Without any double-strand breaks, base editors are less toxic to cells and less prone to off-target effects.
It’s worth noting that most base editors actually DO involve nicking of one strand, which is done after the chemical base alternation to bias the cell towards repairing the non-edited strand.
The editing efficiency of non-nicking base editors is significantly lower than that of nicking versions (though the precise ratio varies depending on the specific edit site)
Finally the cell’s enzymes also notice a mismatch between the strand with the new template DNA and the old strand without it, and decide that the longer, newer strand is “correct” and connect it back to the main DNA sequence.
It’s worth noting that this only happens some of the time. Often the cell will either fail to ligate the edited strand back together or it will remove the edited bases, undoing the first half of the edit.
In regards to bridge RNAs, I do not yet believe they will work for any human applications. The work in Hsu’s paper was all done in prokaryotes. If this tool worked in plants or animals, they would have shown it.
In fact, despite what human geneticists often say about epistasis being minor and rare, plant genetics people seem to find that interactions between genes are a big deal, explaining most (!) of the variance in crop yields.[5] So, if I’m not mistaken, “of all these genetic variants statistically associated with the polygenic trait, what’s the best subset of edits to make, if I want the largest expected impact” is a nontrivial question.[6]
I was curious about the finding of epistatic effects explaining more of the variance than traditionally assumed, so I took a look at the study you referenced and found something worth mentioning.
The study is ludicrously underpowered to detect anything like what they’re trying to show. They only have 413 genetically distinct rice plants in the study, compared to 36,901 SNPs.
This study is underpowered to detect even SNPs that have an effect on the trait in question, let alone epistatic effects. So I don’t give their results that much weight.
I agree with your overall conclusion though; I think we’ll likely see the first applications of polygenic embryo selection in animals (perhaps cows?) before we see it in humans.
It’s worth noting that most base editors actually DO involve nicking of one strand, which is done after the chemical base alternation to bias the cell towards repairing the non-edited strand.
The editing efficiency of non-nicking base editors is significantly lower than that of nicking versions (though the precise ratio varies depending on the specific edit site)
It’s worth noting that this only happens some of the time. Often the cell will either fail to ligate the edited strand back together or it will remove the edited bases, undoing the first half of the edit.
In regards to bridge RNAs, I do not yet believe they will work for any human applications. The work in Hsu’s paper was all done in prokaryotes. If this tool worked in plants or animals, they would have shown it.
I was curious about the finding of epistatic effects explaining more of the variance than traditionally assumed, so I took a look at the study you referenced and found something worth mentioning.
The study is ludicrously underpowered to detect anything like what they’re trying to show. They only have 413 genetically distinct rice plants in the study, compared to 36,901 SNPs.
This study is underpowered to detect even SNPs that have an effect on the trait in question, let alone epistatic effects. So I don’t give their results that much weight.
I agree with your overall conclusion though; I think we’ll likely see the first applications of polygenic embryo selection in animals (perhaps cows?) before we see it in humans.