CRISPR-Cas9 Generates Heritable Mutations in Zebrafish

Swedish scientists have discovered that the use of CRISPR-Cas9 to address disease could create unforeseen and hereditary changes in DNA and are urging caution when applying the revolutionary genetic engineering tool for medical purposes.  

Adam Ameur, associate professor at Uppsala University and the Science for Life Laboratory (SciLifeLab), says the team studied the effects of CRISPR-Cas9 in zebrafish. “Since DNA molecules and their mechanisms are similar in all animals, we think the results should be similar in humans, for example,” he says.

When the group studied the genome of more than 1,000 zebrafish from two generations, the researchers found unexpected mutations of various types. In some cases, DNA fragments that were larger than anticipated underwent changes, while in other cases mutations occurred in the wrong location in the genome. Unforeseen mutations were found in first-generation zebrafish, but also in their offspring.

Such unwanted mutations have been studied in cells, but insights into the potential consequences for living organisms have so far been limited.

“Knowing these unexpected mutations are heritable is important, since they can have long-term consequences for future generations. But that can happen only if you change the genome of embryos or germ cells,” adds Ida Höijer of Uppsala University and SciLifeLab.

In healthcare, methods tailored to correct genes in a particular tissue or cell type are now being developed. Although such treatments pose no risk to future generations, caution is advisable.

“CRISPR-Cas9 can be an amazingly valuable tool in health care. But we need to minimize the risk of unwanted effects, and we can do this by carefully validating the modified cells with the latest DNA sequencing technologies,” Ameur says.

The study, entitled CRISPR-Cas9 induces large structural variants at on-target and off-target sites in vivo that segregate across generations, was published recently in Nature Communications.