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#autism#autistic#more#variants#someone#never#broken#asd#mutations#different
Discussion (87 Comments)Read Original on HackerNews
General problem statement: Many different genetic variants are associated with autism, some strongly, most very weakly. Many have suspected that this plethora of genetic variants might converge onto a smaller set of biological pathways affecting neurodevelopment in ways that results in an autism phenotype or phenotypes. This has been our hope, because the alternative scares the hell out of a scientist. The saying goes that if you met one person with autism, you've met one person with autism...meaning there is a ton of heterogeneity within the autism spectrum, even if a certain set of core autism symptoms are displayed. So there was a existential crisis that there is no "autism", just a billion autisms, where your sample size is always N=1. By demonstrating evidence that many variants converge on the same biological pathways, there is hope that understanding autism is tractable.
I'd expect one of the things that makes this difficult, too, is that there's a missing component of the "machine" - the genetics affect the pathways, which affect (maybe?) things like signal propagation or network regulation in the brain, but the actual effect of that is on the patient's experience of consciousness, and it's difficult for someone to get more than N=1 of those via commonly accepted legal methods - otherwise, we're all just looking at the outside of the box and saying "huh, this box acts differently than that box, weird."
Analogy: Two programs can produce nearly identical behavior at the UI level, but be implemented very differently. Diagnosis operates partly at the "interface" level, but what happens underneath can differ greatly.
What I know of the brain is that it’s basically a chaos machine - a ton of activity that’s just on the edge of a cascade, a bunch of feedback loops, a bunch of emergent behavior, and it’s kind of impressive we function at all to begin with, so it’s not surprising there’s so many ways to perturb the output behavior.
I think the majority of the public would like to better understand how we came into this position. There's nothing wrong with the topic of autism as research, but it's been a political football for so long that there are many reasonable doubts about methodology, diagnosis, and relevance to everyday healthcare. I understand there may be complications with some patients that require medical diagnosis and intervention, but does that not imply there should be a much more meaningful label on those cases than just the broad umbrella term of "autism"?
On one extreme, we have people thinking they're autistic when they're actually just awkward and inexperienced in life. On the other, we have people with epilepsy who prefer the label "autism" even though they're merely correlated. Something is wrong here. Not with the science, but the discussion.
Also nature is absurdly cavalier about using whatever it’s got at hand, so it’s not so much “metric socket wrench #5” as “the pry-bar/hammer/thing we use to hold the hood open” that gets fucky when the genes go wrong.
We already do treat it as the latter. The medical definition of autism is basically just any neurodevelopmental disorder that isn’t ADHD.
"we do, autism is everything that isn't ADHD"
...what? I must be stroking out, but I have no idea what point you're making here...?
In the end, maybe we are just all unique individuals with our character sliders set in various forms.
The concern is that autism as a rigorous category may be useless, but that doesn't mean that autistic people are suddenly neurotypical -- a term that is more politically than scientifically oriented. People who are not autistic broadly are allistic, to be precise with language. They may be neurodivergent in other ways.
What's even the point of having a general diagnosis umbrella, if the symptoms are different?
Same with IQ, if everyone is 150IQ, then everyone is still 100IQ, as per the definition, so "normal".
Divergence can only be mentioned when talking a base value to diverge from. What if neurotypicals are actually the neurodivergent ones?
For ASD 3 and 2 it's even easier to see it's not "everyone".
Anyway, we do not really know what is causing it, have no real idea what it even is. But we must apply occam's razor very very quickly!
If I were to include additional biological possibilities, I'd include: a) birth control -> waiting to have children until a later age, more de novo mutations due to age. b) assortive mating, since some careers tend to attract those on the within and on the edges of the spectrum., c) perhaps controversially, and with the very little research on the subject, endocrine disruption from plastic waste exposures.
Is it politically correct to write about later stage pregnancies? It would be insta ban only a few years ago.
Perhaps soon we will be able to openly discus something else, that may cause endocrine disruption, not just plastics!
as we built better telescopes, we found more stars
It seems there is a high rate of mutations, making the non-mutant ensemble incredibly fragile. How did this work in the past? Was there significant selection against mutant varieties?
1. common variants. Common variants are genetic variants weakly associated with autism that we all have to some degree or another, and that only result in autism given a sufficient number of them are found in a person..or at least that's a common idea and pretty well supported. These variants are inherited.
2. rare de novo variants: These are spontaneous genetic variants that the parents did not have, but there was a mutation during production of sperm, for example. Many times, rare de novo variants that occur in highly conserved genes cause tremendous neurodevelopmental problems, spanning death often prenatally, other conditions, and for, autism, most frequently with severe intellectual disability.
Common variants are heritable and common, and are part of the normal spectrum. Only with a very large load do these result in the severest conditions, I think, like intellectual disability.
Occurrence of rare de novo variants are associated with things like age of father (older, less reliable production of sperm without genetic mutations), pesticide exposures, etc.
There is also a real immune factor involved, as well as environmental exposures, which can interact with genes.
Suppose that there was a gene that made you more likely to be good at white collar thinkwork. You meet your partner at a professional event and have a baby. The baby now has between zero and two copies of the gene. And depending on gene dominance, the probability of at least repeating the ratio of the previous generation is like 75% IIRC.
Repeat, and fold back in. Next generation, you have a couple folks with both mutations, who exhibit an even stronger affinity for quiet thoughtful work (and people). Their kids will have a 100% chance of carrying at least one copy, right? The numbers for the third gen will be even higher.
This is all massively simplified but yeah. Mendel has the answers. The picture is even clearer if you suppose multiple genes whose effects stack, which appears to be the case with the ol 'tism.
And, finally, there is the lived experience of why this happens so much. Speaking as someone on the spec, I could never imagine life partnership with an allistic person, nor can I imagine such a person putting up with my deficiencies and quirks. Moreover, quite literally all my friends are also autspec and would never interface with someone who isn't. So I believe ASD is strongly selected for by people with ASD.
But given the volumes I'd expect we are in the hockey stick armpit of an exponential curve. Like HIV bubbling away in 1950s Africa long before we even had a name for the condition, nineteenth century colonial industrialism probably quietly worked up a stock of the relevant mutations, and the mutants found each other in the grand blender of the 20th century's upheavals.
As it were, silicon valley is one of the precipitants of sex, war, and intellect.
I am profoundly grateful I grew up in a situation that didn't cause me to self isolate into a subculture.
I have all sorts of other problems, but I appreciate that one more as I age.
https://www.factcheck.org/2026/08/trump-and-rfk-jr-repeat-fa...
In toto, the conclusion of the paper:
> Together, these findings define a dual-layered model of molecular convergence in ASD: convergence through shared interaction networks in the wild-type state and convergence through recurrent functional consequences of interaction rewiring in the mutant state. More broadly, this work establishes a scalable framework for systematic interrogation of the autism proteome, enables prioritization of druggable protein interfaces, and provides a rational foundation for precision therapeutic strategies aimed at restoring neurodevelopmental trajectories.
I have no grounding here. Does anyone want to have a go at teasing the meaning out?
Instead, evidence has been growing that epistasis, the nonlinear interaction between genes and other genomic regions, predominates in explanations of most phenotypes.
What this paper does is show where upstream of the genome various combinations of mutations can interact to cause damage during development, thus leading to the phenotype. Rather than correcting a particular mutation, or targeting drugs to their protein products, we may find downstream protein-protein interactions that are strong drivers of the phenotype, and hopefully find ways to prevent/reverse these effects.
It hopefully gives hints which will be tested,better understood, and show actual mechanisms in humans. But probably not for years.
Patient: What's the good news?
Dr: We have a two step treatment to improve your social-emotional life.
Patient: What's the bad news?
Dr: The first step is, we have to turn you into a frog...
His mother nearly bankrupted herself paying for private school for kids on the spectrum. His parents sued the local school system because they didn't have any teachers who had any skill with autistic children. couldn't protect him from bullying and couldn't or wouldn't follow the IEP. (Note: this is one of those events that ruin retirement plans). The state claims to have resources for my partner and her child, but when they try to get help, the state says it didn't realize she would need that much help.
Then there is the never-ending struggle to get appropriate psychiatric and psychological help for him, and if you think it's hard to find a psychiatrist for ordinary mental illnesses, finding someone who knows how to deal with kids on the spectrum is almost impossible.
His disability has had a negative impact on my relationship with his mother. As she has to make room for her child's emotional outbursts, I make room for my partner's angst about having a child who will never function on his own. There is a big loss of day-to-day intimacy because you never know when you will have to put up an emotional barrier against his behavior.
yea, in my eyes, that counts as broken
This isnt a moral judgement, theres nothing wrong with being disabled, but it remaims a disability that many people struggle due to.
These people are not operating within the nominal range of human behavior that might be classified as "functional."
Only 20-30% of adult Autistics can even hold a job. Not a 'good' job, mind you, ANY job.
But I agree broken is not the right word for those poor folks because they were never functional to begin with!
I would guess that even if this platform has more autistic people due to being tech focused, autistic tech nerds and programmers are on the extreme end of high-functioning. Many low-functioning autistic people will never be able to have a job or live by themselves.
This is the same issue as high-functioning ADHD'ers saying "ADHD is my superpower", meanwhile people with severe ADHD do significantly worse than the general population in basically any metric, up to having a lower life expectancy.
This isnt to say its morally bad, theres nothing wrong with being autistic or having ADHD, but it is a disability. Just like someone who's deaf can live a totally happy life but still be disabled because they are not able to hear, someone with autism is disabled because they are not able to process social cues at the same speed, even if they are a great person and have a good life.