CRISPR’s ‘ancestry problem’ misses cancer targets in those of African descent

Engineering plants, tailoring lab animals, and probing basic biology can all be done with the help of the 10-year-old gene-editing tool. Unlike lab mice, which are usually inbred and genetically identical, people's genomes are different.

People of African descent are more likely to have their genomes differ from those used to steer CRISPR to a specificGene. Failing to account for ancestry slightly skewed a massive sweep for cancer genes, causing it to miss genes important as drug targets in those of recent African descent

Luca Pinello of the Massachusetts General Hospital says that the study shows a clear example of the problem. Tools to avoid it are proposed by the scientists.

The first step in editing a human gene is to design a short strand ofRNA. The guideRNA leads to the right spot. The guide RNA may not match the genome being edited.

The guideRNAs are usually based on a few people's genes that don't fully capture human diversity Europeans and Asians have ancestors who left Africa a long time ago, but people with African ancestry are more diverse.

Sean Misek, a PhD student at the Broad Institute of MIT and Harvard and the lead author of the new preprint, wanted to explore ancestry issues with CRISPR in cancer biology. The Cancer Dependency Map was used by his team to knock out 18,000 genes in 1000 lines of cancer cells. The project was looking for genes that could be targeted with drugs.

The team, which included senior authors Jesse Boehm at the Massachusetts Institute of Technology and Broad and Rameen Beroukhim of Broad and the Dana Farber Cancer Institute, found that CRISPR failed to knock out 2% to 5% of the genes. The errors were more common in the cell lines from people with recent African ancestry. Misek says that we are missing cancer drug targets in people of African descent.

Pinello's lab and others have shown how ancestry mismatches can cause CRISPR to cut the genome in the wrong spot when it is used to treat diseases such as sickle cell disorder which affect people of African ancestry. It's possible that off-target cuts will lead to cancer. Olorunseun Ogunw of Hunter College of the City University of New York says that the exclusion of diverse populations in genome studies can contribute to cancer health inequity.

Both teams have built free web tools that compare a proposed guideRNA with tens of thousands of genomes procured from diverse populations. The Boehm and Beroukhim labs have a website called ancestrygarden.org that allows users to assess the impact of ancestral diversity. Pinello's team checks for off targets. Misek says the goal is to push people to rethink how they use the lab.

The web tools should help in the fight against breast cancer, says a researcher. Adam Phillippy is a researcher at the National Human genome Research Institute. Tools like this can help alleviate the bias in the first place.