patient.

Although this theory has yet to be tested in clinical trials, the researchers showed that MEK inhibitors — a class of cancer drugs that can dampen ETS2 signaling — were able to reduce inflammation not only in macrophages, but also in intestinal samples taken from people with IBD.

This appears to represent a new avenue toward a novel class of treatments for IBD patients. “Some of these MEK inhibitor drugs have side effects, and what we’re trying to do now is to make them more selective and safer, so that in chronic diseases like IBD, we can offer patients a drug that can turn off the inflammatory process and improve their health,” Lee said.

Now Crick researchers are turning their attention to the four other diseases that have been linked to the chr21q22 genetic desert, to see if altering ETS2 activity might also help alleviate the excess inflammation that appears to drive the conditions.

“One of the most important is an inflammatory liver disease called primary sclerosing cholangitis.“It’s a particularly nasty disease because it can cause liver failure and people need a transplant. It can also have a higher risk of liver cancer in younger people. And at the moment there are no drugs that have been proven to work, so there’s very little to offer patients,” he says.

Scientists also predict that studying genetic deserts will provide vital information that will help improve our understanding of the various pathways involved in tumor development.

For example, cancer researchers They have identified a gene desert called 8q24.21 that is known to contribute to cervical cancer.since the human papillomavirus, the main cause of the disease, is embedded in this part of the genome.

In doing so, the virus boosts a gene called Myc that is a known driver of cancer. Studies suggest that the connection between 8q24.21 and Myc may also play a role in several types of ovarian, breast, prostate and colorectal cancer.

Richard Houlston, from the Institute of Cancer Research in London, says that a number of genetic variants have been found in gene deserts that have been found to contribute to the inherited risk of many common cancers. Knowledge of these genes will enable drug discovery and cancer prevention.

However, Houlston notes that translating this knowledge into new therapies for cancer is harder than for IBD because tumors are not static targets but evolve over time. “That’s the challenge, because Crohn’s and other bowel conditions don’t evolve,” he says.

Lee hopes the Crick’s work on IBD will serve as a model for researchers to find new ways to understand the pathways involved in all types of autoimmune and inflammatory diseases.

Scientists at the institute are now investigating other genetic deserts that have been associated with conditions such as lupus.a disease in which the immune system damages the body’s tissues, causing symptoms such as skin rashes and fatigue.

Other research centres around the world, such as the University of Basel in Switzerland, are also studying how isolated hereditary mutations in gene deserts could cause some rare genetic diseases. Three years ago, scientists in Basel discovered how one such mutation could cause babies to be born with limb malformations due to its regulatory effects on a nearby gene.

Lee predicts that understanding the functions of gene deserts will ultimately help improve the drug development process. “Making new drugs for these diseases is a no-go,” he says. “Only about 10 percent of drugs that go into clinical trials are ultimately approved, so 90 percent of them fail because they don’t improve patients’ health. But if you know that the drug you’re going to develop targets a pathway that’s supported by genetics, the chances of it being approved are at least three to five times greater.”