Genome-wide identification of genetic interactions in human cells using CRISPR/Cas9

• Applicant: Dr. Maximilian Billmann
• Subject Area: General Genetics and Functional Genome Biology ; Biochemistry ; Bioinformatics and Theoretical Biology ; Cell Biology
• Term: from 2018 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398518031

The human genome has been fully sequenced for almost two decades, providing a reference map for genetic elements. A major focus of systems biology and genomic medicine is to link genotype to phenotype, yet we remain far from accurately predicting disease states from genome sequence. Genetic interaction maps in model organisms have shed light on this problem, highlighting how combinations of genome variants can impact phenotypes. While technical challenges have limited similar endeavors in human cells, the disruptive CRISPR-based genome editing technology enables this combinatorial mutation approach. We propose to systematically map genome-wide genetic interactions using CRISPR/Cas9 in human HAP1 cells. While the experimental tools are largely in place, major computational challenges need to be addressed to realize the potential of these data. Based on initial genome-wide CRISPR/Cas9 screens across 53 genetic backgrounds, I propose to develop novel computational methods for quantifying genetic interactions. I will also develop algorithms to optimally expand our screening efforts to the most informative ~3.5 million gene pairs (~200 genetic backgrounds) and subsequently define a compressed gene set that covers most of the measured information. Finally, I will develop methods for structuring the genetic interaction data and integrating genome-scale existing data such as protein-protein interactions, to guide interpretation of the global organizational principles of human gene function. Together, we will deploy CRISPR/Cas9-based screening and information-based genetic background selection to generate the first genome-wide genetic interaction map of a human cell. These efforts will provide us with a functional map of human gene function, which will impact the broader community’s efforts to understand the biology of human cells and how genetic variants lead to disease.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Chad Myers, Ph.D.