I ordered this one off of amazon. AFAICT it does nothing for me. But that's a pretty minor update, because even those who use it say the effects are "subtle", and frankly I think snorting oxytocin is probably bullshit and does nothing beyond placebo even for normal people. I did have a couple other people try the one I bought, and their results indeed sounded like a nothingburder.

Depth is tagged on each individual variation; the frame shift has depth 41, the others have depth anywhere from 40 to 60.

I have not found the frameshift mutation in dbSNP, but I'm not confident that I've understood the UI or intended usage patterns, so I'm not confident it's not in there. The SNPs I haven't looked for in there yet.

I admit I was somewhat surprised as well. On a gut level, I did not think that the very first things to check would turn up such a clear and simple answer.

For my family this is much more of a "wow that makes so much sense" than a "wow what a surprise". It tracks extremely well with how I acted growing up, in a bunch of different little ways. Indeed, once the hypothesis was on my radar at all, it quickly seemed pretty probable on that basis alone, even before sequencing came back.

A few details/examples:

• As a child, I had a very noticeable lack of interest in other people (especially those my own age), to the point where a school psychologist thought it was notable.
• I remember being unusually eager to go off to overnight summer camp (without my parents), at an age where nobody bothered to provide overnight summer camp because kids that young were almost all too anxious to be away from their parents that long.
• When family members or pets died, I've generally been noticeably less emotionally impacted than the rest of the family.
• When out and about with the family, I've always tended to wander around relatively independently of the rest of the group.

Those examples are relatively easy to explain, but most of my bits here come from less legible things. It's been very clear for a long time that I relate to other people unusually, in a way that intuitively matches being at the far low end of the oxytocin signalling axis.

About a month ago, after some back-and-forth with several people about their experiences (including on lesswrong), I hypothesized that I don't feel the emotions signalled by oxytocin, and never have. (I do feel some adjacent things, like empathy and a sense of responsibility for others, but I don't get the feeling of loving connection which usually comes alongside those.)

Naturally I set out to test that hypothesis. This note is an in-progress overview of what I've found so far and how I'm thinking about it, written largely to collect my thoughts and to see if anyone catches something I've missed.

Under the hypothesis, this has been a life-long thing for me, so the obvious guess is that it's genetic (the vast majority of other biological state turns over too often to last throughout life). I also don't have a slew of mysterious life-long illnesses, so the obvious guess is that's it's pretty narrowly limited to oxytocin - i.e. most likely a genetic variant in either the oxytocin gene or receptor, maybe the regulatory machinery around those two but that's less likely as we get further away and the machinery becomes entangled with more other things.

So I got my genome sequenced, and went looking at the oxytocin gene and the oxytocin receptor gene.

The receptor was the first one I checked, and sure enough I have a single-nucleotide deletion 42 amino acids in to the open reading frame (ORF) of the 389 amino acid protein. That will induce a frameshift error, completely fucking up the rest of protein. (The oxytocin gene, on the other hand, was totally normal.)

So that sure is damn strong evidence in favor of the hypothesis! But, we have two copies of most genes, including the oxytocin receptor. The frameshift error is only on one copy. Why isn't the other copy enough for almost-normal oxytocin signalling?

The frameshift error is the only thing I have which would obviously completely fuck up the whole protein, but there are also a couple nonsynonymous single nucleotide polymorphisms (SNPs) in the ORF, plus another couple upstream. So it's plausible that one of the SNPs messes up the other copy pretty badly; in particular, one of them changes an arginine to a histidine at the edge of the second intracellular loop. (Oxytocin receptor is a pretty standard g-protein coupled receptor, so that's the mental picture here.) I did drop the sequences into alphafold, and I don't see any large structural variation from the SNPs, but (a) that histidine substitution would most likely change binding rather than structure in isolation, and (b) this is exactly the sort of case where I don't trust alphafold much, because "this is one substitution away from a standard sequence, I'll just output the structure of that standard sequence" is exactly the sort of heuristic I'd expect a net to over-rely upon.

It's also possible-in-principle that the second receptor copy is fine, but the first copy frameshift alone is enough to mess up function. I think that's unlikely in this case. The mRNA for the frameshifted version should be removed pretty quickly by nonsense-mediated decay (I did double check that it has a bunch of early stop codons, NMD should definitely trigger). So there should not be a bunch of junk protein floating around from the frameshifted gene. And the frameshift is early enough that the messed up proteins probably won't e.g. form dimers with structurally-non-messed-up versions (even if oxytocin receptor normally dimerizes, which I'd guess it doesn't but haven't checked). At worst there should just be a 2x lower concentration of normal receptor than usual, and if there's any stable feedback control on the receptor concentration then there'd be hardly any effect at all.

Finally, there's the alternative hypothesis that my oxytocin signalling is unusually weak but not entirely nonfunctional. I do now have pretty damn strong evidence for that at a bare minimum, assuming that feedback control on receptor density doesn't basically counterbalance the fucked up receptor copy.

Anyway, that's where I'm currently at. I'm curious to hear others' thoughts on what mechanisms I might be missing here!

Just got my whole genome sequenced. A thing which I could have figured out in advance but only realized once the results came back: if getting a whole genome sequence, it's high value to also get your parents' genomes sequenced.

Here's why.

Suppose I have two unusual variants at two different positions (not very close together) within the same gene. So, there's a variant at location A, and a variant at location B. But (typically) I have two copies of each gene, one from each parent. So, I might have the A and B variants both on the same copy, and the other copy could be normal. OR, I could have the A variant on one copy and the B variant on the other copy. And because modern sequencing usually works by breaking DNA into little chunks, sequencing the chunks, and then computationally stitching it together... those two possibilities can't be distinguished IIUC.

The difference is hugely important if e.g. both the A variant and the B variant severely fuck up the gene. If both are on the same copy, I'd have one normal working variant and one fucked up. If they're on different copies, then I'd have zero normal working variants, which will typically have much more extreme physiological results.

The easiest way to distinguish those two possibilities, IIUC, is to get the parents' genomes. In one case, I'd see the A and B variant in the same parent, and the other parent would have a normal gene. In the other case, I'd see the A variant in one parent and the B variant in the other.

In principle there are other ways to distinguish the two possibilities (like long-read sequencing), but getting the parents' sequence is probably the cheapest/easiest.

I totally buy that peoples' verbal models aren't at a local nadir of connectedness-to-reality. The thing which seems increasingly disconnected from reality is more like metis, peoples' day-to-day behavior and intuitive knowledge, institutional knowledge and skills, personal identity and goals, that sort of thing.

I'm notably not thinking here primarily about examples like e.g. heritability of IQ becoming politicized; that's a verbal model, and I do think that verbal models have mostly become more reasonable modulo a few exceptions which people highlight.

Why don't we live in a world where wealth can buy a society defenses against such egregores?

I would point to the non-experts can't distinguish true from fake experts problem. That does seem to be a central phenomenon which most parasitic egregores exploit. More generally, as wealth becomes more abundant (and therefore lots of constraints become more slack), inability to get grounded feedback becomes a more taut constraint.

That said... do you remember any particular evidence or argument which led you toward the story at top of thread (as opposed to away from your previous understanding)?

Without commenting on the specifics, I agree with a lot of the gestalt here as a description of how things evolved historically, but I think that's not really the right lens to understand the problem.

My current best one-sentence understanding: the richer humans get, the more social reality can diverge from physical reality, and therefore the more resources can be captured by parasitic egregores/memes/institutions/ideologies/interest-groups/etc. Physical reality provides constraints and feedback which limit the propagation of such parasites, but wealth makes the constraints less binding and therefore makes the feedback weaker.