Shedding Light on the Dark Genome

Newly described proteins lead to promising new drug therapies

In high school biology we were taught that thousands of different proteins give shape to the cells in our skin, muscle, nerves, organs and connective tissue. Each protein is built from a chain of amino acids according to a template encoded in our DNA - the genome.

While scientists have successfully recorded most of the roughly three billion "letters" in the human genome, they have not fully unraveled the "proteome" - the corresponding set of proteins in the body. In fact, nearly one in three of our proteins have not been characterized in any detail, and more than 6,000 proteins encoded by this "dark" genome remain largely unstudied.

The quest to better understand the dark genome - and perhaps uncover new treatments for disease - has long been a driving passion for Tudor Oprea, MD, PhD, professor and chief of the Translational Informatics Division in The University of New Mexico's Department of Internal Medicine.

"Only about 3,000 human proteins are well-studied, well understood," Oprea says. "Think about it - our pharmacology and biochemistry textbooks cover about 15 percent of the human proteome. A lot more work is needed to complete the rest of the puzzle."

Oprea is a leading researcher in the Illuminating the Druggable Genome (IDG) project, funded by the National Institutes of Health. It includes U.S. researchers at the University of California, Davis, University of California, San Francisco, University of North Carolina at Chapel Hill, Washington University in St. Louis, the Icahn School of Medicine at Mount Sinai, the University of Miami and Massachusetts General Hospital, as well as collaborators in England, Denmark, Romania and India.

In the first two months of this year Oprea received a $1 million continuation of his multi-year grant for the IDG Knowledge Management Center, and he will also share in a new $588,000 award with a colleague at The Jackson Laboratory in Bar Harbor, Maine.

Oprea and Larry Sklar, PhD, distinguished professor in the UNM Department of Pathology, Maralyn S. Budke and Robert E. Anderson Distinguished Endowed Chair in Cancer Drug Discovery and director of the UNM Center for Molecular Discovery, also partner with a colleague at the University of Miami School of Medicine in the IDG's Resource Dissemination and Outreach Center.

Last year, Oprea's IDG Knowledge Management Center proposed an elegant four-part scheme for categorizing the genome according to how extensively genes - and the proteins they code for - have been studied.

Until now, the knowledge deficit has tended to be self-perpetuating, because scientists are more likely to receive funding to study those areas of the genome that are already relatively well described - a little like the tipsy man looking for his keys under the streetlight because that's where the light is.

Through the IDG consortium, NIH is leading the global effort to guide scientists toward exploring understudied proteins, some of which are sure to be promising targets for new drug therapies.

In fact, 2018 was an outstanding year for adding new pieces to the puzzle: a record 14 new drug targets entered the market as new medicines were approved in the U.S., Europe and Japan. And at the moment, the IDG has 400 additional "dark" puzzle pieces in its cross-hairs, with more breakthroughs anticipated soon.