The dark side of the genome: ‘An untapped gold mine’ for drug discovery

Vast medical advances in unlocking our genetic code flow from a deep study of just 1 to 2 per cent of the total DNA that is the human genome. The nature and function of the remaining 98-99 per cent are largely unknown – “in the dark” – and dubbed the dark genome. They hold vital hidden secrets needed to identify and treat diseases that befuddled scientists and doctors.

Take childhood cancer cases, schizophrenia, and autoimmune diseases, for example.

Cancer is a disease of aging or exposure to agents like tobacco that cause catastrophic changes to the DNA of normal cells. How, then, do children develop cancer without the effects of aging and with only limited exposure to cancer-inducing agents?

Schizophrenia and bipolar disorder are among the most inherited mental disorders, yet their causes are not well understood; as are the reasons why only some people develop autoimmune diseases such as rheumatoid arthritis, in which the immune system attacks and destroys the joints.

Scientists are beginning to unravel this region of the human genome, once considered junk, and the early findings suggest the dark genome acts as regulatory forces on the activities of many genes. If 1 to 2 per cent of the entirety of DNA can uncover so many secrets (but leave so many unexplained) imagine the bonanza of scientific discoveries that might flow from 5, 10, 20 per cent and beyond?

“If we want to know ourselves, we cannot continue to focus only on 1 per cent of our own genome,” says Tomas Mustelin, professor of rheumatology at the University of Washington in  Seattle.

Pawan Dhar, a professor of biotechnology at Jawaharlal Nehru University in New Delhi, spells out the goal of the current dark genome research.

“Dark genome is a treasure house for the next generation of drug discovery molecules,” Dhar responds in an interview. “It is time to explore this untapped gold mine.”

One research team in Singapore is researching whether the dark genomes are acting as possible “mediators of cancer.”

Historically, the lack of attention to the dark genome was due to the absence of technologies to analyze these DNA elements. In addition, conventional “group think” that genes should have a defined sequence and signature made researchers overlook functional signs right under their noses.

Newer technologies finally have allowed scientists to sequence pieces of DNA and apply artificial intelligence and machine learning approaches or computational approaches to extract information. This has led to remarkable discoveries in the dark genome with implications for several human diseases.

One such example is the research of Sudhakaran Prabakaran, a former faculty member at the University of Cambridge and now Chief Executive Officer and Chief Technology Officer of NonExomics, Inc., in Boston.

“My research (at Cambridge) demonstrated that the entire human genome makes proteins pervasively and not necessarily just from the regions that we call ‘genes’,” says Prabakaran. “We showed that ‘novel’ proteins from the so-called dark matter regions of the genome are capable of forming structures, performing functions, and [that these proteins] are disrupted in a number of diseases, including schizophrenia and bipolar disorder.”

Schizophrenia and bipolar disorders are known to have genetic causes. Current treatments are ineffective and have adverse side-effects, likely because they only target proteins encoded by the “known” 1-to-2 per cent of genes.

Exploring beyond the traditional definition of what genes mean and where they are located, Prabakaran and colleagues discovered genes that may explain genetic causes of these diseases; hence, new ways to diagnose and treat these debilitating mental disorders.

“What we showed is that the novel proteins that were made in the dark genome are disrupted – either mutated or differentially expressed – in schizophrenia and bipolar patients,” said Prabakaran. His team has discovered about 250,000 plus protein-coding genes in the dark genome that can form new “druggable” targets to cure these conditions.

Scientists are using the information to develop drugs for hard-to-treat cancers.

The bulk of the dark genome is made of transposable DNA sequences or “jumping genes” that can move from one location to another in the genome. When misplaced, such a DNA can completely turn the gene on or off, make a new protein, or turn a healthy gene into a cancer-causing gene. A simple analogy would be adding random letters to a sentence, making it uninterpretable or changing its meaning.

Thankfully, there are mechanisms in place in our body that restrict the expression of these mobile DNA elements and their movements.

Researchers from Memorial Sloan Kettering Cancer Centre in New York have reported that one of the rare events of misplacement – dark genome-jumping genes into tumor-suppressor genes – is the reason behind aggressive childhood cancers. Such placement destroys the work of genes that function as the brakes to prevent cancer formation. Scientists are using the information to develop drugs for these hard-to-treat cancers.

The DNA elements of the dark genome also have implications for autoimmune diseases – conditions in which the immune system mistakenly attacks body tissues such as joints in rheumatoid arthritis.

Our immune system is “educated” to be tolerant of ourselves and react only to foreign molecules, such as viruses. However, the transposable DNA sequences of the dark genome that selectively express in conditions of stress, aging, UV light exposure and many more pose challenges to the immune system’s ability to discriminate between self and foreign.

Mustelin says that the dark genome transposable DNA elements can make the body’s tissue look “foreign” by making proteins that the immune system has not seen before including the ones that mimic viruses.

The discoveries may explain how, when, and why autoimmune diseases arise. They may also allow for earlier diagnosis and a personalized medicine approach to treat the right patient with the right medication and at the right time, says Mustelin.

The stretches of DNA between genes are called intergenic sequences, and they are “naturally” non-coding.

Using a combination of bioinformatics and experimental pipeline tools, Dhar and his team repurposed “intergenic” sequences of the dark genome from various organisms, including bacteria and fruit flies, to make synthetic peptides that can be used as a treatment for cancer, Alzheimer’s, infections and many more.

In explaining the antimicrobial applications of his discoveries, Dhar says “molecules synthesized from the dark genome have a better possibility of success, as microbes probably never met them during evolution and do not have a memory of their presence. Therefore, the chances of developing microbial resistance against ‘dark peptides’ is far less.”

Current discoveries are based on the information flow from DNA to proteins through RNA, called “coding RNA” and constituting only 1-2 per cent of the known genome. In contrast, the bulk of the dark genome has been shown to comprise a diverse repertoire of “non-coding RNAs” that lack the instructions to make proteins.

So, why do cells spend their energy and effort to make these RNA that are not going to be functional, wondered Jay Shin, Group Leader, Laboratory of Regulatory Genomics, A*STAR Genome Institute of Singapore.

By combining advanced experimental robotics approaches, Shin and his team found that these non-coding RNA molecules of the dark genome act as “control centres” of cells. They interact with genes, proteins, other RNA and even with each other to form complex regulatory networks to fine-tune the activities of cells. “And without (non-coding RNAs), you know, we’ve seen cells can die or can cause disease,” says Shin.

Shin says that identifying and understanding the function of non-coding RNAs of the dark genome could create untapped opportunities for precision medicine. For example, modulating specific non-coding RNAs can make cancer cells more sensitive to drug treatments, he said.

“Our genome is obviously very complex; we need to not only focus on what we are comfortable with like protein-coding genes but also on molecules of the dark genome, such as non-coding RNAs, that regulate and modulate what’s known,” says Shin.

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Bhargavi Duvvuri


Bhargavi Duvvuri, Ph.D., is a health scientist with expertise in autoimmune diseases. She is a fellow in global journalism at the Dalla Lana School of Public Health, University of Toronto.


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