Computationally designed hyperactive Cas9 enzymes

Pascal D. Vos, Giulia Rossetti, Jessica L. Mantegna, Stefan J. Siira, Andrianto P. Gandadireja, Mitchell Bruce, Samuel A. Raven, Olga Khersonsky, Sarel J. Fleishman, Aleksandra Filipovska and Oliver Rackham ()
Additional contact information
Pascal D. Vos: Curtin University
Giulia Rossetti: QEII Medical Centre
Jessica L. Mantegna: Curtin University
Stefan J. Siira: QEII Medical Centre
Andrianto P. Gandadireja: Curtin University
Mitchell Bruce: Curtin University
Samuel A. Raven: Curtin University
Olga Khersonsky: Weizmann Institute of Science
Sarel J. Fleishman: Weizmann Institute of Science
Aleksandra Filipovska: QEII Medical Centre
Oliver Rackham: Curtin University

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract The ability to alter the genomes of living cells is key to understanding how genes influence the functions of organisms and will be critical to modify living systems for useful purposes. However, this promise has long been limited by the technical challenges involved in genetic engineering. Recent advances in gene editing have bypassed some of these challenges but they are still far from ideal. Here we use FuncLib to computationally design Cas9 enzymes with substantially higher donor-independent editing activities. We use genetic circuits linked to cell survival in yeast to quantify Cas9 activity and discover synergistic interactions between engineered regions. These hyperactive Cas9 variants function efficiently in mammalian cells and introduce larger and more diverse pools of insertions and deletions into targeted genomic regions, providing tools to enhance and expand the possible applications of CRISPR-based gene editing.

Date: 2022
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DOI: 10.1038/s41467-022-30598-9

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