Profiling the genome hundreds of variations at a time using CRISPR–Cas9

 

Geneticists have been using model organisms ranging from the house mouse to the single-cell bakers’ yeast, Saccharomyces cerevisiae, to study basic biological processes that regulate human development and physiology, and that can be compromised in various diseases. This has been possible because many of the genes that control these processes in humans are also present with similar functions in those other species; and because genes in model organisms can be mutated and deleted in the laboratory at will. Thus far, however, even in easy-to-manipulate yeast, genes had to be deleted one-gene at a time, often with additional undesired sequence modifications left behind in their genome.

A team at Harvard’s Wyss Institute led by its Core Faculty member George Church now presents a CRISPR-Cas9-based strategy in Nature Biotechnology that solves both of these problems. Using baker’s yeast, the researchers developed a high-throughput approach that allows researchers to precisely alter hundreds of different genes or features of a single gene at once in individual yeast cells with 80 to 100% efficiency, select cells from the population that show specific behaviors, and identify the gene alterations that either trigger or prevent them.

“Our method not only offers a more efficient and precise way to perform high-throughput “functional genomics” in yeast than what was possible with previous methods. It will also allow us to model and test subtle human gene variations in yeast cells that have been loosely associated with certain traits or disorders, and find out which ones may actually be relevant,” said Church, Ph.D., who also is Professor of Genetics at Harvard Medical School (HMS) and of Health Sciences and Technology at Harvard and the Massachusetts Institute of Technology (MIT).

 

“This newest application of the CRISPR-Cas9 technology that emerged through a dynamic collaboration between the Church and Collins labs opens yet another path towards discovery of previously hidden molecular mechanisms by which cells regulate their physiology, and when dysregulated, lead to infections as well as human disease,” said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.

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