
Signatures of positive selection in autism spectrum disorder genes - gwern
http://journals.plos.org/plosgenetics/article?rev=2&id=10.1371/journal.pgen.1006618
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searine
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).

~~~
cgiles
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.

~~~
searine
>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](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](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](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.

~~~
cgiles
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?

~~~
searine
> 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.

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phkahler
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.

~~~
guelo
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.

~~~
lalaland1125
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.

------
maratd
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
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
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
> 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.)

------
grzm
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
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.

