this is the exact first thing that popped into my head as well :)

Nice work Ben!

Hmm, not sure how to achieve (1) without just not targeting genes in those region of the genome that are prone to low-level chromosomal loss. In other words, seems unlikely that *some* successful guides targeting gene X would lead to this while others would not, right?

Yup, chromatin can inhibit Cas protein access.

But when a gene is transcribed, or DNA is replicated, chromatin is removed, so Cas proteins have a chance to find their target site.

And, if your gene of interest is never accessible (on) in a cell model, no particular reason to need to knock it out!

Best for last, the project was led by the incomparable Laura Drepanos, a computationalist in GPP (who, fun fact, will be applying to grad school this fall). I've not seen a more methodical and comprehensive analysis, or read a better first-draft of a manuscript.

I ❤️ this paper.

Happy screening!

A more points to wrap things up:
• We also provide the designs for a new mouse library, Julianna
• This new guide selection screen is implemented in CRISPick for Cas9 knockout (off-target for CRISPRi is a another story, stay tuned!)
• Libraries are on their way to @addgene.bsky.social