Scientists have created the first large-scale map of direct interactions between proteins in the human genome and predicted dozens of new genes that could be involved in cancer.
This diagram shows about 14,000 interactions between proteins discovered through the systematic process the scientists used in this study.
Photo courtesy of Thomas Rolland
The reference map of the “human interactome” describes about 14,000 direct interactions between proteins and other proteins, which is seven times more than any previous map of its kind has uncovered. The interactome is the set of physical connections between proteins, RNA and DNA segments in a genome, or the network of components that stick together.
CIFAR Senior Fellow Frederick Roth (University of Toronto), co-director of the program in Genetic Networks, and Marc Vidal at Harvard Medical School co-led the international research team that wrote the paper in Cell.
Using lab experiments and computer modelling, the scientists identified interactions and then zoomed in on genes that they knew to be related to diseases such as cancer, analyzing how their interactions were different.
“We show, really for the first time, that cancer genes are more likely to interconnect with one another than they are to connect to randomly chosen non-cancer genes,” Roth says. “Once you see that proteins associated to the same disease are more likely to connect to each other, now you use this network of interactions as a prediction tool,” he says.
For example, two known cancer genes encoded two proteins that interacted with CTBP2, a protein encoded at a location tied to prostate cancer, which can spread to nearby lymph nodes. These two proteins are implicated in lymphoid tumours, and so the researchers studied what role CTBP2 plays in the development of lymphoid tumours and found that it is likely involved in suppressing them.
Using their predictive method, the researchers found that 60 of their predicted cancer genes fit into a cancer pathway.
Discoveries like these are crucial for understanding how cancer and other diseases develop and ultimately, how to treat and prevent them. The vast majority of genetic interactions in the human body are a mystery. Roth compares the situation to having a car with an incomplete list of parts and very little knowledge of how the parts fit together.
“If somebody has a disease we actually need to repair the car,” he says.
Each gene can encode multiple parts, and researchers are working toward a comprehensive understanding of where all of those parts are and how they connect. Studies in baker’s yeast have mapped interactions for the entire genome, but the new study is the biggest done yet for humans.
The study also reveals that the network of genetic interactions in humans covers a much broader area of the genome than some past research has suggested. Studies often focus on those proteins that are known to be interesting, or tied to disease, which has created a bias in our understanding of where most interactions occur, Roth says.
“One major conclusion of the paper is that when you look systematically for interactions, you find them everywhere.”
Roth says the research is central to the goals of CIFAR’s Genetic Networks program, particularly building the map of how genotype, the set of genes, connects to phenotype, an organism’s characteristics, such as appearance and predisposition to disease. A major part of this effort among fellows has been sequencing cancer genomes.
This research was funded in part by the National Human Genome Research Institute, the National Cancer Institute, the National Institute of Child Health and Human Development, the National Institute of Mental Health, the Canada Excellence Research Chair program, the Krembil Foundation, the Ontario Research Fund and the Avon Foundation.