News of Note—Detecting CRISPR’s off-target effects; Gene variants that protect against obesity

CRISPR technology for genome editing (Source: AstraZeneca)
A team of researchers collaborated with AstraZeneca to develop a technology called Discover-Seq that uses the DNA repair process to discover off-target CRISPR gene edits. (AstraZeneca)

AstraZeneca’s approach to detecting off-target CRISPR effects

CRISPR gene editing holds promise for treating a variety of diseases, but fears of off-target effects—meaning misdirected DNA cuts—have held back the technology. Scientists at the Gladstone Institutes and Innovative Genomics Institute collaborated with AstraZeneca to develop a new way of identifying off-target CRISPR cuts. The technology, dubbed Discover-Seq, is centered around the natural repair process that cells use to repair DNA after it’s been cut. The researchers discovered that one particular repair factor, MRE11, is among the first to arrive at sites that have been cut, they explained in the journal Science. Discover-Seq uses MRE11 to identify all the DNA sites that have been cut—including those edited erroneously. It could be useful in improving CRISPR’s accuracy, the researchers believe. (Release)

How MC4R gene variants protect against obesity

Scientists at the University of Cambridge in the United Kingdom have discovered a set of genetic variants that protect against obesity. Using genetic data from half a million participants in the UK Biobank, they focused in on MC4R, a gene known to play a role in regulating weight. They found that 1 in 1,000 people have two copies of specific gene variants that make them about five pounds lighter than people who don’t have the variants. And those variants also lowered the risk of type 2 diabetes and heart disease by 50%. The team performed several lab experiments that showed the variants leave MC4R in the “on” position, and that the gene sends signals through a pathway called beta-arrestin. They believe the discovery that this pathway protects against obesity and its complications could inspire a new class of weight-loss drugs, they said in the journal Cell. (Release)

Reverse engineering glioblastoma cells to find new drug targets

Scientists at the University of Toronto used CRISPR-Cas9 genome screening to explore the biology of the deadly brain cancer glioblastoma, and in so doing uncovered a potential new drug target. They took tumor stem cells from 10 patients and used CRISPR to determine which genes were driving the cancer’s growth. They knocked out each of the 20,000 genes, one by one, in a “reverse engineering” process that they said uncovered several genetic vulnerabilities in the cancer, including the gene DOT1L, which turned out to be vital to tumor survival. When they blocked DOT1L in an animal model, they found that tumor growth slowed and survival improved, they reported in the journal Cell Reports. (Release)

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