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Thousands of Off-Target Mutations Plague CRISPR Gene Editing

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DNA

In recent months, headlines touting CRISPR’s potential ability to cure everything from HIV to blindness have dominated science news.

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May 31, 2017 | by Sarah Hand, M.Sc.

It’s an inconvenient truth that’s not often reported in the news: the CRISPR-Cas9 gene editing technique is currently not as precise as we’d hoped. A recent study, set to be published in the journal Nature Methods, has highlighted this fact by reporting that the technology may introduce hundreds or thousands of so-called off-target mutations into the genome.

“We feel it's critical that the scientific community consider the potential hazards of all off-target mutations caused by CRISPR, including single nucleotide mutations and mutations in non-coding regions of the genome,” said study author Dr. Stephen Tsang, Laszlo T. Bito Associate Professor of Ophthalmology and associate professor of pathology and cell biology at Columbia University Medical Center.

In recent months, headlines touting CRISPR’s potential ability to cure everything from HIV to blindness have dominated science news. Instead of just treating a genetic condition, the CRISPR-Cas9 gene editing platform is designed to correct disease-causing mutations in a fast and targeted manner. .

While researchers in the US have yet to test this technique on a human patient, a clinical trial involving CRISPR gene editing has already been initiated in China. Despite its precision, researchers have identified CRISPR’s propensity to alter all areas of the genome, potentially creating damaging mutations.

In their preclinical studies, researchers use predictive computer algorithms to identify the most likely areas affected by these off-target mutations. They then use this information to inspect these areas to confirm whether they have been affected by unintentional changes.

“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,” said study author Dr. Alexander Bassuk, professor of pediatrics at the University of Iowa.



To investigate how problematic these CRISPR-associated off-target mutations are, Tsang and his colleagues performed whole-genome sequencing on two mice that had undergone the technique. They scanned the sequence for any mutations that might have been caused by CRISPR gene editing, including single-nucleotide alterations.

While the CRISPR technique was confirmed to have corrected a mutation that causes blindness, the researchers found that gene editing was associated with over 1,500 single-nucleotide mutations and over 100 potentially more serious larger mutations.

Importantly, none of the identified mutations had been previously predicted by the commonly-used computer algorithms. The researchers noted that the mutations were not associated with a visually-obvious phenotype, however there’s no guarantee that they had no effect on the normal functioning of the mice.

“Researchers who aren't using whole genome sequencing to find off-target effects may be missing potentially important mutations,” said Tsang. “Even a single nucleotide change can have a huge impact.”

Despite their worrying findings, the researchers say that they’re still optimistic about the CRISPR gene editing technique. Their hope is that this research will help others develop more efficient and targeted methods for gene editing that minimize the potential for harmful off-target mutations.


Keywords:  CRISPR, Gene Editing, Gene Mutation


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