CRISPR gene editing causes hundreds of unintended, off-target mutations

A new study finds that the revolutionary CRISPR-Cas9 gene editing technique can cause large numbers of unwanted insertions and deletions of genetic material, writes Jana Howden.

Illustration of a DNA molecule.
While CRISPR technology allows precise editing of DNA, new research shows that it can have many unintended consequences.
Endai Huedl / Getty

CRISPR-Cas9 gene editing technology allows researchers to delete, repair, or replace flawed genes with precision and speed. But is it too good to be true?

New research to be published in Nature Methods shows that the technology may cause unwanted side effects, capable of introducing hundreds of unintended mutations into the genetic material of treated organisms.

A team of US based researchers from Stanford University, Columbia University and the University of Iowa sequenced the whole genome of mice that had previously undergone CRISPR gene editing.

The CRISPR-Cas9 technique works by locking onto a string of DNA where it makes a calculated cut at a precisely determined location. This allows scientists to then insert new bits of DNA into the newly formed gap, or to delete or replace flawed genetic material.

Yet despite targeting specific regions of DNA, the technique can sometimes affect other parts of the genome and cause off-target mutations.

The researchers first used CRISPR to correct a faulty gene in mice that was causing blindness.

Later, by looking at the full genomes of the mice, they also found that two of the mice treated with CRISPR technology had undergone 1500 unintended single nucleotide mutations, as well as more than 100 large deletions and insertions of genetic material.

How could such significant side effects of this promising technology have so far flown under the radar?

One of the study’s authors, Alexander Bassuk from the University of Iowa, points to computer algorithms, which are used to isolate regions of the genome most likely to be affected by off-target mutations associated with the technology.

“These predictive algorithms seem to do a good job when CRISPR is performed in cells or tissues in a dish, but whole genome sequencing has not been employed to look for all off-target effects in living animals,” Bassuk explains.

None of the unintended mutations found in the mice were predicted by computer algorithms, and they were only found because the research team conducted an analysis of the full genome.

Nonetheless, the affected mice didn’t present any obvious problems that could be pinned on the off-target mutations, and the researchers remain hopeful that unintended side-effects may be reduced in future.

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