Since the Human Genome Project It was completed in 2003, Scientists sought to locate new regions among the 3 billion letters of our genetic code that may play a critical role in disease.. With the help of technologies that allow whole genome samples to be analyzed more quickly and cheaply than ever before, a large number of genome-wide association studies – known as GWAS in English – have been published that identify genetic variants linked to different chronic diseases.
For many geneticists, this turned out to be the easy part. The hard part was understanding their relevance. For example, although GWAS identified DNA segments associated with inflammatory bowel disease at 215 different chromosomal sites, scientists were only able to determine the exact mechanisms involved at four of them.
One of the biggest challenges is that many of these DNA fragments are found in so-called genetic deserts, strips of the genome that seemed to contain nothing relevant, genetic “junk” that could be discarded.Less than 2% of the human genome is devoted to coding genes that produce proteins, while much of the remaining 98% has no obvious meaning or purpose.
“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, gene deserts were 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 his colleagues at the Crick Institute published a New research on a specific gene desert known as chr21q22Geneticists have known about this genetic 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, it was always difficult to decipher its function.
For the first time, Crick scientists were able to show that chr21q22 contains an enhancer, a 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 delved deeper into the study, 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, flooding affected tissues and secreting harmful chemicals that attack them. The new study showed that when ETS2 is boosted in macrophages, nearly all of their inflammatory functions are enhanced.
Lee describes it as “the central responsible for 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, adding: “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? By tracing back in time, Lee’s colleagues at the Crick’s Ancient Genomics Laboratory were able to show that the disease-causing mutation in the chr21q22 region first entered the human genome between 500,000 and one million years ago. This particular DNA change 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 foreign pathogens.. Before antibiotics were invented, it was very useful to be able to activate a greater inflammatory response through the ETS2 gene.“In the first few hours after a bacteria appears, the macrophage response is triggered,” Lee explains.
Consequently, Completely blocking ETS2 could leave IBD patients vulnerable to future infectionsHowever, 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 not yet been 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 towards a class of novel treatments for IBD patients. “Some of these MEK inhibitor drugs have side effects, and what we are trying to do now is to make them more selective and safer, so that in the case of chronic diseases like IBD we can offer patients a drug that can turn off the inflammatory process and improve their health,” says Lee.
Now the Crick researchers are turning their attention to the other four diseases that have been linked to the chr21q22 genetic desert, to see if altering ETS2 activity can 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 have identified a gene desert called 8q24.21 that is known to contribute to cervical cancer because the human papillomavirus, the main cause of the disease, embeds itself 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, said that in gene deserts, a number of genetic variants were found that were found to contribute to the inherited risk of many common cancers. Knowledge of these genes will lead to drug discovery and cancer prevention.
However, Houlston notes that translating this knowledge into new therapies for cancer is more difficult than for IBD, because tumors are not static targets but evolve over time. “This is 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 of understanding the pathways involved in all kinds of autoimmune and inflammatory diseases. Scientists at the institute are now investigating other genetic deserts that have been linked to 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. “Developing new drugs for these diseases is a waste of time,” he says. “Only 10% of drugs that go through clinical trials are ultimately approved, so 90% of them fail because they don’t improve patients’ health. But if you know that the drug you’re going to develop is targeting a pathway supported by genetics, the chances of it being approved are at least three to five times higher,” he adds.
BBC World