New Study Finds CRISPR/Cas9 Drives Unexpected Genomic Changes

New Study Finds CRISPR/Cas9 Drives Unexpected Genomic Changes


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The widely used gene scissor (CRISPR/Cas) can alter the genetic content of cells to study the molecular roles of genes and has gained great clinical relevance in gene therapy to treat genetic diseases. A new study by Claudia Kutter’s research group at the Department of Microbiology, Cellular and Tumor Biology at Karolinska Institutet, has found that genetic scissoring leads to unexpected genomic changes.

“We found that CRISPR/Cas9 causes unpredictable genomic effects on the target that impacted cancer cell growth. Instead of slowing down, the cancer cells grew faster. As CRISPR/Cas genome engineering has become a mainstream tool in research and clinical applications, we believe that our new insights, along with our innovative and robust approach, will be useful in assessing genomic changes,” says Dr. corresponding author Claudia Kutter, senior researcher at the Department of Microbiology, Cellular and Tumor Biology, Karolinska Institutet.

The research team developed a novel approach to decipher genomic changes at high resolution and to uncover variable genomic effects at the targeted locus.

“To explain the surprising phenotype of the cells, we combined the latest technological approaches. First, we specifically enriched our targeted gene sequence in microdroplets (Xdrop). Second, we read the genetic sequence using long-read sequencing technology nanopore (ONT-LRS). Finally, we developed a sophisticated computational pipeline that deciphered the exact changes in the genomic sequence,” says first author Keyi Geng, a Ph.D. student in Claudia Kutter’s research group. .

The paper is published in Genome research. The research team is currently studying other CRISPR/Cas effects in human cells, with a particular focus on cancer cells that have escaped cancer treatments.

“It helps us understand how our genetic material is repaired if damaged. Although CRISPR/Cas is very powerful, we need to find better ways to control CRISPR/Cas activity in human cells. Making CRISPR/Cas safer for patient treatments is therefore a major challenge. effort in my group,” says Claudia Kutter.

More information:
Keyi Geng et al, Target-enriched nanopore sequencing and de novo assembly reveal co-occurrences of CRISPR-Cas9-induced complex on-target genomic rearrangements in human cells, Genome research (2022). DOI: 10.1101/gr.276901.122

Provided by Karolinska Institutet

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