Signatures of positive selection in autism spectrum disorder genes | Hacker News Reader

Signatures of positive selection in autism spectrum disorder genes

journals.plos.org

92 pointsgwern62 comments

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).

1 & 2: This is setting the bar rather high, no? I hate GWAS, but am surrounded by people who do them all the time. To show any kind of function for a SNP is hard, to do it in humans is very, very hard for something like this involving nervous system function, and to prove the difference in function is "adaptive" virtually impossible. The furthest people go, and fairly rarely, is to show an eQTL and spin some unconvincing tale about how the difference in expression might have some effect.

But array-based methods do have one advantage which is that the 450K for example is heavily concentrated in genes and promoters. So the variant, which indeed does not span just one nucleotide, does have at least putative functions, which are simply the known functions of the gene, although yes, you cannot say whether the variant itself is helpful, harmful, or null on the functions of the gene. It is at least a step up from people who come to me (bioinformatics) and ask me to use my divining rod to guess what their SNP 100Kbp from the nearest gene might do.

3. Putting it in an abstract is fairly desperate, I agree. But broadly speaking the way you know you aren't getting total nonsense is if a lot of related terms cluster towards the top. Which looks to be what they got. It looks a lot cleaner than most GOEA results I see.

Perhaps you could educate me on what would be proof of positive selection. Would it be at least convincing evidence, if not proof, if you showed that phenotype P is associated with variant V, and variant V is associated with positive traits X,Y,and Z after controlling for P (so you can rule out direct links between P and X/Y/Z which bypass V)? From what I have seen, investigations into functions of individual SNPs are almost invariably a waste of time ending in handwavy stories so I wonder if there is a better approach.

>This is setting the bar rather high, no?

I understand what you are saying, but "signatures of positive selection" has a very specific technical definition and associations are not it. It means allele fixation in a population due to quantifiable selective pressure (or quantifiable selective pressure proxy statistics).

When it comes to quantifying evolution, I want to see them attempt to validate molecularly or an attempt to infer selection mathematically. For example, show that the SNP is non-synonymous and causes protein change, and then rescue. Show that it's in a promoter, splice site or enhancer and rescue. Show extended runs of haplotype homozygosity thats significant. Show a selective sweep in the region, or a peak of LD. Show a higher than expected diversity in the target gene between species, and a derth within-species. Run PAML or do some comparative genomics to show the SNP being novel and adaptive. Show me a skewed allele frequency spectrum. There are lots of ways to show positive selection that are outside the toolbox of a lot of GWAS people. HAR1 for example was an absolutely beautiful story of a bioinformatic prediction of adaptive evolution, followed by amazingly solid functional validation : https://www.ncbi.nlm.nih.gov/pubmed/16915236

Alternatively, this paper is a tour-de-force of detecting adaptive evolution bioinformatically. https://www.nature.com/articles/nature10944

If feel like there is this big disconnect between the world of GWAS and the world of population genomics, and this paper was really frustrating because I was open to the hypothesis but it fell flat on the delivery.

Anyway, if you want to know more, check out https://www.ncbi.nlm.nih.gov/pubmed/16285858 this review. It's by one of the eminent population geneticists in the field and really covers the different signals of selection well, and intuitively.

> It is at least a step up from people who come to me (bioinformatics) and ask me to use my divining rod to guess what their SNP 100Kbp from the nearest gene might do.

Hey, I feel you. I know the struggle all too well.

Thanks for the links, I will check them out. An embarassing correction: the 450K is (as you well know) not a SNP array. Can you tell I've been doing more than my fair share of methylation stuff recently?

The fundamental problem I have with your reply, though, is that the authors were not really concerned with any particular SNP. They wanted to make statements about the group of ASD-related SNPs. Clearly it is infeasible to do most of the things you have suggested here with >100 SNPs. Given that, what do you suggest they should have done?

> Given that, what do you suggest they should have done

Not used the term positive selection. If they hadn't done that this would have been boring, but fine.

Points 1 through 3 are all correct, but I would like to know why you believe 4 is wholly speculative?

Poor wording. The idea that autism-related variants convey intelligence is speculative.

Would you say its less speculative to say that divergent intelligences are more frequently found in ASD people?

OK yes this is speculative.

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.

Well "were" doesnt preclude "are". To say "are" however requires a whole set of other evidence much harder to obtain.

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?

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?

I see, yea I misunderstood. Thanks for the clarification.

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.

>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.

Nobody thinks the process has stopped. The argument instead is that the environment has changed over time, and some traits that once increased the organism's odds of reproduction relative to peers no longer have that effect.

Whether those with "certain ASD risk alleles" tend to have more or fewer children than those without is an empirical question, but I certainly wouldn't be shocked to find that the fitness benefits to "neurogenesis and cognitive ability" have declined.

>Whether those with "certain ASD risk alleles" tend to have more or fewer children than those without is an empirical question, but I certainly wouldn't be shocked to find that the fitness benefits to "neurogenesis and cognitive ability" have declined.

Getting very near indisputable now:https://www.gwern.net/docs/genetics/selection/2017-kong.pdf

The decline is actually quicker than you would think, TBH. Cognitive ability decreases reproductive fitness in this environment in women but not in men, so I imagine the decline will halt once we reach some sort of equilibrium, assuming dimorphism isn't possible quickly. I imagine selecting for dimorphism in this trait, though it would happen eventually, would take too long to matter.

Not too worried as "unnatural selection" will overwhelm this small effect shortly.

So Idiocracy was right?

Idiocracy did a fantastic job of summarizing one aspect. Unfortunately we don't have an equally memorable option to cover the other aspects.

Idiocracy assumes not just more education = fewer kids = more wealth, but also more kids = increased odds of reproduction and that these traits are reliable across generations.

We've proven more education -> fewer kids, and more wealth -> more education. So far as I know, we've not proven or disproven fewer kids -> more education, more education -> more wealth, and more kids -> increased net reproduction, at least not across enough generations.

Certainly these SEEM reasonable conclusions, and some have only been proven in the short-term. It might be that more kids -> less wealth -> less education -> net loss of reproduction. e.g. having 12 kids does give you more chances to push your genes to later generations, but the odds for each kid to get to reproduce are not the same as if there were fewer kids. If that difference is big enough then too many kids is a losing strategy. (in agrarian economies children are a resource, but if children can't work, the odds of the entire families' genes passing on are reduced for every new child past a certain point)

Idiocracy also assumes that intelligence is highly hereditable and highly correlated to wealth - In reality that connection is far fuzzier (likely technically true, but at such a low degree that environmental factors can easily matter more)

Still though - it was an amazingly effective communication of a complex topic. And I'll admit that there are news stories I read that stir my hindbrain into hear the little "bloop" noises of adding to the family tree from that scene.

Intelligence (g) is highly hereditable on the right hand side of the bell curve. Where non-shared environment (there is no measurable shared environmental component to g) is on the left hand side where people can end up with a g below their genetic potential.

Basically it is relatively easy for the environment to push an individual below their potential, but near impossible to pull them above once a basic minimum is met.

Social stratification factor also needs to be factored into that equation.

Intelligence might correlate with wealth in societies with free markets... but lower classes in a stratified society won't have access to resources that translate intelligence into success.

Come now, Mike Judge was a physicist and a programmer—not a biologist!

There's less selection pressure now because there's less mortality. A lot of people get to pass on their defective genes now that would not have been able to a couple hundred years ago.

There is huge selection pressure now in that many people don't even have kids. Any gene (or other inheritable trait like culture) which increases the probability of having kids will be strongly selected for.

In rich countries the selection pressure is greater than at anytime in human history. In the past no factor (other than luck) could strongly influence the number of children you had survive to adulthood as much as birth control does.

> There's less selection pressure now because there's less mortality.

There are two pathways to selection. You're only focusing on one. Sexual selection is alive and well.

Have you ever seen the film "Idiocracy"?

Are you familiar with the Flynn Effect?

Which seems to have stopped over the last 20 years or so.

…and which only ever applied to the low g fraction anyway.

There are still relatively strong effects. Whatever genes are statistically linked to things like less education, for example, are flooding the gene pool relative to others. There are plenty of dimensions like this.

Evolution relies on differential reporoductive success. You’d need to show those with the alleles are having more offspring and I’m not sure this would be the case in modern society with our low birth rates especially amongst highly educated portions of the population.

That is true at the entire-species level assuming a uniform selection pressure against the entire species. However, evolution also occurs when a species adapts specific traits to fill an environment niche. Traits can still be selected for when the trait involved allows the organism to compete for a different set of resources. Humans also do not reproduce randomly. Currently, it is widely accepted in the Western world that people get to choose who they have children with, and that choice can select for similar traits. Marriage customs in other cultures are different, but still can have an effect on trait selection. For example, the royal families of Europe positively selected for some fairly harmful traits (like hemophilia), because other traits (already belonging to the family) were also being positively selected for filling the niche of royalty.

Consider something like a "Highlander" allele, that has a chance to randomly appear in the general population, granting them the same stipulations as in the movie. Given that there can be only one, this particular allele has terrible reproductive success in the sense that practically no offspring will ever survive. However, the gene will always tend to exist in the population. Now, if there is some event that occurs that increases the maximum of number of Highlanders, this event will put positive selection pressure on the allele, even though the general population can reproduce much faster.

The demographics of the educated middle classes would suggest that nothing that contributes to making you middle class is under positive selection anymore.

Explain?

The most effective way to stop people having children in the modern world is to educate them and provide them with a middle class job. Any genetic trait that contributes to making it more likely for you to become educated or acquire a middle class job is going to become less frequent in the population now.

Another very effective way to stop people having children is to given them heavy retirement and old age medical care subsidies -- without having to depend on children for one's retirement / old age, one will have fewer children.

All that said, fertility rates among the middle class are not zero. They may be below replacement rate (ok, they are below replacement rate), but being non-zero means evolution still applies.

Also, obviously in the wider population (that is, world-wide) we might well be selecting against traits that lead to middle-class status (by having lower fertility rates in the middle-class), but still, within middle-class populations we're likely still selecting for those traits.

Yes evolution still applies.

Unless the middle class is a separate population to the rest of humanity then the evolution that is happening in the human population right now is selection against traits that lead to being middle class.

This selection is probably the strongest of any in human history looking at the demographic trends. When looked at dispassionately it is truely breath taking how huge this is.

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?

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 , 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'.

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.)

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.

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.

> 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 , 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.)

> 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.

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.

"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.

"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.

Look into the scale in question. We're not talking about crippled mute kids banging their heads into walls or attacking their teachers.

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.

Ah, this is a compelling argument against eugenics, nice.

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_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).

> 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.

> 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.

our ancestors thousands of years ago appear to have had substantially lower genetic risk of disease

If I understood you correctly, environment pressure relaxed for former traits. But then the new human environment caused the presure for other set of mutations to kick in, even if they're counterproductive for old environment...

Selection is performed at the level of populations, where there must be a net fitness benefit for positive selection. For your messy argument to work, there must be a change in the evolutionary context such that a trait that was once favored loses it fitness benefit, and instead any detrimental effects that were 'carried along' are now on display.

There really is no 'hiding' in evolution; if a trait has deleterious effects, even only in specific genetic or environmental contexts, then they are felt. It is this brutally simple force that permits such complex systems to function effectively.

> 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

I see it as almost axiomatically true, but I think the difference is you are taking a narrow definition of what constitutes a "bad" trait. Examples:

- Immune system: protects us from microbes but contributes to atherosclerosis, autoimmunity, and age-associated chronic inflammation

- Mitochondria: Generates ATP but also oxidative stress

- Infant brain size: makes humans as smart as we are but increases maternal mortality

- Body mass/volume: gives greater protection against predation but increases energy requirements

- Intelligence & brain volume: improves on-the-fly adaptability but costs a lot of energy to run

In the most general case, any gain-of-function adaptation which adds a new protein/organelle/limb/etc has a built-in bad trait which is that it costs resources to produce, DNA to maintain, and also adds another potential point of failure. The equilibrium point between benefit and costs is where evolution will land.

So I would argue that the reason we have X IQ points or Y neurons is exactly the same reason we have Z mitochondria: any more and the costs would have exceeded the benefits in the ancestral environment. The fact that we can seemingly get more benefits than costs from increased intelligence now merely reflects the fact that our environment has changed.

Also, JBS Haldane wrote an anti-eugenics book many years ago which used exactly this sort of argument.

  if it were true, we would see all sorts of genetic
  correlations where one good trait systematically
  boosts a bad trait

Doesn't this happen every time a rainforest canopy tree falls in a storm?

A simpler and more coherent argument against eugenics is that it rapidly constrains a population's genotypical variation.

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?

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.

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