Re the “Appendix: Cheap DNA segment sensing” section, just going to throw out a thought that occurred to me (very much a non-expert). Let’s say we’re doing IVS, and assume we can separate spermatocytes into separate microwells before they undergo meiosis. The starting cells all have a known genome. Then the cell in each microwell divides into 4 cells. If we sequence 3 of them, then we know by process of elimination what the sequence on the 4th cell is, at a very high level of detail, including crossovers, etc. So we kill 3 cells and look at their DNA, and then we know what DNA the remaining living cell has without doing anything to it.
Okay, DNA sequencing is still fairly expensive, so maybe it’s super crazy to do it 3 times to get a single cell with known DNA. But:
Maybe sequencing will get cheaper.
The same trick should work for existing cheap methods that give coarser information. Eg. one can freely decondense the sperm DNA for FISH, without worrying about damaging the cell, because it’s one of the 3 that’s going to die anyway.
If it’s too hard to separate the cells into microwells while they’re still dividing, maybe there are alternate things we could do like just watching the culture with a microscope and keeping track of who split from who and where they ended up (plus some kind of microfluidics setup to shuffle the sperms around to where we want them).
In theory one could do “entanglement sequencing”, wherein you capture the four meiotic “grandchildren” of a single gametogonium (progenitor stem cell that produces gametes). This is impractical as far as I know, because both oogenesis and spermatogenesis are complex and all but require a bunch of surrounding tissue. Spermatogenesis in particular involves a complicated process where many partially-differentiated progenitor cells stay tightly connected as they pass through the seminiferous tubules. Oocytes might be more feasible to indirectly sequence, e.g. by looking at the polar body emitted after false fertilization.
You’re talking about if we do have IVS. In that case, yes, plausibly you could do it. But this wouldn’t enable recombinant chromosome selection unless you have a way of sensing index; which is plausibly easier, but IDK how much easier. And anyway, the hardest part of CS is chromosome transplantation.
It would enable simple gamete selection. But that kinda sucks.
If you have full IVS, there’s almost certainly more powerful things you can do; if nothing else, you can do a ton of CRISPR editing of cultured iPSCs, and then IVS.
Thanks for the reply & link. I definitely missed that paragraph, whoops.
IMO even just simple gamete selection would be pretty great for avoiding the worst genetic diseases. I guess tracking nuclei with a microscope is way more feasible than the microwell thing, given how hard it looks to make IVS work at all.
To give some numbers, consider 10k sperm. We look in the embryo selection powers:
For 10k, i.e. e4.0, you get about 2.7 raw SDs, for embros; for sperm you multiply by the sperm SD scale, which is 1/√2 because sperm have half the variance of embryos. That’s about 1.9 SDs. Then you do a round of embryo selection, with say 10 embryos, for about .7 more raw SDs (because you’re mainly selecting on the maternal DNA). Total is 2.6 raw SDs. As IQ points this is like 13 IQ points. It’s pretty interesting, but not groundbreaking; and even with 10k sperm, could actually be pretty expensive, like would plausibly be at least several $100k. Another order of magnitude sperm would be another OOM expensiver, and only a very small bump in power. I haven’t run the numbers for disease reduction, and yeah it would probably be pretty nontrivial (because the marginal returns for diseases are high at the beginning, starting at a normal genome), but yeah it also does not qualify as strong GV.
To be clear, this would be awesome and someone should totally try, and it could plausibly synergize with other stuff. It’s just not a priority for getting to strong GV.
(BTW I think you asking about entanglement sequencing caused me to a few days later realize that for chromosome selection, you can do at least index sensing by taking 1 chromosome randomly from a cell, and then sequencing/staining the remaining 22 (or 45), and seeing which index is missing. So thanks :) )
Re the “Appendix: Cheap DNA segment sensing” section, just going to throw out a thought that occurred to me (very much a non-expert). Let’s say we’re doing IVS, and assume we can separate spermatocytes into separate microwells before they undergo meiosis. The starting cells all have a known genome. Then the cell in each microwell divides into 4 cells. If we sequence 3 of them, then we know by process of elimination what the sequence on the 4th cell is, at a very high level of detail, including crossovers, etc. So we kill 3 cells and look at their DNA, and then we know what DNA the remaining living cell has without doing anything to it.
Okay, DNA sequencing is still fairly expensive, so maybe it’s super crazy to do it 3 times to get a single cell with known DNA. But:
Maybe sequencing will get cheaper.
The same trick should work for existing cheap methods that give coarser information. Eg. one can freely decondense the sperm DNA for FISH, without worrying about damaging the cell, because it’s one of the 3 that’s going to die anyway.
If it’s too hard to separate the cells into microwells while they’re still dividing, maybe there are alternate things we could do like just watching the culture with a microscope and keeping track of who split from who and where they ended up (plus some kind of microfluidics setup to shuffle the sperms around to where we want them).
Yep, this is the standard first “clever person starts thinking about nondestructive sequencing” thing. E.g. I wrote about it here: https://tsvibt.blogspot.com/2022/06/non-destructively-sequencing-gametes-by.html and Gwern mentions it. It’s addressed in the present article here:
You’re talking about if we do have IVS. In that case, yes, plausibly you could do it. But this wouldn’t enable recombinant chromosome selection unless you have a way of sensing index; which is plausibly easier, but IDK how much easier. And anyway, the hardest part of CS is chromosome transplantation.
It would enable simple gamete selection. But that kinda sucks.
If you have full IVS, there’s almost certainly more powerful things you can do; if nothing else, you can do a ton of CRISPR editing of cultured iPSCs, and then IVS.
Thanks for the reply & link. I definitely missed that paragraph, whoops.
IMO even just simple gamete selection would be pretty great for avoiding the worst genetic diseases. I guess tracking nuclei with a microscope is way more feasible than the microwell thing, given how hard it looks to make IVS work at all.
I think the numbers just kind of suck. I didn’t go into them much because gamete selection seems largely hypothetical. Like, the procedure here seems kinda expensive per-spermatocyte (guy who divides into 4 sperm). I gesture at how to compute it here: https://www.lesswrong.com/posts/2w6hjptanQ3cDyDw7/methods-for-strong-human-germline-engineering#The_power_of_single_gamete_selection
To give some numbers, consider 10k sperm. We look in the embryo selection powers:
For 10k, i.e. e4.0, you get about 2.7 raw SDs, for embros; for sperm you multiply by the sperm SD scale, which is 1/√2 because sperm have half the variance of embryos. That’s about 1.9 SDs. Then you do a round of embryo selection, with say 10 embryos, for about .7 more raw SDs (because you’re mainly selecting on the maternal DNA). Total is 2.6 raw SDs. As IQ points this is like 13 IQ points. It’s pretty interesting, but not groundbreaking; and even with 10k sperm, could actually be pretty expensive, like would plausibly be at least several $100k. Another order of magnitude sperm would be another OOM expensiver, and only a very small bump in power. I haven’t run the numbers for disease reduction, and yeah it would probably be pretty nontrivial (because the marginal returns for diseases are high at the beginning, starting at a normal genome), but yeah it also does not qualify as strong GV.
To be clear, this would be awesome and someone should totally try, and it could plausibly synergize with other stuff. It’s just not a priority for getting to strong GV.
(BTW I think you asking about entanglement sequencing caused me to a few days later realize that for chromosome selection, you can do at least index sensing by taking 1 chromosome randomly from a cell, and then sequencing/staining the remaining 22 (or 45), and seeing which index is missing. So thanks :) )