CRISPR-Cas9 can Cause Off-target Mutations

CRISPR-Cas9 can Cause Off-target Mutations

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Highlights:
  • CRISPR-Cas9 has been heralded as the gene editing tool of choice to correct genetic disorders
  • While there have been previous concerns on safety, clear studies were unavailable to validate the concerns
  • Researchers at the Wellcome Sanger Institute in the UK have published a study in Nature Biotechnology on the off-target mutations caused by CRISPR-Cas9
  • Prof. Allan Bradley and fellow researchers including PhD student Michael Kosicki examined the effects of the genomic editing tool on mouse stem cells and human retinal epithelial cells.
  • The team found unexpected effects which included large deletions, insertions or mutations which took place DNA kilobases away from the target site where CRIPSR-Cas9 was used.
  • These potentially harmful mutations can disturb healthy cell and gene functioning
  • Editing errors can have serious consequences if other important genes are switched Off or On to the extent of causing cancerous lesions
  • The researchers also warn that such errors cannot be easily picked up with standard genotyping

CRISPR -Cas9 Study in Detail

So far studies on genetic alterations caused by CRISPR-Cas9 were limited to nearby areas of the target site and this led to the conclusion that CRISPR was fairly specific. However, researchers at the Wellcome Sanger Institute in the UK have published a study in Nature Biotechnology on the off-target mutations caused by CRISPR-Cas9.
CRISPR-Cas9 can Cause Off-target Mutations

The team explored mutant alleles due to Cas-9 at the site of X-linked PigA in male embryonic stem cells of mice. They found that cells edited with intronic guides showed loss of the exon next to it. This further led to deletions which in turn caused lesions many kilobases away from the original site of editing. Significantly, 23 out of 133 recovered alleles had single-nucleotide polymorphisms, deletions and insertions.

To understand and analyze DNA damaged due to genomic editing, the researchers examined edited female human retinal epithelial cell lines (RPE1). PCR genotyping and Sanger sequencing indicated deletions, insertions, inversions and lesions.

The research results indicate that safety needs to be revisited in using CRISPR-Cas9 when genomic editing is carried out ex vivo. Short range PCR assays are unable to pick up the extensive damage. The researchers warn that robust genomic analysis is required to identify cells with normal genomes before this is used clinically. 

Reference:
  1. Kosicki, Michael., Tomberg, Kart., & Bradley, Allan. "Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements." cited in Nature Biotechnology (2018), July 19, 2018


Source-Medindia

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