DNA image

What lies beyond: Uncovering the secrets of the dark genome

Institute scientists exploring genetic variants in the dark genome hoping to shed light on congenital heart disease and healthy ageing

17 January 2023

Portrait of A/Prof Emily Wong in our laboratory

Most of us understand the concept of inherited disease - that we can inherit gene mutations from our parents that increase our risk for particular diseases, including heart disease.

But what we and the scientific community don’t yet fully understand is what lies beyond these genes and what secrets it may hold that could change our understanding of how and why genetic diseases occur.

This area is known as the ‘dark genome’, and it’s of particular interest to the Institute’s Associate Professor Emily Wong and her team who are delving into the genetic unknown thanks to an $8 million Snow Medical Research Foundation Fellowship.

What is the dark genome?

Genes provide instructions to our cells to create molecules called proteins. These proteins perform a wide range of functions in our bodies. When this process is disrupted, disease can occur.

The dark genome refers to the parts of the genome that don’t create proteins. This ‘dark’ area makes up a staggering 98 percent of our genome and was once thought of as merely junk.

But scientists like the Institute’s Associate Professor Emily Wong know there are many secrets to be uncovered within this vast, yet poorly understood, part of our genome.

“There’s not a lot known about this dark area of the genome relative to the parts that make genes and encode proteins - so our work is trying to figure out how regions in that other 98 percent of the genome encode functional information,” says Associate Professor Emily Wong.

“This is particularly important because we know from previous studies that these regions play major roles in disease – we just don’t yet fully understand why and how.”

Introducing enhancers and silencers

The part of the dark genome Associate Professor Wong and her team are focusing their work on are regions called enhancers.

Every one of our cells has the exact same genome -- but what determines if this cell becomes a heart or a liver cell is controlled by DNA regions called enhancers.

Enhancers are controlling regions that are responsible for regulating the genes that make proteins, including what dosage of genes need to be expressed.

They’re critical to how our bodies develop, but the way they function or malfunction - and the role they play in contributing to heart disease – has remained largely unknown.

“Currently, when people screen for a genetic disease, they only look at protein-coding regions because we understand how these regions work,” says Associate Professor Wong.

“However, many disease-causing variants are not at protein-coding regions.”

Along with enhancers, Associate Professor Wong and her team are also studying the enhancer’s opposite: the silencer.

Silencers, as the name suggest, repress gene expression, whereas enhancers increase gene expression.

“Silencers very important in a multicellular organism, like humans, because it's not only what genes are expressed, but you also need to have a method of turning genes off as well so as to maintain the right balance to keep our cells and therefore our bodies functioning properly.”

Decoding the language of enhancers and silencers

One of the main focus areas for Associate Professor Wong and her team’s work is to understand the genetic code, or language, of enhancers and silencers.

“We talk about it in terms of grammar because you can think of these DNA regions as encoding a series of words amidst gibberish, but we don't yet understand what all the words are and how words need to be arranged for this region to function correctly,” says Associate Professor Wong.

“So essentially, we are working to decipher these words to understand the book of a human genome. It is similar to cryptology in a way.”

To understand this language, the team are using both computational and experimental approaches.

“We are taking the latest developments in computational biology, which includes things like deep learning - which I'm sure lots of people have heard about with the popularity of ChatGPT – and we are applying this kind of technology to the human genome,” says Associate Professor Wong.

“Once we think we understand the language, then we go into the lab and test whether they're saying what we think they're saying. So for example, if the computational methods are telling us this particular arrangement of DNA pieces need to be next to each other for this region to be acting as a regulator for an important protein to make heart muscle cells, then we can take these two regions and we can synthetically make this DNA sequence and test it in the lab.”

Thanks to the latest technology, Associate Professor Wong and her team are able to create tens of thousands of sequences at a time.

“This level of output is important for our lab because it allows us to take powerful data science approaches that recognise patterns and allow us to distil the grammar and the rules of the dark genome,” says Associate Professor Wong.

“We've been focused on developing these capabilities in our lab.”

Understanding the role of enhancers and silencers in congenital heart disease

The ultimate aim of Associate Professor Wong’s work is to understand how enhancers and silencers work to then better understand their role in disease, which could one day lead to new treatments for heart disease and other chronic conditions.

One of the team’s first projects is trying to shed light on what drives congenital heart disease – where the cause remains unknown in around 80 percent of cases.

Associate Professor Wong and her team are working with the Institute’s Professor Sally Dunwoodie and Associate Professor Eleni Giannoulatou who are studying families with inherited congenital heart disease.

“Professor Dunwoodie and Associate Professor Giannoulatou have sequenced the entire genome and currently they are looking at those changes at protein-coding regions that are linked to congenital heart disease, but they haven't looked at the enhancers and silencers – which is the area we are interested in,” says Associate Professor Wong.

“Currently, the causal genetic variant for the majority of congenital heart disease cases is not identified. By looking at the dark genome, we hope to be able to identify some of these causal genetic variants.

“In the longer term, we hope this research could help us to better understand the causes of many different diseases, not just congenital heart disease.”

Associate Professor Wong and her team will also explore the role enhancers play in how our bodies age. The aim is to try and decipher why exercise is beneficial for heart health.

It’s very early days but it is hoped it could lead to a whole new field of healthy ageing therapeutics where ageing hearts are being rejuvenated.

Supporting discovery research through long-term funding

This work would not be possible without the $8 million Snow Medical Research Foundation Fellowship that was awarded to Associate Professor Wong in 2022.

The funding has allowed Associate Professor Wong to grow her team significantly - from two staff members to eleven.

“We now have four PhD students, one honours student, five postdocs, and one research assistant on our team - and most of these staff have been hired this year,” says Associate Professor Wong.

The team now includes staff members with expertise in computer science, molecular science, and proteomics, which is the study of proteins, and there are plans to recruit another staff member with a background in human genetics.

“I have not only been able to recruit excellent people, but I’ve also been able to get a strong team together that is interdisciplinary - that diversity is really important because it allows us to address the research in a more holistic way,” says Associate Professor Wong.

Having eight years of funding secured has also allowed Associate Professor Wong to dedicate her time to her research, rather than the business side of science.

“It’s transformative to have this funding because instead of worrying about grants and thinking short term, it allows me to plan longer term and to consider what we can achieve in a bigger vision of science than what I was able to do previously,” says Associate Professor Wong.

“Some of our work is in ageing, so we need time to allow the animals we work with to age. It also allows us to invest in the latest single-cell sequencing technologies – which come with significant costs. So having that long-term funding takes the pressure off in many areas of our research.”

For Associate Professor Wong, one of the biggest advantages of the Snow Fellowship is the fact that it allows her team to focus on discovery research that has the potential to transform our understanding of the human genome.

Associate Professor Wong says: “Translational research, directly applicable to human health, is well-funded but limited in scope. Just as exploring new places requires venturing into the unknown, so does biomedical advancement. In Australia and much of the world, translational research often overshadows discovery research. However, the benefits of discovery science are enormous. For example, imagine how many more problems we'd solve in the human body if we could read the genome and understand the story.”

Acknowledgement of Country

The Victor Chang Cardiac Research Institute acknowledges Traditional Owners of Country throughout Australia and recognises the continuing connection to lands, waters and communities. We pay our respect to Aboriginal and Torres Strait Islander cultures; and to Elders past and present.

Victor Chang Cardiac Research Institute - The Home of Heart Research for 30 Years