Yale researcher receives award to investigate “dark matter” of the human genome
Sarah Slavoff’s work studying the “dark matter” of the human genome could lead to the development of more effective treatments for melanoma.
Courtesy of Elizabeth Watson
Sarah Slavoff, an associate professor of chemistry and of molecular biophysics and biochemistry, won the 2022 Emerging Leader Award from the Mark Foundation for Cancer Research for her work studying the “dark matter” of the human genome.
Slavoff, who was also recognized for the potential implications of her research in the fight against melanoma, will receive an annual grant of $250,000 for three years. The award will fund her project to investigate proteins that have not yet been identified and their links to melanoma, a type of severe skin cancer.
“The work for the Mark Foundation is going to allow us to really deeply identify these genes that are associated with melanoma treatment resistance, or novel unannotated genes, to fully demonstrate their mechanisms of action so that we can understand what they’re doing and how that’s affecting the tumor cells,” Slavoff said.
Slavoff first became involved in this branch of research during her time as an NIH Ruth L. Kirschstein Postdoctoral Fellow at Harvard University. Although the Human Genome Project was officially completed in 2003, scientists suspected that there were parts of the genome that remained unknown. Alan Saghatelian, Slavoff’s mentor at Harvard and the Dr. Frederik Paulsen Chair at the Salk Institute for Biological Studies, used mass spectrometry proteomics to study the proteins present in a given biological sample.
They discovered that, of the thousands of spectra that could be collected in a single experiment, there were some that could not be identified. While at Harvard, Slavoff played an important role in developing the first technologies to begin this identification process.
“She [Slavoff] published several papers as a postdoc but the most notable was work describing the discovery of nearly 100 previously unknown microproteins,” Saghatelian said. “Her work showed a large class of unannotated microproteins that exist stably within cells, suggesting that microproteins should be able to function similarly to longer proteins and lay the foundation for functional studies to characterize these genes. Furthermore, the field has identified thousands of microproteins encoding genes in various genomes, and Dr. Slavoff’s work was one of the critical findings that drove this field forward.”
Slavoff continued researching this area in her own lab at the Yale Institute of Biomolecular Design and Discovery. Her work focuses on developing not only new methods to detect the unknown microproteins of the human genome, but also ways to understand its function.
The concept behind the term “dark matter” is that there are genes within the human genome, sometimes referred to as ghost proteins, that have always existed and been expressed but remained undetected because they were smaller than the cutoff size that is used to analyze the genome: 100 amino acid units.
“Our hypothesis is that some of these novel genes in this dark matter of the proteome might be associated with the mechanisms by which melanoma escapes from current treatments,” Slavoff said. “If we can identify that, then we can learn something about those mechanisms, and even more importantly, hopefully an aspirational goal for the future is that they could inform new therapies.”
A particular area of interest for Slavoff is the potential connection between “dark matter” and human diseases.
She has worked in conjunction with Ruth Halaban, a senior research scientist in dermatology at the Yale Cancer Center, to study its relationship in particular with metastatic melanoma.
“Now we’re moving toward asking if this dark matter is linked to disease, and there’s lots of preliminary evidence from other groups around the world that it is,” Slavoff said. “We’re asking this specific question with the Mark Foundation about, really a pernicious problem, which are cancers that are drug-resistant or can’t be treated.”
There are two primary methods that are used to treat patients suffering from melanoma. Patients can either take drugs that can combat the driving enzymes within a tumor or undergo the process of immunotherapy to mobilize the immune system against the tumor. These methods, although capable of shrinking tumors, are not always effective. Roughly half of melanoma patients cannot be treated, according to Slavoff. By focusing upon this “dark matter” as opposed to the genes traditionally targeted by current treatments, Slavoff hopes to find a way to formulate more effective treatments for melanoma patients.
Jason Crawford, director of the Yale Institute for Biomolecular Design and Discovery, acknowledged the potential ramifications of the research being conducted by Slavoff’s lab. He further noted the strong sense of teamwork that Slavoff fosters in her lab.
“She is very caring for her students and is a strong mentor and tries to establish a sense of teamwork and team goals,” Crawford said. “She’s a leader in the area of microproteins, so she and her lab are really pushing the envelope in this new area, a largely understudied area.”
Slavoff came to Yale in 2014.