Unlocking the Mysteries of the Human Genome Could Revolutionize Our Understanding of Disease
Olivia Corradin is an assistant professor of Biology at MIT and a core member of the Whitehead Institute. She investigates the genetic and epigenetic changes in gene regulatory elements that influence human disease.
By: Daniel de Woff
In the last decade alone, researchers have identified well over a hundred thousand genetic variants—permanent changes in the DNA sequence that makes up our genome—that can contribute to the likelihood of developing disease. Olivia Corradin and her team of researchers in the Corradin Lab at MIT are making the most of all this data to derive insights that could revolutionize our understanding of disease. “Our strategy at the Corradin Lab is to understand disease by understanding how the genome functions,” she says.
Extracting disease insights from an identified variant is complicated because most of the genetic risk factors for disease aren’t located in genes. The human genome has about 3 billion base pairs of DNA, but less than two percent of these are protein-coding genes. That means about 98 percent of the human genome is comprised of noncoding DNA. So, if the genetic variants that have been linked to different diseases don't affect proteins, what are they affecting? Corradin explains that some variants affect things like the splicing of RNA, but the majority of them are located in gene regulatory elements—areas of the genome that control which genes are turned on and off in different parts of the body.
“Our strategy at the Corradin Lab is to understand disease by understanding how the genome functions”
As a child, Corradin could often be found poring through her collection of National Geographic magazines. Glossy prints of anomalies, like blue-footed boobies and duck-billed platypuses, were her favorites; she was entranced with the weird ones. In high school she learned about DNA, nature’s four-letter alphabet: A(denine), T(heymine), C(ystosine), G(uanine); four chemicals, a double helix carrying the instructions for the development and functioning of every living organism. Such diversity across the planet, all derived from the same building blocks, responsible for not just the platypus and the boobie, but for humans as well. Corradin’s essential conundrum, pondering the multiformity that springs from one genome so similar across human beings, even other species, would eventually lead her to pursue research opportunities that allowed her to explore how the genome works.
As a graduate student at Case Western University, Corradin had a revelation while scanning the results of an experiment. She noticed a pattern: “I realized that the genetic variants in the dataset were localizing to regions where multiple regulatory elements are active at the same time in the same general region of the genome,” she says. “That just screamed to me, ‘You have to look at how genetic variants act in combination to get a clearer picture of the link to disease. If one variant affects this large region, what are the genetic variants next door doing?’.” To this day, Corradin explores how regulatory elements work together and how the genetic variants underlying these elements work together as well.
When considering genetic variants in the context of disease, it makes sense to understand which part of the body is affected. “Whether a variant affects skin cell function or brain cell function leads you to a very different hypothesis about how the disease works, let alone how you would treat it,” says Corradin. Traditionally, researchers have studied one variant at a time to see if it functions in a particular type of cell (e.g., neurons or T-cells). But, says Corradin, this strategy only gives you one clue about what part of the body is affected, which leads to many hypotheses about how a genetic variant may be contributing to disease pathology. Instead, Corradin’s approach is to examine variants in an entire genetic region. This strategy gives her multiple clues that can be used collectively to identify where the genetic variant is having an impact, thus narrowing down the hypotheses.
While her approach could be applied to any number of diseases, multiple sclerosis (MS) has proven to be of particular interest to the Corradin Lab. MS works by attacking the brain’s myelin, a layer of proteins and fatty acids that protects the brain’s neurons. Corradin recently conducted a study to find out more about the cells responsible for myelin, and whether genetic changes influence their function. She notes that there are already a fair number of effective therapies that slow the course of the disease, but they work by preventing the immune system from attacking the brain rather than addressing the actual deficits in the brain.
“By understanding which genetic changes influence the functions in the brain, we can think about therapeutics that directly treat the deficits that arise during the course of the disease,” says Corradin. “The idea that you could use a therapy to promote myelination in the brain is considered a great way to treat the symptoms directly rather than the cause. And if you're experiencing neurogenerative symptoms, you want to treat those directly.”
On the opposite end of the spectrum, Corradin researches the link between genetic variations and opioid addiction. In a recently published paper, she was able to identify a confluence of vulnerabilities tied to opioid dependence. Rather than looking at the genetic variants themselves, she focused on structural changes in the genome for clues, which revealed some unexpected findings. The assumption was that exposure to opioids creates a clear signature of change in the brain. For example, one might expect that after an opium overdose there would be changes in the genes that express opioid receptors, or perhaps a more ubiquitous but common change. But Corradin was surprised to see very different reactions from person to person.
Further inspection, however, showed that these variable changes tended to occur in a similar area of the genome. It was a discovery that Corradin says opened the door to considering how those particular genes are important during the course of the disease. It also changed the way she thinks about these types of epigenetic studies, and how we may be able to use differences that are specific to the individual to derive uniform principles about disease.
Looking forward, Corradin suggests that as we consider the development of therapeutic strategies, it’s important to take a holistic approach to treatment of the disease and the patient. “We have a tendency to focus on the one causal tissue for the disease rather than thinking about the system that is affected. Now that we have these large data sets that describe not only the diseases themselves but also how cells function in the human body, we can ask more detailed questions,” she says. On a related note, she acknowledges that researchers tend to want to express their work in the clearest way possible—which is a good thing. But she cautions stakeholders at every level, from the lab to the real-world, that it is essential to accept the complexity of disease biology if we’re going to make strides and reap the benefits of the work.
Watch the interview with Prof. Corradin here: https://youtu.be/DaO0cs8IlSA