TsviBT

Karma: 6,568

TsviBT Mar 28, 2025, 9:13 PM
2 points
0
in reply to: River’s comment on: The principle of genomic liberty

But really my objection is why the fuck would you think causality works like that?

Not sure why you’re saying “causality” here, but I’ll try to answer: I’m trying to construct an agreement between several parties. If the agreement is bad, then it doesn’t and shouldn’t go through, and we don’t get germline engineering (or get a clumsy, rich-person-only version, or something).

Many parties have worries that route through game-theory-ish things like slippery slopes, e.g. around eugenics. If the agreement involves a bunch of groups having their reproduction managed by the state, this breaks down simple barriers against eugenics. I suppose you might dismiss such worries, but I think you’re probably wrong to do so—there is actually significant overlap between your apparent stances and the stances of eugenicists, though arguably there’s a relevant distinction where you’re thinking of harming children rather than social burdens, not sure. The overlap is that you think the state should make a bunch of decisions about individuals’s reproduction according to what the state thinks is good, even if the individuals would strongly object and the children would have been fine.

So, first of all, I’m just not sufficiently sure that it’s wrong to make your future child blind. I think it’s wrong, but that’s not a good enough reason to impose my will on others. Maybe in the future we could learn more such that we decide it is wrong, but I don’t think that’s happened yet. But if we’re talking about forcibly erasing a type of person, it’s not remotely enough to be like “yeah I did the EV calculation, being my way is better”. For reference, certainly the state should prevent a parent from blinding their 5 year old; but the 5 year old is now a person. I acknowledge that the distinction is murky, but I think it’s silly to ignore the distinction. Being already alive does matter.

Second of all, it’s not just blind people. It’s all the categories I listed and more. Are you going to tell gay people that they can’t make their future child gay? Yeah? No? What about high-functioning autists? ADHD? Highly creative, high-functioning mild bipolar? How are you deciding? What criterion? Do you trust the state with this criterion? Should other people?

TsviBT Mar 28, 2025, 5:45 PM
2 points
0
in reply to: River’s comment on: The principle of genomic liberty

Why? A human body without a meaningful nervous system inside of it isn’t a morally relevant entity, and it could be used to save people who are morally relevant.

Isn’t that what I just said? Not sure whether or not we disagree. I’m saying that if you just stunt the growth of the prefrontal cortex, maybe you can argue that this makes the person much less conscious or something, but that’s not remotely enough for this to not be abhorrent with a nonnegligible probability; but if you prevent almost all of the CNS from growing in the first place, maybe this is preferable to xenochimeric organs.

If I imagine myself growing up blind, and then I learned that my parents had engineered my genome that way, I would absolutely see that as a boundary violation and a betrayal of bedrock civility.

Fair enough, I think I would too. As I argued in the article, this is one mechanism by which the long-term results of genomic liberty are supposed to be good: children whose parents made genomic choices that weren’t prohibited but maybe should have been, can speak out, both to convince other people to not make those choices, and to get new laws made.

But if you mean something stronger, “would turn down sight if it were offered for free”, it seems obvious to me that any blind person expressing that view has something seriously wrong in their head in addition to the blindness,

Ok. And does this opinion of yours cause you to believe that if given the chance, you ought to use state power to, say, involuntarily sterilize such a person?

We don’t let adults abuse children in any other way, even if the adult was subject to the same sort of abuse as a child and says they approve of it.

We do let adults coerce their children in all sorts of ways. It’s considered bad to not force your child to attend school, which causes very many children significant trauma, including myself. Corporal punishment of children is legal in the US. I think it’s probably quite bad for parents to do that, but we don’t prohibit it.

We may have uncertainty about whether a particular person we can conceptualize will actually come to exist in the future, but if they do come to exist in the future, then they aren’t hypothetical even now.

I agree with this morally, but not as strongly in ethical terms, which is why I listed it under ethics (maybe politically/legally would have been more to the point though).

So it absolutely does make sense to have laws to protect future people just as much as current people.

Not just as much, no, I don’t think so. Laws aren’t about making things better in full generality; they’re about just resolution of conflict, solving egregious collective action problems, protecting liberty from large groups—stuff like that.

Blind people don’t strike me as a “type of person” in the relevant sense. A blind person is just a person who is damaged in a particular way, but otherwise they are the same person they would be with sight.

That’s nice. I bet we could find lots of examples of people with some condition that you would argue should be prohibited from propagating in this way, and who you’d describe as “just a person who is damaged in a particular way”, and who would object to the state imposing itself on their procreative liberty. Are you disagreeing with this statement? Or are you saying that the state should impose itself anyway?

Such people are monsters. They are the enemy. Depriving them of the power to effectuate their goals is a moral crusade worth making enormous sacrifices for.

Ok. So to check, you’re saying that a world with far fewer total blind / deaf / dwarf people, and with far greater total health and capability for nearly literally everyone including the blind / deaf / dwarfs, is not worth there being a generation of a few blind kids whose parents chose for them to be blind? That could be your stance, but I want to check that I understand that that’s what you’re saying. If so, could you expand? Would you also endorse forcibly sterilizing currently living people with high-heritability blindness, who intend to have children anyway?

If you are concerned the politics of advancing genetic engineering, suggesting that it might be ok seems like a blunder

Not sure what you mean by “ok” here. I would strongly encourage parents to not make this decision, I’d advocate for clinics to discourage parents from making this decision, I wouldn’t object to professional SROs telling clinicians to not offer this sort of service, and possibly I’d advocate for them to do so. I don’t think it’s a good decision to make. I also think it should not be prohibited by law.

TsviBT Mar 28, 2025, 3:45 PM
8 points
6
in reply to: Sting’s comment on: The vision of Bill Thurston

I predict any reasonable cost-benefit analysis will find that intelligence and health and high happiness-set-point are good, and blindness and dwarfism are bad.

This is irrelevant to what I’m trying to communicate. I’m saying that you should doubt your valuations of other people’s ways of being—NOT so much that you don’t make choices for your own children based on your judgements about what would be good for them and for the world, or advocate for others to do similarly, but YES so much that you hesitate quite a lot (like years, or “I’d have to deeply investigate this from several angles”) before deciding that we (the state) ought to use state force to impose our (some political coalition’s) judgements about costs and benefits of traits on other people’s reproduction.

I think good arguments for “protection of genomic liberty for all” exist, but I don’t think “there are no unambiguous good directions for genomes to go” is one of them.

I think it is a good argument. Since it’s ambiguous, and it’s not an interpersonal conflict, and there are (at least potentially) people with a strong interest in both directions for their own children, the state should be involved as little as is reasonable. This is a policy about which I think it would be more truthful to say “a world following this policy ought to be desirable, or at least not terribly objectionable, to the great majority of citizens”.

If you don’t protect people’s propagative liberty, some people will have good reason to strongly object to that world.

If you do protect people’s propagative liberty, some other people might believe they have good reason to strongly object. I discuss at least one acknowledged exception to the proposed protection here: https://www.lesswrong.com/posts/rxcGvPrQsqoCHndwG/the-principle-of-genomic-liberty#Propagative_liberty

But I’m arguing to those people that their objection should not be so strong that they ought to fight to prohibit, by law, this sort of propagative liberty.

TsviBT Mar 28, 2025, 12:58 PM
2 points
0
on: What Uniparental Disomy Tells Us About Improper Imprinting in Humans
Excellent! Thank you for researching and writing up this article.

A few notes, from my discussion with Morpheus:
- A single UPD has 1/23rd incorrect imprinting, so to speak. It’s plausible that a fairly benign UPD has some small effect that’s barely noticeable—but then if you have a zygote with many incorrect imprints, say ¹⁄₂ or ¹⁄₄ incorrect imprinting, that these effects would add up a lot and be quite detrimental, producing an epigenomic near-miss.
- Indeed, we might sort of suspect this by default. On the model that says “Paternal/Maternal imprints make you grow More/Less”, having lots of missing imprints could make you grow way too much or way too little, whereas a few imprints might have only a small overall effect on growth.
- It’s kinda curious that there’s these large effects from single regions being misimprinted. Is it the case that the large effects are always caused by the version of imprinting that makes there be zero or near zero expression? This would make some sense; you’re basically deleting a gene. But if not, what’s going on with the large deleterious effects? (It’s not crazy to think that ~2x overexpression would have deleterious effects; e.g. maybe that’s what’s happening with some/many trisomy disorders.)
- It would be nice to understand weaker deleterious effects from less-bad UPDs. But since there are very few UPD cases, they might be hard to detect.
- One approach could be analogous to the situation with the worst UPD disorders. There we can compare with genetic mutations that knockout (or upregulate) the gene in a way that corresponds to the UPD disorder. We could do the same by looking at people with genetic mutations in other regions believed to be sex-linked imprinting regions. There should be much larger cohorts of such cases compared to UPD cases. So we could maybe detect subtler health problems.

TsviBT Mar 28, 2025, 12:01 PM
4 points
2
in reply to: River’s comment on: The principle of genomic liberty
Thanks.

If one is going to create an organ donor, removing consciousness and self-awareness seems essential.

If you can’t do it without removing almost all of the nervous system, I think it would be bad!

These are all worth doing if we can figure out how.

Possibly. I think all your examples are quite alarming in part because they remove a core aspect. Possibly we could rightly decide to do some of them, but that would require much more knowledge and deliberation. More to the point: I’m not making a strong statement like “prohibit these uses”. I’m a weaker statement: “Genomic liberty doesn’t really protect these uses, in the way it does protect propagation, beneficence, etc.”. In other words, I’m just saying that those uses aren’t in the territory that the principle of genomic liberty is trying to secure as its purview, as I’m proposing it.

On the negative externalities question, I actually strongly disagree with the counterexample of a blind couple choosing to blind their child. That’s child abuse! It’s no different than gouging your child’s eyes out! Don’t allow that!

I agree that it’s a tough case, like several others of that type. I think there’s both moral and ethical/political differences with harming a living child though. Some moral differences:
- Gouging the child’s eyes out is much more of a boundary violation and betrayal of bedrock civility. They’d then have very good reason to treat whoever did that as abjectly hostile.
- You’re causing a switch from one type of body to another; the growing consciousness was growing fitly for the first type, and you took that away, leaving that consciousness somewhat hanging.
- It could very well be that a sighted person approves of their life by their own lights and doesn’t wish to be blind, and a blind person approves of their life by their own lights and doesn’t wish to be sighted, but a sighted person who is blinded doesn’t approve of that happening and wishes it weren’t so.
- Diversity of capabilities is good. Blind people may think differently, and, as it were, see things you don’t naturally see. Ditto for many other phenotypes. I think you get less of this benefit if you maim a child vs. through germline engineering (where the adaptation is from birth). (You can of course argue that this isn’t enough of a benefit to genomically do it, and I’d certainly agree with this as a guess and wouldn’t do that with my own child and wouldn’t recommend others do it, but it’s still a benefit.)
- See https://www.lesswrong.com/posts/JFWiM7GAKfPaaLkwT/the-vision-of-bill-thurston
An ethical difference:
- It makes sense to have laws that protect existing people; a right to not be killed or maimed is a very basic right for a state to enforce. This doesn’t apply as much to a hypothetical future child, in terms of what it makes sense to have laws about.
A political difference:
- As I suggested, I think we ought to set the world up in such a way that the great majority of people don’t have good reason to oppose the creation of germline engineering technology. If you start going “well, surely we have to stamp out this type of person” you’re pretty quickly eroding / betraying that coalition. Hence propagative liberty as a tentpole principle.
A moral philosopher might also argue that it’s less “person harming” to make an alteration before the child has begun growing, though I’m not sure what that’s intended to mean.

The vision of Bill Thurston

TsviBTMar 28, 2025, 11:45 AM

27 points

2 comments4 min readLW link

TsviBT Mar 27, 2025, 8:38 PM
2 points
0
in reply to: DaemonicSigil’s comment on: Methods for strong human germline engineering
(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 :) )

TsviBT Mar 27, 2025, 11:06 AM
21 points
16
in reply to: henry’s comment on: Policy for LLM Writing on LessWrong
IMO a not yet fully understood but important aspect of this situation is that what someone writes is in part testimony—they’re asserting something that others may or may not be able to verify themselves easy, or even at all. This is how communication usually works, and it has goods (you get independent information) and bads (people can lie/distort/troll/mislead). If a person is posting AIgen stuff, it’s much less so testimony from that person. It’s more correlated with other stuff that’s already in the water, and it’s not revealing as much about the person’s internal state—in particular, their models. I’m supposed to be able to read text under the presumption that a person with a life is testifying to the effect of what’s written. Even if you go through and nod along with what the gippity wrote, it’s not the same. I want you to generate it yourself from your models so I can see those models, I want to be able to ask you followup questions, and I want you to stake something of the value of your word on what you publish. To the extent that you might later say “ah, well, I guess I hadn’t thought XYZ through really, so don’t hold me to account for having apparently testified to such; I just got a gippity to write my notions up quickly”, then I care less about the words (and they become spammier).

TsviBT Mar 26, 2025, 7:53 AM
25 points
6
on: TsviBT’s Shortform
If there are some skilled/smart/motivated/curious ML people seeing this, who want to work on something really cool and/or that could massively help the world, I hope you’ll consider reaching out to Tabula.

https://www.lesswrong.com/posts/SsLkxCxmkbBudLHQr/

TsviBT Mar 26, 2025, 7:49 AM
8 points
0
on: Tabula Bio: towards a future free of disease (& looking for collaborators)
I chatted with Michael and Ammon. This made me somewhat more hopeful about this effort, because their plan wasn’t on the less-sensible end of what I uncertainly imagined from the post (e.g. they’re not going to just train a big very-nonlinear map from genomes to phenotypes, which by default would make the data problem worse not better).

I have lots of (somewhat layman) question marks about the plan, but it seems exciting/worth trying. I hope that if there are some skilled/smart/motivated/curious ML people seeing this, who want to work on something really cool and/or that could massively help the world, you’ll consider reaching out to Tabula.

An example of the sort of thing they’re planning on trying:

1: Train an autoregressive model on many genomes as base-pair sequences, both human and non-human. (Maybe upweight more-conserved regions, on the theory that they’re conserved because under more pressure to be functional, hence more important for phenotypes.)

1.5: Hope that this training run learns latent representations that make interesting/important features more explicit.

2: Train a linear or linear-ish predictor from the latent activations to some phenotype (disease, personality, IQ, etc.).

IDK if I expect this to work well, but it seems like it might. Some question marks:
- Do we have enough data? If we’re trying to understand rare variants, we want whole genome sequences. My quick convenience sample turned up about 2 million publicly announced whole genomes. Maybe there’s more like 5 million, and lots of biobanks have been ramping up recently. But still, pretending you have access to all this data, this means you see any given region a couple million times. Not sure what to think of that; I guess it depends what/how we’re trying to learn.
- If we focus on conserved regions, we probably successfully pull attention away from regions that really don’t matter. But we might also pull attention away from regions that sorta matter, but to which phenotypes of interest aren’t terribly sensitive to. It stands to reason that such regions or variants wouldn’t be the most conserved regions or variants. I don’t think this defeats the logic, but it suggests we could maybe do better. Example of other approaches: upvote regions that are recognized as having the format of genes or regulatory regions; upvote regions around SNPs that have shown up in GWASes.
- For the exact setup described above, with autoregression on raw genomes, do we really learn much about variants? I guess what we ought to learn something about is approximate haplotypes, i.e. linkage disequilibrium structure. The predictor should be like “ok, at the O(10kb) moment, I’m in such-and-such gene regulatory module, and I’m looking at haplotype number 12 for this region, so by default I should expect the following variants to be from that haplotype, unless I see a couple variants that are rarely with H12 but all come from H5 or something”. I don’t see how this would help identify causal SNPs out of haplotypes? But it could very well make the linear regression problem significantly easier? Not sure.
- But also I wouldn’t expect this exact setup to tell us much interesting stuff about anything long-range, e.g. protein-protein interactions. Well, on the other hand, possibly there’d be some shared representation between “either DNA sequence X; or else a gene that codes for a protein that has a sequence of zinc fingers that match up with X”? IDK what to expect. This could maybe be enhanced with models of protein interactions, transcription factor binding affinities, activity of regulatory regions, etc. etc.
More generally, I’m excited about someone making a concerted and sane effort to try putting biological priors to use for genomic predictions. As a random example (which may not make much sense, but to give some more flavor): Maybe one could look at AlphaFold’s predictions of protein conformation with different rare genetic variants that we’ve marked as deleterious for some trait. If the predictions are fairly similar for the different variants, we don’t conclude much—maybe this rare variant has some other benefit. But if the rare variant makes AlphaFold predict “no stable conformation”, then we take this as some evidence that the rare variant is purely deleterious, and therefore especially safe to alter to the common variant.

TsviBT Mar 25, 2025, 4:04 AM
7 points
−1
on: Straightforward Steps to Marginally Improve Odds of Whole Brain Emulation
Something I’d like WBE researchers to keep in mind: It seems like, by default, the cortex is the easiest part to get a functionally working quasi-emulation of, because it’s relatively uniform (and because it’s relatively easier to tell whether problem solving works compared to whether you’re feeling angry at the right times). But if you get a quasi-cortex working and not all the other stuff, this actually does seem like an alignment issue. One of the main arguments for alignment of uploads would be “it has all the stuff that humans have that produces stuff like caring, love, wisdom, reflection”. But if you delete a bunch of stuff including presumably much of the steering systems, this argument would seem to go right out the window.

https://www.lesswrong.com/posts/jTiSWHKAtnyA723LE/overview-of-strong-human-intelligence-amplification-methods#Brain_emulation

TsviBT Mar 24, 2025, 6:29 PM
6 points
2
in reply to: Yejun Y.’s comment on: Tabula Bio: towards a future free of disease (& looking for collaborators)
I don’t know what they have in mind, and I agree the first obvious thing to do is just get more data and try linear models. But there’s plenty of reason to expect gains from nonlinear models, since broadsense heritability is higher than narrowsense, and due to missing heritability (though maybe it ought to be missing given our datasets), and due to theoretical reasons (quite plausibly there’s multiple factors, as straw!tailcalled has described, e.g. in an OR of ANDs circuit; and generally nonlinearities, e.g. U-shaped responses in latents like “how many neurons to grow”).

My guess, without knowing much, is that one of the first sorts of things to try is small circuits. A deep neural net (i.e. differentiable circuit) is a big circuit; it has many many hidden nodes (latent variables). A linear model is a tiny circuit: it has, say, one latent (the linear thing), maybe with a nonlinearity applied to that latent. (We’re not counting the input nodes.)

What about small but not tiny circuits? You could have, for example, a sum of ten lognormals, or a product of ten sums. At a guess, maybe this sort of thing
1. Captures substantially more of the structure of the trait, and so has in its hypothesis space predictors that are significantly better than any possible linear PGS;
2. is still pretty low complexity / doesn’t have vanishing gradients, or something—such that you can realistically learn given the fairly small datasets we have.

TsviBT Mar 24, 2025, 6:02 PM
17 points
17
on: Will Jesus Christ return in an election year?

[The Memes] Maybe the “Yes” people are buying “Yes” for the lulz. It’s kinda fun to tell people that you bet that Jesus Christ would return this year!

Maybe you mean this expansively, but it doesn’t ring true to me as stated because my main guess for many / most bettors would be more serious: they’re “manifesting” or “hyperstitioning”—or more generally, they think there’s some good effect from nudging other peoples’s sense of what is other peoples’s investment in 2nd-coming worlds.

TsviBT Mar 24, 2025, 2:25 AM
−1 points
0
in reply to: bhauth’s comment on: The principle of genomic liberty
Downvoting because it seems like you’ve barely read anything I wrote and also don’t know anything about genetics or intelligence, and are now posting AI slop, but I will upvote a thoughtful post making an argument using information and logic that address why people think it might work.

TsviBT Mar 23, 2025, 7:20 PM
2 points
1
in reply to: ProgramCrafter’s comment on: The principle of genomic liberty
Yeah this seems like an important question. I’m not sure what to think. Ideally someone with more background in medical ethics could address this. E.g. I’m not sure how to navigate what would happen if, for example, law enforcement claimed it needed access to some info (e.g. to enforce regulations about germline engineering, or to use in forensic investigation of a crime); or if there were a malpractice suit about a germline engineering clinic, or something. I’m also not sure what is standardly done, and what the good and bad results are, in situations where a child might have an interest in their parents not sharing some info about them.

But certainly, in a list of innovation-positive ethical guidelines for scientists and clinicians regarding germline engineering, some sort of strong protection of privacy would have to be included. This is a good point, thanks.

TsviBT Mar 23, 2025, 9:32 AM
3 points
0
in reply to: samuelshadrach’s comment on: The principle of genomic liberty
Yeah I’m not, like, trying to sneak this in as a law or something. It’s a proposed policy principle, i.e. a proposed piece of culture.

My main motive here is just to figure out what a good world with germline engineering could/would look like, and a little bit to start promoting that vision as something to care about and work towards. I agree that practical technology will push the issue, but I think it’s good to think about how to make the world with this technology good, rather than just deferring that. Besides the first-order thing where you’re just supposed to try to make technology end up going well, it’s also good to think about the question for cooperative reasons. For one thing, pushing technology ahead without thinking about whether or how it will turn out well is reckless / defecty, and separately it looks reckless / defecty. That would justify people pushing against accelerating the technology, and would give people reason to feel skittish about the area (because it contains people being reckless / defecty). For another thing, having a vision of a good world seems like it ought to be motivating to scientists and technologists.

TsviBT Mar 23, 2025, 7:13 AM
2 points
2
in reply to: bhauth’s comment on: The principle of genomic liberty

near-evolutionarily-optimal range. That has not happened with intelligence,

What makes you think this? As I said, it’s not clear to me that there’s been much selection pressure for intelligence in the past few thousand years.

Also, the “evolutionary optimum” can change. E.g. calories are not much of a problem in the developed world, but that’s recent.

Also, there’s always an influx of de novo mutations, and evolution has limited selection power. I’m not clear on the math here exactly, and I think kman has suggested that mutational load isn’t the main source of IQ-associated SNPs, but it demonstrates that it’s far from ironclad logic to infer from evolutionary pressure on a trait that the trait should be near optimum in linear variants. The brain is one of the organs with the most diverse gene expression profile (I mean, more genes are expressed in the brain than in most other tissues); and IIRC most genes are expressed in the brain (not confident of this, maybe it’s more like ¹⁄₃ or ¹⁄₂. But anyway, there’s a lot of genes potentially relevant to brain function, so there’s a lot of surface area for mutational load to drag things down a bit.

genes are not simply choosing a level of intelligence.

I don’t know what you mean by this. Are you talking about pleiotropy? Between what and what? I mean of course genes do lots of things, but IIUC so far as we’ve observed, the correlations between most measured traits are pretty small (and usually positive between traits most people would judge desirable, e.g. lower risk of mental illness and higher intelligence).

TsviBT Mar 23, 2025, 5:24 AM
2 points
−2
in reply to: bhauth’s comment on: The principle of genomic liberty
I’ll repeat that I’m not very learned about genetics, so if you want to convince even me in particular, the best way is to respond to the strongest case, which I can’t present. But ok:

First I’ll say that an empirical set of facts I’d quite like to have for many traits (disease, mental disease, IQ, personality) would be validation of tails. E.g. if you look at the bottom 1% on a disease PRS, what’s the probability of disease? Similarly for IQ.

or beyond those?

I rarely make claims about going much beyond natural results; generally I think it’s pretty plausible there’s some meaningful thing we could feasibly do that’s like +6 -- +8 SDs on intelligence, but I’m much less confident about the +8 SD claim, and not super confident of the +6 SD. Like, I think the default expectation ought to be that we can meaningfully get to +6 SDs; this seems like the straightforward conclusion. (I’m just restating the intuition / impression.)

Why do you expect that only a very small fraction of natural SNP differences are needed to get the extremes of natural results

Assuming linearity, the math is fairly straightforward. In the simplest model, with 10,000 fair +1/-1 coins (representing all the variance in a trait, so some coins are environmental), an SD is 50 coins and the average is 5,000. So there’s 100 SDs of variance available. Obviously this is mostly meaningless in terms of the trait, as linearity would not remotely hold, but my point is that the issue isn’t the math of additive selection. See here for more (e.g. about if the coins are biased https://tsvibt.blogspot.com/2022/08/the-power-of-selection.html#7-the-limits-of-selection ).

IQ seems to have thousands of small contributions from different regions. 10% of the variance is therefore in the ballpark of 10 trait SDs. Again, I’m not saying you can get to 250 IQ; what I’m saying is that the math of selection and variance isn’t the problem. Lee et al. state “In the WLS, the MTAG score predicts 9.7% of the variance in cognitive performance[...]”; this was in 2018, I would bet we can do substantially better now.

Lee, James J., Robbee Wedow, Aysu Okbay, Edward Kong, Omeed Maghzian, Meghan Zacher, Tuan Anh Nguyen-Viet, et al. ‘Gene Discovery and Polygenic Prediction from a 1.1-Million-Person GWAS of Educational Attainment’. Nature Genetics 50, no. 8 (August 2018): 1112–21. https://doi.org/10.1038/s41588-018-0147-3.

Why do you expect that effects would be linear?

TBC I certainly don’t expect the effects to be literally linear even in the typical human range; it’s more that expect them to be fairly linear. Like if the answer is that a trait-mean couple that selects their child’s genome to have a (carefully, accurately as best anyone can) predicted IQ of mean 170 actually tends to have a child with mean IQ 155, I’d shrug and be like “huh, that’s weird and surprising, let’s investigate and make sure to communicate this fact to parents”; and I think this possibility is nontrivially strategically relevant; and it means we should accurately describe this plausible outcome, in order to not overhype etc.; but I wouldn’t be totally shocked. If the child tends to have a mean IQ of 125, I would be shocked, yeah. (The 170 vs. 155 thing would be hard to notice for a while because testing intelligence at that range is barely feasible, but just saying for illustration.)

Also, certainly I would expect strong nonlinearities at the extreme tails at some point. I’d certainly strongly advice against, maybe even condemn, pushing noticeably outside the regime of adaptedness.

Why do I expect the effects to be fairly linear in the human envelop, to the point where increasing a bunch of causal variants increases the trait?

Some of my impressions come from here: https://arxiv.org/pdf/1408.3421 “On the genetic architecture of intelligence and other quantitative traits”, Stephen D.H. Hsu, 2014

and from https://gwern.net/embryo-selection

(TBC, I’m not saying these sources present the strongest arguments; I’m just saying where my impressions historically come from.)
1. Breeding programs in non-humans work well, so there’s plenty of variance for those traits, no huge nonlinear walls that you hit, etc. This is far from dispositive; intelligence could plausibly be different from traits like egg production or weight, maybe it’s important that you’re checking along the way, etc.
2. Linear PGSes work well for many traits (height in humans; various traits for cows I think; even IQ, up to 10%).
3. SNP heritability estimates are substantial; the number in my head for IQ is >.3 of the variance. Though my impression is also that these are maybe controversial? I dunno.
4. It’s far from obvious to me that there’s been much selection for IQ in the past couple thousand years. But if there were a case that the selection has been strong, that would shift me.
5. There’s a theoretical argument, which IDK if it should hold much weight, but I like it: since DNA segments get shuffled around a lot, there’s selection pressure for things to work reasonably well with other things. E.g. DNA segments that have really bad effects when combined with some other segments would be selected against; and DNA segments that improve mechanisms for repairing/smoothing-out/compensating bad epistases between other segments will be selected for. In general this smooths things, which makes the landscape more linear. (I understand that specific epistases are much rarer than single variants, and therefore relatively invisible to selection; but I think my point stands somewhat, though this could be clarified and maybe basically disproven with good quantitative analysis.)
6. I just haven’t seen evidence of this nonlinear wall that’s right between 140 and 160, or whatever the claim is. It’s just people saying “maybe there’s a U-shaped curve of something” or “maybe there’s a high fan-in latent with a cutoff after the latent in the final IQ sum” which makes sense, but AFAIK is basically just speculation. It also isn’t super compelling speculation if we’re talking about a super polygenic trait in a super-complex organ where I’d expect there to be lots and lots of ways to tune and fix and just upregulate stuff. Like, my actual guess would be that there’s a whole spectrum of functional forms, from linear (substantial, according to h estimates!) through small ORs of ANDs, through large ORs of highly sensitive ANDs and other nonlinear forms; and these are all mixed together; and this does imply something; but it doesn’t imply that you can’t have quite large effects on the trait with germline engineering.
7. My impression is that the upper tail of IQ does get a little weird, and maybe g stops existing as much / the distribution of different tests stops being as one-dimensional? But IIUC (not sure, heard this from a psychometrician) there’s no observed threshold in the effect of IQ on other traits, despite people looking, though it’s quite hard to measure past 150ish. And e.g. this random paper claims to find quite substantial SNP heritability in a cohort with estimated rarity >4 SDs, though it’s not a huge cohort (1238 in the selected cohort) and I didn’t study it so maybe it’s very flawed / meaningless, IDK. https://www.nature.com/articles/mp2017121 In other words, to the small extent that we can look at the extreme tails, I at least haven’t heard of big results saying “aha! actually the genetics of IQ on the tails is quite different than near the mean!”.
8. (Also there’s sibling studies that IIUC say we are indeed picking up causality, though that’s not directly relevant to linearity.)

TsviBT Mar 23, 2025, 3:13 AM
2 points
0
in reply to: bhauth’s comment on: The principle of genomic liberty
I’m basing this off of selection, not editing. I haven’t looked into the genetics stuff very much, because the bottleneck is biotech, not polygenic scores.

Would look forward to your rebuttal! I just hope you’ll respond to the strongest arguments, not the weakest. In particular, if you want to argue against the potential effectiveness of selection methods, I think you’d want to either argue that PGSes aren’t picking up causal variants at all (I mean, that there’s a large amount of correlation that isn’t causation); or that the causality would top out / have strongly diminishing returns on the trait. Selection methods would capture approximately all of the causal stuff that the PGS is picking up, even if it’s not even due to SNPs but rather rarer SNVs. (However, this would not apply to population stratification or something; then I’d think you’d want to argue that this is much / most of what PGSes are picking up, and there’d be already-made counterarguments to this that you should respond to in order to be convincing.)

TsviBT Mar 23, 2025, 2:47 AM
2 points
−2
in reply to: bhauth’s comment on: The principle of genomic liberty

What I meant was smart people having more kids.

I mean, I’d encourage most people in general to choose to have kids, but yeah, trying to influence other people’s reproductive choices on the level of persons is creepy and eugenicsy; it’s much more practically and motivationally contiguous with even creepier and eugenicsier stuff such as racist immigation policies, etc.

but in what sense is that true that’s not true of, say, your smarter relative having the kids instead?

In a huge quantitative sense. You and I differ at very roughly 4 million SNVs (maybe more like 5-10, but 4 is a convenient number). My sibling and I differ at roughly half that, 2 million SNVs. If I had a child without germline engineering, I’d pass on 2 million SNVs. If it’s my sibling’s child, it’s 1 million SNVs.

If I use selection, I’m still passing on 2 million SNVs, though in a way selected for association with some traits—but the selection is pretty weak in the scale of SNVs; it’d correspond, morally, to something like hundreds or thousands of edits, I think (haven’t gone through this carefully). In other words, O(0.1%), even if you count the alteration as being totally unrelated DNA. Similarly for editing. You could have a 180 IQ super-healthy kid with a natural lifespan of 110 years, with a genome that would be nearly indistinguishable from being your non-GE’d child. (Unless you whole genome sequence them and find a surprising coincidence of health and IQ alleles drawn from your own genome / a couple dozen SNPs that weren’t in either parent.)

I mean, if you don’t care about that, God bless you. I think most people do care about it though.

TsviBT

The vi­sion of Bill Thurston

The vision of Bill Thurston