The dark genome and diseases
Panay Island in the Philippines is famous for its sparkling white sands and constant influx of tourists, but this amazing place hides a sad secret.
This island has the highest frequency of incurable movement disorder called X-linked parkinsonism dystonia, abbreviated as XDP. like disease Parkinson’s, people with XDP experience a range of symptoms that affect the ability to walk as well as the ability to react quickly to different situations.
Since XDP was first discovered in the 1970s, the disorder has so far only been seen in people of Filipino descent. The reason for this was a mystery for a long time until geneticists realized that all these people had a unique variant of a gene called TAF1.
The onset of symptoms appears to be driven by a transposon in the middle of this gene, which can alter its function in ways that damage the body over time. This gene variant is thought to have appeared for the first time about two thousand years ago and then became fixed in the population. “The TAF1 gene is an essential gene, meaning that it is needed for the growth and reproduction of all types of cells,” Boke says. “When you change its expression, you end up with this very specific defect that appears in this horrible form of parkinsonism.”
The above case is a simple example of why some DNA sequences in the dark genome can control the function of different genes or activate or suppress the process of converting genetic information into protein in response to environmental signals.
The dark genome also carries instructions for making different types of molecules known as non-coding RNA. Non-coding RNA molecules have different roles such as helping to form proteins, inhibiting the protein production process or helping to regulate gene activity. “The RNAs produced by the dark genome act like conductors, directing how the DNA responds to the environment,” Onezin says.
Non-coding RNA is now increasingly considered as a link between the dark genome and various chronic diseases.
The common thinking is that if we continuously give the dark genome the wrong signal (eg, through a smoking lifestyle, poor diet, and inactivity), the RNA molecules that are produced can put the body into a disease state and alter gene activity in some way. which increases inflammation in the body or causes cell death.
Some non-coding RNAs are thought to affect the activity of a gene called p53, which normally acts to prevent the formation of tumors. In complex diseases such as Schizophrenia or Depressors of unfavorable sets of non-coding genes may act in concert to decrease or increase the expression of certain genes.
Our growing understanding of the importance of the dark genome has now led to new approaches to treat these diseases. While the pharmaceutical industry usually focuses on proteins, some have come to believe that trying to disrupt the non-coding RNAs that control the genes responsible for these processes may be a more effective approach.
In the field of cancer vaccines, where companies genetically sequence a patient’s tumor sample to identify a suitable target for the immune system to attack, most approaches have focused only on protein-coding regions. However, the German pharmaceutical company Curroc is pioneering an approach in which it also analyzes non-coding regions of proteins in the hope of finding a target that can disrupt the source of cancer.
Onezin’s company, Haya Therapeutics, is pursuing a drug development program that targets a set of non-coding RNAs that cause scar tissue, or fibrosis, in the heart. The formation of scar tissue in the heart can lead to heart failure.
Researchers hope that this approach can minimize the side effects of many common drugs. “The problem with protein-based medicine is that there are only about 20,000 proteins in the body, and most of them are expressed in different cells and in pathways unrelated to disease,” Onezin says. But the dark genome is very specific in its activity. “There are non-coding RNAs that regulate fibrosis only in the heart, so with a drug based on those, you might get a very safe drug.”
We know very little about what geneticists describe as ground rules: how these non-coding sequences interact to regulate gene activity. And how do these complex chains of interactions manifest themselves over time in the form of disease and, for example, cause the neurodegeneration seen in Alzheimer’s disease?