7 ms·

Signatures of positive selection in autism spectrum disorder genes

92 points by gwern 9y ago

maratd 9y ago
Thank you for this research. There is an unfortunate simplistic perception of the evolutionary process where if an adaptation evolves, it's all positive. There is no reason for it to be that way. You can easily have mutations where you gain intelligence 80% of the time, but suffer a penalty 20% of the time, and still have that mutation spread through the population. The same gene that grants you gifts, can penalize as well, depending on environment. We're starting to tackle problems that don't have simple solutions like vaccines, antibiotics, drugs, and proper hygiene. How do you fix genes that are responsible for our greatest accomplishments, but also inflict terrible suffering at the roll of the dice?
- gwern 9y ago
  I think in this case the simplistic perception is correct. 'autism spectrum disorder' here is not severe autism but more of a symptom scale which includes such dreaded symptoms as being able to think logically and systematically; in other words, diagnostic heterogeneity: "Common risk variants identified in autism spectrum disorder" https://www.biorxiv.org/content/early/2017/11/25/224774 https://www.biorxiv.org/content/early/2017/11/25/224774 , Grove et al 2017. So I think in this case, there actually is selection for intelligence and it's only the diagnostic heterogeneity which makes it look like selection for 'autism'.
  - mjburgess 9y ago
    I think there's a contradiction here. In selecting for intelligence a harm is acquired: the risk of sevre autism. So "simplistic perception" is not correct. By selecting for intelligence, we incidentally acquire a problem.
    - gwern 9y ago
      > In selecting for intelligence a harm is acquired: the risk of sevre autism. Not sure what you mean here. You can have simultaneous selection for and against 'autism spectrum disorder', if it is heterogeneous. If for example it is a mix of actual social dysfunctionality/brain damage and greater intelligence/abstracting/systematizing, you could have selection against the former and selection for the former, and the net measured effect on the mixture could go either way. (This is not as odd as it sounds. We seem to see something very similar with the Neuroticism trait: the overall trait appear bad for you, which makes sense since it's usually seen as not very good to have a lot of, but if you break it down into its 'facets', some of them are good for you: "Genetic contribution to two factors of neuroticism is associated with affluence, better health, and longer life" http://biorxiv.org/content/early/2017/06/06/146787 http://biorxiv.org/content/early/2017/06/06/146787 , Hill et al 2017. It's analogous to how there are minimal sex differences on Big Five personality when examined at the Big Five factor level, but when broken down to their sub-factors, sex differences jump out at you.)
    - Obi_Juan_Kenobi 9y ago
      > By selecting for intelligence, we incidentally acquire a problem. That is directly at odds with the analysis in the Grove et al. paper; the genetic basis of increased educational attainment is distinct from that associated with 'severe' autism. I think this is a case of wanting to see patterns that aren't necessarily there; we'd like to see a nice even spectrum of behavior, with undesirable extremes at the ends. It's a nice reductive interpretation of complicated data. The problem is that it doesn't seem to fit. At least so far; genomic studies are very useful, especially as a starting point, but ultimately mechanistic explanations that generate testable genetic hypotheses are the gold standard for biology. And for good reason. Still, given that what evidence exists does suggest a different framework, I'd be very hesitant to conclude that there is a trade-off.
  - lumberjack 9y ago
    "think logically and systematically" is a rather bizarre way of describing all the symptoms of ASD, which are behaviors that are definitely not what we would think of as intelligent behavior.
    - gwern 9y ago
      Look into the scale in question. We're not talking about crippled mute kids banging their heads into walls or attacking their teachers.
      - watwut 9y ago
        It holds true also for high functioning autists. Inability to control emotions or evwn recognize them a.k.a. angry outbursts over small inconvenience/not getting your way/etc is one of symptoms for example.
  - sidlls 9y ago
    "Being able to think logically and systematically" is not a symptom of ASD. Look: simply being smart is not in and of itself a symptom of ASD. There are a number of symptoms associated with the spectrum that actually have very little to do with intellectual ability. It's inappropriate and factually wrong to make the statement that logical and systematic thinking is symptomatic of ASD.
  - Obi_Juan_Kenobi 9y ago
    Some relevant snips from that paper: > We find that the observed excess in ASD subjects of alleles positively associated with education attainment is confined to Asperger’s and childhood autism, and it is not seen here in atypical autism nor in other/unspecified PDD. In simple terms: looking broadly, there appears to be meaningful genetic differences between diagnoses of childhood autism and Asperger's vs. pervasive developmental disorders (in lay terms, I'd call this 'full blown autism'). Basically, the genetic stuff that's linked to educational attainment is different from the stuff that leads to 'severe' autism. This is especially interesting because these potentially 'good' and 'bad' traits are likely affecting the same time and location of development: > Interestingly, both common and rare variation in ASD preferentially affects genes expressed during corticogenesis, highlighting a potential spatiotemporal convergence of genetic risk on this specific developmental epoch, despite the disorder’s profound genetic heterogeneity. Worth noting that this is a pretty significant paper and serves as a solid foothold for the 'not a trade-off' interpretation of intelligence vs. autistic behavior. I.e., the latter is not necessarily a consequence of 'too much' of the former.
  - makomk 9y ago
    If I'm following your argument correctly, you're suggesting that treating autism as a spectrum is really just lumping together people with actual, severe autism with people who are just more intelligent than average. That's not how it works. Autistic spectrum disorders come with issues with sensory processing[1], planning, actually eating, actually doing anything, social interaction, and a whole bunch more, for pretty much everyone as far as I can tell including the well-paid, successful software developers. The fundamental thing determining where someone is on the spectrum is how able they are to convince people they're "normal", for whatever value of normal is seen as most important. (This is a common enough misconception that some of the more politically active folks even had a hashtag, #SoHighFunctioning, mocking it.) [1] More specifically, with handling sets of sensory stimuli that society expects everyone to be able to cope with. It's a somewhat open question to what extent "disability", in this case, means "different from what society expects". (Oddly enough, I don't think this even used to be part of the official diagnostic criteria despite being really common.)
    - tormeh 9y ago
      No, being slightly autistic doesn't make you more intelligent, but it makes you use that intelligence differently. If you consider the dichotomy between "fast" and "slow" thinking, my hypothesis is that mild autism causes you to think slowly more often. This can be both useful and harmful, but in many modern professions it's advantageous.
- trevyn 9y ago
  Ah, this is a compelling argument against eugenics, nice.
  - gwern 9y ago
    Well, it's also false. Specifically, if it were true, we would see all sorts of genetic correlations where one good trait systematically boosts a bad trait. This is almost never true, and it is especially not true of intelligence: in almost every single case, the genetic correlation with intelligence and a good trait is positive, and negative with a bad trait. Autism (and myopia) are the only exceptions out of scores of calculated genetic correlations with intelligence in humans: https://en.wikipedia.org/wiki/Genetic_correlation#Human_correlations https://en.wikipedia.org/wiki/Genetic_correlation#Human_corr... (This is one reason I've been so skeptical of it: why would it be such an outlier?) This rather pervasive pattern is one reason that the 'systemic integrity' interpretation of intelligence seems to be increasingly popular. Even if you bought the idea that the autism (symptoms measured in healthy people in OP) really are bad, the effect of selection on intelligence would be to reduce all sorts of diseases and problems and only slightly increase a rare disorder (and glasses).
    - maratd 9y ago
      > Specifically, if it were true, we would see all sorts of genetic correlations where one good trait systematically boosts a bad trait. And what if it's true for a short period of time until a new mutation arises that eliminates the double edged sword? Most of our adaptations are really really old. They've had enough time to "perfect" themselves. What if evolution isn't clean or pretty? What if it's a messy business where a gene arises that gives a small edge, but brings with it a host of problems. It'll still spread because of that edge and it may take millions of years to sort out and eliminate the side-effects.
      - gwern 9y ago
        > What if it's a messy business where a gene arises that gives a small edge, but brings with it a host of problems. Because it doesn't. That sort of pleiotropy just is not common, empirically, in humans. Hundreds or thousands of genetic correlations tend to confirm this: there are loads of free lunches. Why is that? A lot of it looks like relaxed selection (eg my other submission shows that our ancestors thousands of years ago appear to have had substantially lower genetic risk of disease because it was decreasing over time, but has reversed), the slowness of selection given the small effect sizes vs the constant incoming stream of new mutations, and the demographic history of humanity of massive expansion from a small starting population based on migration of also tiny groups.
phkahler 9y ago
This suggests exactly what I've been thinking about these things, but I'd go one step further than this: >> Accordingly, we hypothesize that certain ASD risk alleles were under positive selection during human evolution due to their involvement in neurogenesis and cognitive ability. I don't think they "were under positive selection", I think they still ARE. So many people like to think that humans evolved to our present state and then act like the process has stopped. The wording here echos that a bit.
- mjburgess 9y ago
  Well "were" doesnt preclude "are". To say "are" however requires a whole set of other evidence much harder to obtain.
  - craftyguy 9y ago
    Why do you think evolution has decided to stop with us after running for several billion years on at least one planet in the universe?
    - deleted 9y ago
      [deleted]
    - acomar 9y ago
      That's not what they're saying. The point is that it's easier to say something about the past with the benefit of hindsight than to say something about on-going action. How would you prove that positive selection for these traits exists right now? What kind of evidence would that take?
      - craftyguy 9y ago
        I see, yea I misunderstood. Thanks for the clarification.
    - cryptonector 9y ago
      The question is whether some specific genes are still being selected for, and the answer is not obvious, though it's a good bet that if they were, and if we're seeing a rise in incidence, then they are.
deleted 9y ago
[deleted]
- deleted 9y ago
  [deleted]
grzm 9y ago
A recent but now deleted comment asked for a more layman's explanation of this paper. Would someone mind providing a summary or pointing to another reference that does so?
- fwip 9y ago
  I'll give it a go. Background: Brains are complicated. We don't have an "autism gene" or a "smart gene" or a "schizophrenia gene." Rather, it is a network of genes acting in concert that give rise to these traits (autism, smart, schizophrenia, etc). The researchers looked at the genes that are involved in autism - certain "alleles" (versions of a gene) are correlated with autism. They were surprised to find that several of these autism-related alleles were also associated with increased intelligence. That is, having one or more "autism-like" alleles may boost your intelligence, without necessarily causing autism. They then looked at the prevalence of these autism-related alleles, and found that it was significantly higher than you would expect to see by random chance. From this, they can conclude that there is positive selection occurring - having at least one autism-related allele results in you being more likely to pass your genetics on to your children. I may be missing a few things; I read the paper pretty quickly.
searine 9y ago
Speaking as an evolutionary genomicist, you shouldn't read much into this result for the following reasons : 1. The authors only show an association between phenotype (autism) and a rare genetic variant. They do not prove any kind of adaptive function to that variant, or use any method to infer adaptive function of that variant. Thus, this isn't finding positive selection, it is finding an association. Associationed locis effect on phenotype can be positive, negative or completely null. All an association is, is a sign post pointing the way to something interesting. It doesn't mean the associated SNP itself is functional. 2. The PGC ASD dataset does not have the power to detect associations at genome-wide base-pair resolution. They had 16,000 individuals, but used a genotyping array. This is great work by PGC and an extremely important dataset, but it is best suited to finding larger associations with disease (spanning thousands of bases), not individual associated causitive nucleotides. It is for this reason that I don't trust claims of an adaptive single-nucleotide loci in the absence of any functional studies or adaptive inference. 3. Nobody in genetics takes GO Term enrichment at face value. It is an extremely noisy analysis that often turns up false positives. It sometimes points you in the right direction, but it really isn't a good analysis to hinge your paper on. This is usually interpreted among colleagues as grasping blindly for a meaningful result. 4. The autism-SNPs->intelligence link is just wholly speculative (edited for clarity).
- danieltillett 9y ago
  Points 1 through 3 are all correct, but I would like to know why you believe 4 is wholly speculative?
  - searine 9y ago
    Poor wording. The idea that autism-related variants convey intelligence is speculative.
    - danieltillett 9y ago
      OK yes this is speculative.
    - 9y ago

92 points by gwern 9y ago

Thank you for this research. There is an unfortunate simplistic perception of the evolutionary process where if an adaptation evolves, it's all positive. There is no reason for it to be that way. You can easily have mutations where you gain intelligence 80% of the time, but suffer a penalty 20% of the time, and still have that mutation spread through the population. The same gene that grants you gifts, can penalize as well, depending on environment. We're starting to tackle problems that don't have simple solutions like vaccines, antibiotics, drugs, and proper hygiene. How do you fix genes that are responsible for our greatest accomplishments, but also inflict terrible suffering at the roll of the dice?

gwern 9y ago
I think in this case the simplistic perception is correct. 'autism spectrum disorder' here is not severe autism but more of a symptom scale which includes such dreaded symptoms as being able to think logically and systematically; in other words, diagnostic heterogeneity: "Common risk variants identified in autism spectrum disorder" https://www.biorxiv.org/content/early/2017/11/25/224774 https://www.biorxiv.org/content/early/2017/11/25/224774 , Grove et al 2017. So I think in this case, there actually is selection for intelligence and it's only the diagnostic heterogeneity which makes it look like selection for 'autism'.
- mjburgess 9y ago
  I think there's a contradiction here. In selecting for intelligence a harm is acquired: the risk of sevre autism. So "simplistic perception" is not correct. By selecting for intelligence, we incidentally acquire a problem.
  - gwern 9y ago
    > In selecting for intelligence a harm is acquired: the risk of sevre autism. Not sure what you mean here. You can have simultaneous selection for and against 'autism spectrum disorder', if it is heterogeneous. If for example it is a mix of actual social dysfunctionality/brain damage and greater intelligence/abstracting/systematizing, you could have selection against the former and selection for the former, and the net measured effect on the mixture could go either way. (This is not as odd as it sounds. We seem to see something very similar with the Neuroticism trait: the overall trait appear bad for you, which makes sense since it's usually seen as not very good to have a lot of, but if you break it down into its 'facets', some of them are good for you: "Genetic contribution to two factors of neuroticism is associated with affluence, better health, and longer life" http://biorxiv.org/content/early/2017/06/06/146787 http://biorxiv.org/content/early/2017/06/06/146787 , Hill et al 2017. It's analogous to how there are minimal sex differences on Big Five personality when examined at the Big Five factor level, but when broken down to their sub-factors, sex differences jump out at you.)
  - Obi_Juan_Kenobi 9y ago
    > By selecting for intelligence, we incidentally acquire a problem. That is directly at odds with the analysis in the Grove et al. paper; the genetic basis of increased educational attainment is distinct from that associated with 'severe' autism. I think this is a case of wanting to see patterns that aren't necessarily there; we'd like to see a nice even spectrum of behavior, with undesirable extremes at the ends. It's a nice reductive interpretation of complicated data. The problem is that it doesn't seem to fit. At least so far; genomic studies are very useful, especially as a starting point, but ultimately mechanistic explanations that generate testable genetic hypotheses are the gold standard for biology. And for good reason. Still, given that what evidence exists does suggest a different framework, I'd be very hesitant to conclude that there is a trade-off.
- lumberjack 9y ago
  "think logically and systematically" is a rather bizarre way of describing all the symptoms of ASD, which are behaviors that are definitely not what we would think of as intelligent behavior.
  - gwern 9y ago
    Look into the scale in question. We're not talking about crippled mute kids banging their heads into walls or attacking their teachers.
    - watwut 9y ago
      It holds true also for high functioning autists. Inability to control emotions or evwn recognize them a.k.a. angry outbursts over small inconvenience/not getting your way/etc is one of symptoms for example.
- sidlls 9y ago
  "Being able to think logically and systematically" is not a symptom of ASD. Look: simply being smart is not in and of itself a symptom of ASD. There are a number of symptoms associated with the spectrum that actually have very little to do with intellectual ability. It's inappropriate and factually wrong to make the statement that logical and systematic thinking is symptomatic of ASD.
- Obi_Juan_Kenobi 9y ago
  Some relevant snips from that paper: > We find that the observed excess in ASD subjects of alleles positively associated with education attainment is confined to Asperger’s and childhood autism, and it is not seen here in atypical autism nor in other/unspecified PDD. In simple terms: looking broadly, there appears to be meaningful genetic differences between diagnoses of childhood autism and Asperger's vs. pervasive developmental disorders (in lay terms, I'd call this 'full blown autism'). Basically, the genetic stuff that's linked to educational attainment is different from the stuff that leads to 'severe' autism. This is especially interesting because these potentially 'good' and 'bad' traits are likely affecting the same time and location of development: > Interestingly, both common and rare variation in ASD preferentially affects genes expressed during corticogenesis, highlighting a potential spatiotemporal convergence of genetic risk on this specific developmental epoch, despite the disorder’s profound genetic heterogeneity. Worth noting that this is a pretty significant paper and serves as a solid foothold for the 'not a trade-off' interpretation of intelligence vs. autistic behavior. I.e., the latter is not necessarily a consequence of 'too much' of the former.
- makomk 9y ago
  If I'm following your argument correctly, you're suggesting that treating autism as a spectrum is really just lumping together people with actual, severe autism with people who are just more intelligent than average. That's not how it works. Autistic spectrum disorders come with issues with sensory processing[1], planning, actually eating, actually doing anything, social interaction, and a whole bunch more, for pretty much everyone as far as I can tell including the well-paid, successful software developers. The fundamental thing determining where someone is on the spectrum is how able they are to convince people they're "normal", for whatever value of normal is seen as most important. (This is a common enough misconception that some of the more politically active folks even had a hashtag, #SoHighFunctioning, mocking it.) [1] More specifically, with handling sets of sensory stimuli that society expects everyone to be able to cope with. It's a somewhat open question to what extent "disability", in this case, means "different from what society expects". (Oddly enough, I don't think this even used to be part of the official diagnostic criteria despite being really common.)
  - tormeh 9y ago
    No, being slightly autistic doesn't make you more intelligent, but it makes you use that intelligence differently. If you consider the dichotomy between "fast" and "slow" thinking, my hypothesis is that mild autism causes you to think slowly more often. This can be both useful and harmful, but in many modern professions it's advantageous.
trevyn 9y ago
Ah, this is a compelling argument against eugenics, nice.
- gwern 9y ago
  Well, it's also false. Specifically, if it were true, we would see all sorts of genetic correlations where one good trait systematically boosts a bad trait. This is almost never true, and it is especially not true of intelligence: in almost every single case, the genetic correlation with intelligence and a good trait is positive, and negative with a bad trait. Autism (and myopia) are the only exceptions out of scores of calculated genetic correlations with intelligence in humans: https://en.wikipedia.org/wiki/Genetic_correlation#Human_correlations https://en.wikipedia.org/wiki/Genetic_correlation#Human_corr... (This is one reason I've been so skeptical of it: why would it be such an outlier?) This rather pervasive pattern is one reason that the 'systemic integrity' interpretation of intelligence seems to be increasingly popular. Even if you bought the idea that the autism (symptoms measured in healthy people in OP) really are bad, the effect of selection on intelligence would be to reduce all sorts of diseases and problems and only slightly increase a rare disorder (and glasses).
  - maratd 9y ago
    > Specifically, if it were true, we would see all sorts of genetic correlations where one good trait systematically boosts a bad trait. And what if it's true for a short period of time until a new mutation arises that eliminates the double edged sword? Most of our adaptations are really really old. They've had enough time to "perfect" themselves. What if evolution isn't clean or pretty? What if it's a messy business where a gene arises that gives a small edge, but brings with it a host of problems. It'll still spread because of that edge and it may take millions of years to sort out and eliminate the side-effects.
    - gwern 9y ago
      > What if it's a messy business where a gene arises that gives a small edge, but brings with it a host of problems. Because it doesn't. That sort of pleiotropy just is not common, empirically, in humans. Hundreds or thousands of genetic correlations tend to confirm this: there are loads of free lunches. Why is that? A lot of it looks like relaxed selection (eg my other submission shows that our ancestors thousands of years ago appear to have had substantially lower genetic risk of disease because it was decreasing over time, but has reversed), the slowness of selection given the small effect sizes vs the constant incoming stream of new mutations, and the demographic history of humanity of massive expansion from a small starting population based on migration of also tiny groups.

phkahler 9y ago

This suggests exactly what I've been thinking about these things, but I'd go one step further than this: >> Accordingly, we hypothesize that certain ASD risk alleles were under positive selection during human evolution due to their involvement in neurogenesis and cognitive ability. I don't think they "were under positive selection", I think they still ARE. So many people like to think that humans evolved to our present state and then act like the process has stopped. The wording here echos that a bit.

mjburgess 9y ago
Well "were" doesnt preclude "are". To say "are" however requires a whole set of other evidence much harder to obtain.
- craftyguy 9y ago
  Why do you think evolution has decided to stop with us after running for several billion years on at least one planet in the universe?
  - deleted 9y ago
    [deleted]
  - acomar 9y ago
    That's not what they're saying. The point is that it's easier to say something about the past with the benefit of hindsight than to say something about on-going action. How would you prove that positive selection for these traits exists right now? What kind of evidence would that take?
    - craftyguy 9y ago
      I see, yea I misunderstood. Thanks for the clarification.
  - cryptonector 9y ago
    The question is whether some specific genes are still being selected for, and the answer is not obvious, though it's a good bet that if they were, and if we're seeing a rise in incidence, then they are.

deleted 9y ago

[deleted]

deleted 9y ago
[deleted]

grzm 9y ago

A recent but now deleted comment asked for a more layman's explanation of this paper. Would someone mind providing a summary or pointing to another reference that does so?

fwip 9y ago
I'll give it a go. Background: Brains are complicated. We don't have an "autism gene" or a "smart gene" or a "schizophrenia gene." Rather, it is a network of genes acting in concert that give rise to these traits (autism, smart, schizophrenia, etc). The researchers looked at the genes that are involved in autism - certain "alleles" (versions of a gene) are correlated with autism. They were surprised to find that several of these autism-related alleles were also associated with increased intelligence. That is, having one or more "autism-like" alleles may boost your intelligence, without necessarily causing autism. They then looked at the prevalence of these autism-related alleles, and found that it was significantly higher than you would expect to see by random chance. From this, they can conclude that there is positive selection occurring - having at least one autism-related allele results in you being more likely to pass your genetics on to your children. I may be missing a few things; I read the paper pretty quickly.

searine 9y ago

Speaking as an evolutionary genomicist, you shouldn't read much into this result for the following reasons : 1. The authors only show an association between phenotype (autism) and a rare genetic variant. They do not prove any kind of adaptive function to that variant, or use any method to infer adaptive function of that variant. Thus, this isn't finding positive selection, it is finding an association. Associationed locis effect on phenotype can be positive, negative or completely null. All an association is, is a sign post pointing the way to something interesting. It doesn't mean the associated SNP itself is functional. 2. The PGC ASD dataset does not have the power to detect associations at genome-wide base-pair resolution. They had 16,000 individuals, but used a genotyping array. This is great work by PGC and an extremely important dataset, but it is best suited to finding larger associations with disease (spanning thousands of bases), not individual associated causitive nucleotides. It is for this reason that I don't trust claims of an adaptive single-nucleotide loci in the absence of any functional studies or adaptive inference. 3. Nobody in genetics takes GO Term enrichment at face value. It is an extremely noisy analysis that often turns up false positives. It sometimes points you in the right direction, but it really isn't a good analysis to hinge your paper on. This is usually interpreted among colleagues as grasping blindly for a meaningful result. 4. The autism-SNPs->intelligence link is just wholly speculative (edited for clarity).

danieltillett 9y ago
Points 1 through 3 are all correct, but I would like to know why you believe 4 is wholly speculative?
- searine 9y ago
  Poor wording. The idea that autism-related variants convey intelligence is speculative.
  - danieltillett 9y ago
    OK yes this is speculative.
  - 9y ago