Mammalian genome writing: Unlocking new length scales for genome engineering
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The final step of engineering is what we call "conversion". It includes introducing Cre enzyme that induces recombination between the 1st loxP site in mouse Taf1 intron 24, and a 2nd loxP site located in human TAF1 intron 24.

Next, we engineered mouse embryonic stem cells (mESCs), first with a loxP site in Taf1's intron 24, followed by integration of a marker cassette (a landing pad) downstream of the gene, and finally we replaced this cassette with the 78-kb human fragment.

We assembled this region from an XDP patient-derived BAC, using the superpower of S. cerevisiae (yeast), into a delivery-ready vector.

Our solution? A "hybrid-convertible" allele:

How could one engineer a mouse carrying a LETHAL allele? A thread 🧵

One step closer to an LLM that understands novel DNA🧬

𝗜𝘁𝗲𝗿𝗮𝘁𝗶𝘃𝗲 𝗶𝗺𝗽𝗿𝗼𝘃𝗲𝗺𝗲𝗻𝘁 𝗼𝗳 𝗱𝗲𝗲𝗽 𝗹𝗲𝗮𝗿𝗻𝗶𝗻𝗴 𝗺𝗼𝗱𝗲𝗹𝘀 𝘂𝘀𝗶𝗻𝗴 𝘀𝘆𝗻𝘁𝗵𝗲𝘁𝗶𝗰 𝗿𝗲𝗴𝘂𝗹𝗮𝘁𝗼𝗿𝘆 𝗴𝗲𝗻𝗼𝗺𝗶𝗰𝘀.

pubmed.ncbi.nlm.nih.gov/41125441

Congrats Andre Ribeiro-Dos-Santos and Matt Maurano!