
New Causes of Autism Found in Noncoding DNA - pseudolus
https://www.simonsfoundation.org/2019/05/27/autism-noncoding-mutations/
======
alexandercrohde
Would this mean gene-therapy could potentially undo autism?

Also, since I believe it's now actually agreed upon that autism rates actually
ARE increasing, and not just increased diagnoses, is there any candidate
theory as to why mutations would be higher in developed countries recently?

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asdf21
Older parents is the presumption.

~~~
MagicPropmaker
Another likely reason is increase in maternal obesity. See:

[https://www.scientificamerican.com/article/maternal-
obesity-...](https://www.scientificamerican.com/article/maternal-obesity-
diabetes-tied-to-increased-autism-risk-in-kids/?redirect=1)

~~~
mleonhard
That study had only 100 children with Autism Spectrum Disorder. We need larger
studies.

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gwern
Fulltext:
[https://www.gwern.net/docs/genetics/heritable/2019-zhou.pdf](https://www.gwern.net/docs/genetics/heritable/2019-zhou.pdf)

~~~
appleflaxen
thank you for posting and hosting this; press releases about papers are so
unhelpful, and should be banned from HN, IMO

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reilly3000
Non-biologist here. It would seem to reason that since non-coding DNA has a
role in RNA manufacturing, it would be susceptible to resonance from specific
energy signals that would invoke its expression, effectively appending new
information to RNA. Once propagated that information made be difficult to
subdue.

Maybe an analogy is an unexpected object being written to a pubsub topic. Each
consumer may have different side-effects based on that object depending on how
well they validate the message. Some will properly ignore it or throw an
error, but others may yield a proper side effect where one should be, or even
a malformed side effect. In any case, once it’s in the log it’s really hard to
get rid of, short of replaying the topic to a new stream that filters out that
data.

This is truly clueless conjecture. This noncoding DNA stuff is fascinating; a
rare bit of unexplored territory in science that seems to be coming into
focus. I think as scientific methods mature around system dynamics and
emergence these types of complex behaviors are finally going to be better
understood.

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astazangasta
This is what my thesis is about (I titled it "Rehabilitating Junk DNA"). It
isn't that complicated. Your resonance comment is gibberish, sorry. The DNA is
a giant tape in base 4 (ATGC). There are programs written at random places on
the tape that in a 64 bit encoding (i.e. triplets of quaternary bits). This is
"coding sequence", about 1% of the genome (itself 3 gigabases, so 30 Mbases of
coding sequence). A tape head (polymerase) comes and reads these out into RNA.
The RNA is like a flash copy that is sent to a compiler (ribosome) that
translates it into a working protein molecule (a sequence of 20 amino acids
with the mapping encoded in base 64, see "genetic code"). There are control
sequences proximal (~within 30k bases) to each program that tell the tape head
when and how much to read each program into flash (i.e., transcribe RNA).
These control sequences are in the 99% non-coding part of the genome. In my
thesis i estimated about another 1% is actual control sequence. The rest may
be random noise, we'll see.

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klmr
Nice explanation but you seem to be saying that at most 3% (being generous) of
DNA would be functional (if the rest is “random noise”). This number is over
twice as small as the lowest estimate (~ 8%) of even the most fervent critics
of ENCODE’s number. I’d love to hear a brief break-down of your reasons, if
possible.

~~~
astazangasta
Eh, I graduated in 2008. ENCODE was only a pilot yet. We didn't know about
lincRNAs. My estimate was based on multi-species sequence alignments so it is
pretty conservative. At the time it was not, however; it was doubling the
amount of functional sequence. To be honest i am not sure what the current
best estimates are based on (i switched fields). 8% seems absurdly high to me,
but there is a ton more evidence now than i had.

~~~
klmr
Ah, I misunderstood your commend as saying that you’re currently working on
the thesis.

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spraak
With the drastically increased prevalence (which improved or over diagnosis
cannot account for) we must look for environmental triggers or factors. Gene
changes simply do not happen this quickly. To be clear, I am not dismissing
looking for genes, but there are many diseases which are environmental in
cause but can be exasperated by a wide variety of genes, i.e. for which we
would not attribute the cause to genes/a single sequence alone.

~~~
Someone1234
> which improved or over diagnosis cannot account for

It is often cited as exactly the reason, and appears to be the scientific
consensus. In fact you can see large swings in diagnosis numbers based on
socioeconomic factors[0], which definitely hints at diagnostic bias.

> The reported increase is largely attributable to changes in diagnostic
> practices, referral patterns, availability of services, age at diagnosis,
> and public awareness.[1][2][3] A widely cited 2002 pilot study concluded
> that the observed increase in autism in California cannot be explained by
> changes in diagnostic criteria, but a 2006 analysis found that special
> education data poorly measured prevalence because so many cases were
> undiagnosed, and that the 1994–2003 U.S. increase was associated with
> declines in other diagnostic categories, indicating that diagnostic
> substitution had occurred.

[https://en.wikipedia.org/wiki/Epidemiology_of_autism](https://en.wikipedia.org/wiki/Epidemiology_of_autism)

[0] [https://www.healthline.com/health-news/the-big-reason-
autism...](https://www.healthline.com/health-news/the-big-reason-autism-rates-
increased-again#2)

[1]
[https://www.ncbi.nlm.nih.gov/pubmed/17367287](https://www.ncbi.nlm.nih.gov/pubmed/17367287)

[2]
[https://www.ncbi.nlm.nih.gov/pubmed/15858952](https://www.ncbi.nlm.nih.gov/pubmed/15858952)

[3]
[https://onlinelibrary.wiley.com/doi/abs/10.1002/mrdd.10029](https://onlinelibrary.wiley.com/doi/abs/10.1002/mrdd.10029)

~~~
wolfgke
> It is often cited as exactly the reason, and appears to be the scientific
> consensus. In fact you can see large swings in diagnosis numbers based on
> socioeconomic factors[0], which definitely hints at diagnostic bias.

A counterthesis based on personal observations: let us assume that there
exists a genetic reason for ASD (plausible), assume that ASD people tend to
work in specific jobs in specific branch of the economy (think software
development and/or research) - also very plausible. Now, additionally, assume
(again very plausibly) that people look for potential partners in their social
milieu and finally assume that people with similar (also slightly autistic)
traits fit better together in a relationship.

This, in my opinion, explains quite well why there is a lot of inbreeding
between people with a slight Asperger bias which, by genetics, leads to an
increase of autism presence (and thus diagnoses) in specific socioeconomic
milieus without any diagnosis bias.

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empath75
This is the kind of thing you could test without just spinning out a just-so
story.

~~~
wolfgke
> This is the kind of thing you could test without just spinning out a just-so
> story.

Scientists could test it, but _I_ surely do not have the capacity and
capability to do so.

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781
Stupid question from a noob: does gene location on a chromosome matter? If I
swap gene A from chromosome 1 with gene B from chromosome 2, will this in
general keep the cell viable and working the same way?

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jballanc
Gene location is _extremely_ consequential, especially in Eukaryotes
(everything that's not bacteria or bugs living near hydrothemal vents). A
couple of things that are influenced by position:

* First, and most immediate, are promoter/suppressor sequences. These are the bits of non-coding DNA that regulate when a gene is turned on or off. If you move a gene away from its promoter, it will not turn on and off at the right times. These sequences are so closely tied to the proper functioning of a "gene" (typically a term that refers to the introns and exons of a coding sequence), that the operating definition of "gene" should probably be expanded to include them.

* Copy number. Chromosomes take a long time to copy, and if you had to copy the whole length of a chromosome from one end to the other you'd never get a chance to divide. So chromosomes contain multiple ORIs (origin of replication). Even so, it takes long enough to copy DNA that genes located near an ORI will have an effective gene dose higher than those located further away (i.e. it will be almost as if you have two copies of the genes close to an ORI and only one copy for those further away). Granted this effect is more pronounced in bacteria with circular chromosomes and a single ORI, where gene dose can differ by a factor of 4 (or even 8) depending on location, but the effect is still there.

* Sub-nuclear localization. This is an area that is still under active study (last I cared to look...which is a number of years ago now), but there does seem to be some order to the location of chromosomes within the nucleus during interphase (i.e. when the cell is not compacting chromosomes and lining them up to split the cell). It's likely that this localization is related to the distribution of various signaling pathways so that, if a gene is expecting to be "turned on" by a specific pathway, but it happens to become dislocated in the nucleus from where the elements of that pathway are doing the work of activating genes, then it may not respond the same way to extrinsic signaling.

* Finally, and most importantly: heterochromatin/epigenetics. In addition to regulation that occurs on a gene-by-gene basis, eukaryotes are also capable of large-scale regional regulation of their chromosomes. Essentially, a signal causes modification of the histones associated with a region of DNA and the entire region becomes "condensed" into heterochromatin. A gene in a heterochromatin region will not become activated _even if_ all of the signals that would normally kick it into gear are going full blast. In other words, if you accidentally move a gene that should be active into a region of heterochromatin, you may as well have removed it from the cell entirely!

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dnautics
I'm going to go against this and say no. We swap gene locations, all the time
wholesale in mice, and usually the effect is limited. That doesn't get you a
paper, so of course you publish when something... more interesting crops up.

It's just that there are many well-studied systems where where there are
profound and severe effects that are singly extremely consequential, where you
go "huh, wouldn't have guessed that" and the cause turns out to be really
subtle.

If we're going with eukarya writ large, it's even less. Basically entire
programs of plant husbandry is the industrial process of performing
chromosomal translocation and overloading, and picking the one out a thousand?
ten thousand? that reveals a commercially useful variant.

And yeast, well we've sliced and diced those chromosomes like no one's
business (but it turns out they are particularly robust). I would go so far to
say as "the general rule is that chromosomal location doesn't matter in yeast,
with a handful of exceptions".

Conversely, there is one gene whose chromosomal location is basically
invariant in _pro_ karya, that's dnaA, which pretty much "has to be close to
the ori".

~~~
gravelc
I'm going to disagree with go with 'sometimes yes and sometimes no'.

Take a construct and transform it into a plant. Check the expression of the
transgene from hundreds of different transformation events, and there'll be
huge variation, from highly expressed to silenced, even though all inserted
transgenes have the same promoter and terminator. Location matters.

However, if the function of gene A is redundant, or it goes to a location when
expression is not affected, or it's just not a very important gene, then it
probably doesn't have any great phenotypic effect.

~~~
dnautics
I would make a bet. Randomly generate 100 spots in the mouse genome, let's say
maybe not in centromeric locations. Don't correct for being inside an ORF or a
promoter. Pick 100 random translocations swapping these spots. 95 of them will
be viable with no obvious phenotype.

~~~
klmr
I broadly agree with your point but careful when saying “no obvious
phenotype”. As my former boss likes to say about work in _C. elegans_ : “Worms
can’t talk. They _seem_ healthy but maybe they’re extremely unhappy.” Less
flippantly, we know that biological systems in general have huge plasticity to
buffer environmental changes. The environment is controlled under lab
conditions, so loss of robustness due to genetic changes will almost never be
detected. We have no good estimate — not even a ballpark! — of how many of
these 95 “no obvious phenotype” cases _actually_ have no phenotype, and
beliefs widely vary.

~~~
tleonardi
I couldn't agree more. Many knock-out mice for protein coding genes don't have
an "obvious phenotype", but they are conserved across species. When studied in
detail they often reveal an effect, be it in the response to environmental
stress or subtle behavioural alterations. I can't find an updated reference,
but results published in 2012 by the Mouse Genetics Project and the
International Mouse Phenotyping Consortium indicate that ~20% of coding gene
knock-out lines examined don't have an "obvious phenotype" [1]. The most
likely explanation for their conservation is that they do have a function and
a phenotype: we just don't know what to look for.

[1]
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3463797/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3463797/)

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onetimemanytime
My guess: older parents + environment. Granted people are having children
later in life but that doesn't account for the increase in cases (Better
detection and incentives in funding to label kids autistic is another
possibility.) So something is now in the air, food or water supply that is
making these changes. Maybe older parents are more prone to this?

~~~
faceplanted
The scientific consensus is that it's the better detection and also that many
places have started diagnosing things as autism that were previously diagnosed
as something else, there's not been any real evidence yet that it's actually
more common in anything but diagnosis.

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PunchTornado
are these in rna genes or outside of rna genes?

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klmr
It seems this study focuses on regulatory regions of coding genes (i.e.
regions of DNA that’s in proximity of coding genes, or in introns), rather
than on noncoding RNAs. This doesn’t exclude the possibility of noncoding RNAs
also having an effect though.

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logicchains
I can't believe somebody downvoted this. Some people must really hate anything
that challenges their life choices.

~~~
MagicPropmaker
We call out smokers for their bad behavior that can harm an unborn child. But
we're not allowed to say anything about over eaters.

~~~
dang
You've posted so many inflammatory things on this topic in the past that I
need to remind you to avoid it here.

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dkoston
How naive or arrogant do scientists have to be to think that we have “junk”
DNA that doesn’t affect how we develop? Wouldn’t it be much more useful to
classify things we don’t understand as “unknown purpose X” so that more people
are inclined to study them?

/end venting

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AnanasAttack
How is that naive or arrogant?

~~~
dkoston
As it seems to imply that this area of our DNA has no significant value. It
seems highly unlikely to me that there is a large mass of DNA in our body that
doesn’t affect our overall system. I relate this to people believing for long
periods of time that animals cannot tell time or remember things for long
periods of time and then later realizing that they can do both.

If we were given an explanation of "this type of DNA used to do X but since Y
happens, it is no longer used", I'd be more apt to believe in "junk DNA".
Without explanation for what it is for or what it was for, saying it is junk
seems naive.

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aszantu
some types of diets seem to help with autism as well as a few antibiotics
which seems to me - as a non scientist - that it might have to do with gut
bacteria as well. anecdotal evidence:
[http://meatheals.com/category/autism/](http://meatheals.com/category/autism/)
in the last one, the 5yo started speaking after diet switch

~~~
klmr
> some types of diets seem to help with autism

Sorry, the actual evidence for this is essential nil. The anecdotes are all
explainable by confirmation bias.
[https://skeptics.stackexchange.com/a/43957/82](https://skeptics.stackexchange.com/a/43957/82)

