Myers Lab Featured in Cell Journal for Genetic Network Mapping Project

Department of Computer Science & Engineering Professor Chad Myers and several of his lab members were featured in the latest issue of Cell for their work on mapping genetic networks. Cell is the flagship, peer-reviewed journal for Cell Press and focused on exciting biological advancements and scientific achievements. The paper, titled, “A global genetic interaction network of a human cell maps conserved principles and informs functional interpretation of gene co-essentiality profiles,” is a collaboration between 16 institutions, with researchers from the University of Minnesota, University of Toronto, The Hospital for Sick Children in Toronto, and the University of Bonn in Germany leading the effort. Several Myers lab members played a key role in this work, with former post-doc Max Billmann and PhD students Xiang Zhang, Arshia Hassan, and Mahfuz Rahman all featured as co-lead authors on the paper. 

Myers’ project mapped a systematically surveyed network of interactions in the human haploid cell line HAP1. A genetic interaction occurs when the combination of two or more mutations results in a surprising effect. Many mutations in the genome have little impact when they occur individually, but when combined with other mutations can affect an organism, such as cause specific traits or disease risk. Using CRISPR technology (short for “clustered regularly interspaced short palindromic repeats”), the research team selectively introduced mutations in approximately 4 million gene pairs, resulting in the discovery of over 89,000 high-confidence gene-gene interactions. 

“The CRISPR cell-line project is a systematic mapping project,” Myers said. “CRISPR allows us to take a human cell line, introduce combinations of mutations into genes, and measure how much it affects their ability to grow in a dish. We are mapping a systematically surveyed network of these interactions in an exhaustive way so that we can start to generalize rules around interactions between genes.”

“Very few people are doing systematic surveys of genetic interactions; that is what is unique about our project,” Myers said. This work builds on nearly two decades of previous work by the Myers Lab and their collaborators, Charlie Boone, Brenda Andrews, and Michael Costanzo (all U. of Toronto) in which they tackled a similar genetic interaction mapping challenge in the yeast model organism. Their yeast work demonstrated how valuable genetic interactions are for understanding gene function. 

“In our yeast research, we mapped a social network of genes,” Myers said. “When we do these experiments, we are connecting genes that when deleted or mutated together, have a surprising effect on growth. Once you start analyzing that network, you can build a map of how everything is related." 

The introduction of CRISPR technology opened the doors to expand this same process of combining systematic mutations to human cells. 

"We are now applying that methodology to the human genome,” Myers said. “Mapping these networks is a way to learn about how genes function, which can broadly push forward our knowledge of human biology and serve as the basis for other research endeavors.”

The exploratory and systematic nature of this project required a true team effort. After the success of the yeast project in 2016, Myers, Boone, and Andrews teamed up with Jason Moffat, an expert in human functional genomics at The Hospital for Sick Children in Toronto, to help transition from yeast to human cells. The team worked together to design experiments and interpret the resulting data. The Toronto groups carried out the large-scale CRISPR screens while the Myers Lab handled the interpretation of the huge amounts of sequencing data, which is used to understand the effects of the mutations introduced in each screen.

“My lab has developed new computational approaches to measure effects of gene mutations from CRISPR screen sequencing data and ensure we are measuring the right things,” Myers said. “That has been a key output of this work - understanding how to use CRISPR technology to get the measurements that we want and then interpreting the interactions we derive from those measurements. This has been a long, iterative process to build a road map for this new technology in order for future researchers to generate tons of data that we can interpret reliably.”

There are several potential long-term applications of this work. The genetic interactions they mapped show how genes work together inside human cells and how those relationships can help explain why diseases develop and vary from person to person. The results suggest that the effects of a disease-causing mutation often depend on the presence of mutations in other genes in the genome, which may either worsen or protect against illness. By identifying these gene partnerships, the research points to new ways to find drug targets, especially for cancers where specific gene combinations can be exploited for treatment. Overall, this work helps lay the groundwork for more personalized approaches to predicting, preventing, and treating disease.

The research was funded primarily by the National Institutes of Health, the Canadian Institutes of Health Research, the Ontario Research Fund, and the National Science Foundation.

Learn more about this work in the latest issue of Cell.