New Causes of Autism Found in Noncoding DNA | Hacker News Reader

New Causes of Autism Found in Noncoding DNA

simonsfoundation.org

149 pointspseudolus122 comments

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?

Older parents is the presumption.

assortative mating - a certain 'type' of person going to college and meeting people they reproduce with - is also implicated.

Was this the polite way of saying "older, smart people"?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927579/ (Autism As a Disorder of High Intelligence [2016])

> The hypothesis that autism risk in offspring is positively associated with high parental intelligence, and high socioeconomic status, traces to Kanner (1943, p. 248), who stated, referring to autistic children, that “they all come of highly intelligent families,” at high levels of educational, socioeconomic and occupational achievement (Kanner and Lesser, 1958; Rimland, 1964). King (1975) reviewed a set of demographic studies motivated by these findings, and reported strong support for the pattern of high socioeconomic status linked with autism, including support from studies (e.g., Lotter, 1966, 1967) that checked all young children (of 8–10 years) in a given geographic area for infantile autism, and thus should be largely independent of confounding ascertainment or help-seeking biases, variation in access to relevant health care, or variation in parental awareness.

Note that these observations are 60+ years old. Read the entire "Socioeconomic status" section of the paper I cite. They argue the same and state genetic testing should be done to back it up. These seems an ideal study for 23andme (yes, yes, I know how a vocal minority feels about this org).

I guess what I'd like to know is (and I'm specifically asking you because you seem to be knowledgeable):

1. It sounds like de-novo mutations are the best theory for 70%+ of autism cases per this paper, right?

2. Does anybody track the "base rate" of de-novo mutations / generation in humans? If so, how many generations back do we have data for, and how many regions?

3. Aren't we seeing an increase in autism is developed nations even within poor uneducated families with young parents?

One study says ~38 individual base mutations per generation, but that increases by about 2 bases per year of the father's age, which is still not much given 6 billion base pairs in humans. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548427/) These studies, however, are missing rearrangements and other spontaneous structural changes which might not modify the genes at all but might change their expression or dosage. We don't have enough data yet about structural mutation rates, the technology to assess that at scale and low cost is only coming online now. Not sure about the incident rate, but since the guidelines for reporting have widened so much in the last decade that might mask any ability to really know.

These also are groups with more access to health care. Do the numbers factor such effects?

Another likely reason is increase in maternal obesity. See:

https://www.scientificamerican.com/article/maternal-obesity-...

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

This "older parents" hypothesis is thrown around very often, but it's entirely based on correlational studies (obviously, it wouldn't be ethically possible to do it in a controlled study).

And there's a very plausible alternative explanation for that correlation: Autism is probably at least partly genetic and autism impacts social interaction. It's very plausible to think that it simply takes people with autistic personality traits longer to find a partner to have children.

No, its also based on the fact that older parents (and especially fathers) lead to more de-novo mutations (which you can already see in sperm) and in this study now they show that especially de-novo mutations play a role.

If the older parents hypothesis was not true, you would not find higher autism rate is younger siblings or how do you account for that in your alternative explanation?

But sure, as they say in the paper, its most likely not a single large effect variant that causes autism but usually the combination of multiple rare variants. The genetically inherited part may also play a rule. For a complex disease such as this, its not a single cause that is responsible even for one patient. A tall basketball player can be tall due to some luck, tall parents and good nutrition all at the same time.

Antidepressant use during pregnancy?

https://jamanetwork.com/journals/jamapediatrics/fullarticle/...

Autism is also hereditary, right? Maybe it has a high enough probability of being passed on through the genes that it is causing the rate to increase over time. It may just be a fluke and we'll see it decrease again over time.

I would think diet

This comment would be more interesting with some kind of source or explanation for your thought.

> since I believe it's now actually agreed upon that autism rates actually ARE increasing

why do you believe that? I'm not aware of any recent research that would point in that direction and disprove the very plausible hypothesis that the increase is an effect of changing diagnosis criteria and increased attention for the topic.

I’m also unfamiliar with any data to suggest the increase in rates is anything but a change in diagnostic criteria. And it’s my field, so I’d OP has data to share, I’d be very appreciative of a link.

https://www.cdc.gov/ncbddd/autism/data.html

This link talks about prevalence rates. I don't see anything talking about an increase in autism rates that is not just explained by increase in diagnoses as the OP claimed

Right. These are the precise prevalence numbers that have been addressed in multiple studies showing that the change is attributable to increases in public awareness / detection efforts, and broadened diagnostic criteria.

Thank you for digging up a link.

Yes, I'd like to know where you are getting that the actual rates are increasing. My wife and I (parent's of a daughter with autism) laugh how every year they claim the numbers increase - 1/100, then 1/50, etc. These are numbers marketed by Autism Speaks and other organizations to make autism appear more wide spread and increase their funding. This does nothing but hurt people with more severe autism. Widening the net so wide so that any social difficulties is considered autism just reduces the availability of services for children with "real" autism. Autism is a spectrum, with people who are completely non-verbal constantly stemming to people with Asperger's Syndrome who excel but have some social difficulties. They really should be distinguished.

Let's separate facts from feelings. At the end of the day it really is irrelevant what indirect emotional consequences the facts have, all that matters is that we get the ones that happen to be true so that we can make the best choices going forward.

I'll try to find the sources and post them on parent.

How am I expressing feelings and not facts?

> Widening the net so wide so that any social difficulties is considered autism

That's an oversimplification of the situation, both the autism spectrum (including the now-reclassified Aspergers), and the entire rest of the DSM. Some of those mental disorders also result in social difficulties.

I'm sure you would like more help for only "deserving", specific children like yours, but increased access means more schools that are able to handle IEPs, more teachers able to cope with special needs children, more understanding by all that yelling at a non-verbal stimming child is counterproductive, It means more attention paid by society, more research into the problem, resulting in figuring out the causes of autism.

It really is a spectrum, and limiting help and research to only individuals to non-verbal, body-rocking, non-stop stimming makes it very hard for research to progress - those individuals are very difficult to communicate with! Someone who's limits of communication is PEC cards, is not able to give any useful sort of description of how a particular medication is affecting them.

We are starting to recognize that it is, as least partially, an anxiety disorder, of which we already have a number of doctor prescribed medications, with anecdotal successful treatment for autism.

(I proffer no opinion on Autism Speaks here.)

I'm not sure what you mean by increased access. The public school system has very limited funds and personnel. There are some schools with no dedicated reading specialist for example (ever fewer have occupational therapist or autism specialist trained in ABA or other methods). In the real world you have to make decisions on what kids need extra help. It would be great to say everyone gets it but that's not feasible.

I'm all for researching across the spectrum and more public awareness.

Methodology: type "autism incidence" into google scholar, filter by articles since 2015 and read some on the first page.

Conclusion: It's still pretty-well ambiguous as far as I can tell. You're right that it's not conclusively increasing.

https://link.springer.com/article/10.1007/s10803-018-3834-0 -- Says true autism rates increased between '85 and '98, but since then only diagnosis of autism has been increasing til '04.

https://www.cambridge.org/core/journals/bjpsych-open/article...

I note that I think it's also pretty well-agreed upon that rates don't match up between countries.

> 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?

This paper is mostly about the impact of de-novo mutations, i.e mutations that are found only in the child and not in its parents. One theory is that as paternal age is rising and a higher paternal age is linked to a higher number of de-novo mutations which leads to a higher chance of de-novo mutation related genetic diseases like in this case autism (and other mental disorders).

Note that the paternal age in developed countries has been at a historic low in the mid 20th century, which may have lead to a historically low rate of mental disorders in the last decades.

> Would this mean gene-therapy could potentially undo autism?

Almost certainly not. Autism is caused by developmental changes. This means that any gene therapy would have to start before the embryo development is even finished, i.e. in the mother’s womb. After that, it’s essentially too late. Think of it this way: Could gene therapy make an adult person taller or smaller? Despite the fact that height has a large genetic component the answer is obviously no, since skeletal growth stops after puberty.

> I believe it's now actually agreed upon that autism rates actually ARE increasing

You’re jumping the gun there. It’s plausible that there are factors that are causing an increase of autism rates (e.g. ageing parents) but so far there’s no positive evidence that this is indeed the case, or that diagnostic changes aren’t the sole reason (see https://en.wikipedia.org/wiki/Epidemiology_of_autism#Changes...).

It all depends on whether it is a structural thing that is established during fetal development, which can not be fixed post birth, or whether it is part of the brains's development post birth.

There is a shit ton of brain development post birth -- not structural (the growth of the initial neurons) but in weeding out pathways and reinforcing certain pathways. A lot of it is based on complex feedback between activity, neurochemical releases and receptors. All of that is fair game to change post birth.

Given that autism (like many other psychology labels) is a label for a diverse group of disorders which we can not fully tease apart accurately at this stage, it is likely true that some forms of autism can be treated post-birth, but others will not be.

> Would this mean gene-therapy could potentially undo autism?

One of the "autisms", possibly - but it's a long long way before that happens.

> Also, since I believe it's now actually agreed upon that autism rates actually ARE increasing

[citation needed]

Also note that most of these are spontaneous mutations, and that this paper doesn’t distinguish between correlation and causation.

My take, this shoes that something is broken it the very mechanism of DNA replication, expression, DNA repair and cell differentiation, but somehow we fail to detect those aberrant genes on late stage. So their regulation in the early development stages is when we need to look, but that’s very tough to do.

Fulltext: https://www.gwern.net/docs/genetics/heritable/2019-zhou.pdf

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

M'lord gwern

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.

resonance from specific energy signals

Did you have something more specific in mind?

Unfortunately no. The article and other literature I could find in my recent googling suggested that free radicals may have something to do with it, but more generally it seems that gene expression is often conditional. Some genetic markers go expressed in some but not in others. Some only express under conditions of chronic stress or specific toxins. The only thing you might be able to say is that merely having information in your genome doesn’t guarantee it will ever be used, but what causes it to be used varies per circumstances that may vary for each type.

I’ll also add that I mean “resonance from specific energy signals” in the most general sense possible, not ‘quantum woo woo’. Like a lock opening when a matching key is inserted and rotated. You want the lock to open with means motion; resonance is motion in response to specific energy, not general energy. It may be awkward to refer to the ridges of a key as energy, but it is in an abstract and absolute sense. My only formal training is in acoustics to that’s part of my lexicon.

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.

Fascinating, thanks for breaking it down into data structures.

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.

As an added complication, a decent proportion of DNA in the genome is meaningful at least in how long it is, because it separates two functional pieces of DNA that interact in 3D space due to the way the DNA wraps around other stuff. If you change the content of this DNA, it doesn't cause disease, but if you change the length, it does.

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.

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

A simpler and perhaps more useful way of thinking of non coding DNA is to use analogy of a recipe. Coding DNA tells you the ingredients used, noncoding tells you when and how to use those ingredients. Both are essential to proper gene regulation, but one is much harder to study.

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.

>(which improved or over diagnosis cannot account for)

Out of curiosity, why not?

> 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

[0] https://www.healthline.com/health-news/the-big-reason-autism...

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

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

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

I good way to corroborate this would be to track the "junk dna errors" percentage of newborns and see if there's a statistical trend.

> 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.

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

> 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.

The genes aren’t changing, but the environment is and the modern environment is interacting poorly with our genetic heritage and increasingly so.

Even so, looking at genes and identifying the pieces is still important. For example having a test that determines risk during pregnancy would be awesome.

Essentially what I'd said, so I agree! I'd like to have more awareness and study of what in the environment is causing it

I'll put in out there (at the risk of being downvoted) : an extremely destructive/insensitive world around a developing child, as a fetus or later, is to me one of the root causes of autism. See Bruno Bettleheim's theories (refrigerator mother, The Emtpy Fortress, etc).

"Autistic people have the conviction that their efforts have no influence on the world, because in the past they were convinced that the world is insensitive to their reactions."

This comes from my personal experience.

> an extremely destructive/insensitive world around a developing child, as a fetus or later

Are you saying i.e. an emotional and social cause? In contrast to e.g. a gene or chemical (physical) cause?

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?

Most likely yes. There's something called chromatin that winds up DNA. Also transcription factors and other factors play a role.

Yes it does matter, see https://en.wikipedia.org/wiki/Chromosomal_translocation

Certain chromosomal translocations cause diseases.

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!

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 prokarya, that's dnaA, which pretty much "has to be close to the ori".

So, two quick points in response:

1. Yeah, I probably overstated the case. It's not as if it's impossible to move a gene somewhere else on a chromosome and have it function completely normally. As you point out, we do this all the time. That said...

2. Genetics is hard, and I'm of the school of thought that one reason it is so hard is because systems are more fragile in meaningful ways than we assume. That is to say, if you attempt a gene translocation 100 times and get 3 successes, most geneticists would be happy with that result and not question the 97 failures. And, indeed, it is entirely possible that the quality of the reagents, the stringency of the protocols, or any of an infinite number of other variables that have little or nothing to do with genetics could be the cause of those 97 failures...or, it could be that 97 times the translocation worked but the product wasn't viable. I know from experience that it is very hard to distinguish between these possibilities, and furthermore that in the publish-or-perish world of academia today there's not any motivation for navel gazing into the reason most genetic protocols are not more efficient. That said, I've seen hints in my past work that make me think location, gene dose, DNA secondary and tertiary structure, etc. are more consequential than the common wisdom would have you believe.

(Oh, and for anyone still reading, I'll share the brain teaser that was my light-bulb moment for the extent of gene dose effect in prokarya: it takes 40 min to replicate the E. coli genome, but during exponential growth E. coli can double in number every 20 min. How?)

https://www.annualreviews.org/doi/abs/10.1146/annurev-genet-...

and

https://www.sciencedaily.com/releases/2010/10/101014144312.h...

The second one relates to a feature at the metaorganismal level; namely the evolution rate. Fun fact: human chromosome 1 is the merger of two simian chomosomes and has two centromeres

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.

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.

In how many samples are you doing this? It’s all about effect size.

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.

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/

It does, genes are translated into protein products that affect cell operation. The relative concentration of these gene>protein products also impacts how a cell operates.

How efficiently genes are turned into proteins is determined by quite a few things, but one of them is definitely based on location. Upstream and downstream transcription factors will impact how many copies of a genes proteins are created.

You could broaden your definition of gene to include proximal regulatory elements. If you take that unit and translocate it the answer is much less obvious.

This is not a stupid question at all. In fact, it is the subject of much active research. The short and extremely oversimplified answer is that a given gene will produce approximately the same protein product no matter where it is in the genome, but the regulation of where and when and how much and under what conditions that protein is produced is highly dependent on the genomic context of the gene.

The correct answer would be -- it depends. But in general, yes, the precise location of a gene on the chromosome matters.

The chromosomes are organized in an intricate three dimensional structure with different levels of hierarchical organization and interacting functionally. See https://en.wikipedia.org/wiki/Topologically_associating_doma... and https://en.wikipedia.org/wiki/Cis-regulatory_module

Yes, but it's dependent on a lot of things. Some chromosomal areas are more important than others. In humans and other mammals, it also matters from which parent the DNA came from (paternal DNA is different from maternal DNA, but a woman will 'rewrite' her father's chromosomes when passing it on to her child and a man his mother's, etc). Any variation in these things could cause developmental disabilities. However, typically things like inversions and translocations and such do not have huge phenotypic differences, whereas things like triploidy or uniparental disomy (inheriting both copies of a chromosome from one parent) have a more obvious manifestation.

Sorry this isn't accurate at all. We don't 'rewrite' any chromosomes. Sometimes during errors in replication changes occur, but these are random. They presumably happen approximately equally in both parents contribution to your DNA (though I don't know this to be 100% confirmed empirically).

Not in terms of primary sequence, but imprinting has an impact on expression and is parentally determined.

Imprinting is a thing, and yes, the sex of the parent matters. A woman does not pass on a male imprinted version of her father's chromosomes. She passes on the female version. While methylation is not part of the 'genetic code', it is part of the DNA molecule, and it does impact genetic expression.

Anyway, in your pseudo-scientific world, how do you explain Angelman and Prader-Willi syndrome? Please... the world must know.

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?

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.

are these in rna genes or outside of rna genes?

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.

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

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.

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

Maybe so, but please don't post unsubstantive comments to HN, or break the site guidelines like this.

https://news.ycombinator.com/newsguidelines.html

We detached this subthread from https://news.ycombinator.com/item?id=20036198 and marked it off-topic.

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

How is that naive or arrogant?

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.

The history of science, and especially biology, suggests that there is a lot of stuff which isn't understood very well. Seeing no importance in an aspect of the natural world can be as much a comment on experimental design and human knowledge ("knowing what to look for") as on the phenomenon ostensibly being studied. Typically "being able to observe an effect" is contingent on some other dependent scientific "knowledge".

Junk DNA means non coding and without benifit. Due to the random nature of mutation such sequences are expected. However, verifying any specific sequence is useless is difficult.

One important consideration is sequence length may have value even if the content is meaningless. Another is random sequences may aid long term adaptation even if they don’t currently do anything. So, if anything Junk is a fairly descriptive term as you may eventually use stuff from a Junk Drawer even if it’s not currently useful.

I don’t believe it exists without benefit. Nature can certainly phase parts of our system out over time (appendix) but to say it is without benefit is a bold statement. I’d argue that we simply don’t know the purpose and dismissing it as non-beneficial is arrogant or naive. Science should be based around evidence rather than lack of.

What is the benefit of having an arch in the nose vs not having one? Or the benefit in light brown hair vs dark brown hair? Or the benefit in light brown eyes vs dark brown eyes?

How about the benefits in male pattern baldness where some of the hair on the scalp is affected by high levels of DHT and some aren't? How about diffused baldness where the way in which a person balds isn't in one particular place and is all over the scalp randomly?

These are all visual, observable examples. But when looking at individual genes, I'm sure you can appreciate that randomness inserts itself there as well - randomly, and not necessarily with any benefit. I don't think its arrogant or naive to appreciate that we are a set of random mutations, some of which have helped us become extremely successful in nature, but some of them don't have those benefits and only survived through luck or selection of other genes in the person they cohabited.

I can absolutely appreciate that we are a series of mutations.

To say that there is no benefit or detriment to having an arched nose or not also seems naive. It’s likely that the shape of your nose can affect how much air passes to your lungs, how likely it is to be sun burnt or not, and many other things. Just because the values or benefits might be minuscule compared to other things doesn’t mean they do not exist. Tiny optimizations are common in all systems and they should not be overlooked.

To say that massive portions of our DNA “have no benefit” without having proof of such, seems naive to me. It’s ok for others to disagree; clearly the majority of the scientific community does. It’s just unfortunate that we have been ignoring the possibility that this large portion of our DNA could have effects on our system. In the article above, it’s not benefits that matter but risks. We shouldn’t only care about parts of our body that may bring benefit but also those which may harm us.

As far as baldness goes, this is a trait that could be seen as a benefit. Some females may desire a mate with high levels of DHT and baldness is a good indicator that a being has high levels. There are many visual traits (see birds) that allow the narrowing of selection for potential mates.

Evolution is not a process of finding a global optimum, just a local one. And traits which have no impact on the chance for a species to reproduce just get carried along for the ride.

An obvious example of this is the Laryngeal nerve. Fish evolved with this nerve being a simple straight line between the brain and larynx. However, in animals which evolved from fish and have necks, we see that the nerve is "trapped" under the aortic arch in the thorax. So this nerve ends up looping through your neck to reach your thorax. Giraffes have this nerve going all the way down their neck and back up again. But this inefficiency has no impact on the survival chances of a species (if your neck is severed you're dead regardless of whether you have an additional nerve running through it) so it's stuck around.

So, there definitely are traits which objectively have no benefit or detriment and have just stuck around. You could argue even some late-life conditions which are detrimental also "stuck around for the ride" because people late in life don't reproduce and thus there is no evolutionary mechanism to affect such traits.

Sure, I even made this point when I pointed out that the appendix has gotten carried along for the ride in another comment.

Do you really believe that 75-98.8% of our DNA serves no purpose and is being carried along for the ride? That doesn't seem like a small inefficiency.

Why would you assume a high grade of efficiency, let alone perfection?

I’m assuming more than 2% efficiency would be achieved. I could be wrong but why would I assume that when most other systems in the body are massively more efficient that DNA would be the outlier?

> To say that massive portions of our DNA “have no benefit” without having proof of such, seems naive to me.

What makes you think scientists have no proof? The whole reason we know junk DNA has no important function for cell biology is that there’s good evidence that says so. There’s some wiggle room with the details but the general picture of this won’t change, and this has been studied for a long time and is fairly well understood.

Whole genome sequencing on humans has only existed for 16 years (1). In 2003, the cost was prohibitive until NGS (next generation sequencing) techniques became commercialized. We can definitely disagree here as 15 years of research which in my worldview is focused mostly on coding DNA and karyotyping doesn’t seem like much to draw this conclusion. There’s plenty of decades old science that has shifted or been rewritten due to the rise of new techniques related to faster computing power.

It’s quite possible that I’m biased based on the labs I’m familiar with and papers I’ve been reading. I just haven’t seen the focus that you are talking about.

1 https://www.yourgenome.org/facts/timeline-history-of-genomic...

Junk DNA has already been studied before whole-genome sequencing existed, and evidence from NGS not only hasn’t overturned that research, it has largely corroborated it. And as for personal biases, I’m a staunch defender of the ENCODE research so I’m certainly not biased in favour of the concept of junk DNA.

Interesting. I may be biased in the other direction after reading "The Epigenetics Revolution" and "Junk DNA" by Nessa Carey.

ENCODE is such an amazing project! Also, thanks for your research on non coding DNA.

But junk is perjorative word which suggests that it is entirely disposable even desirable to remove. That may turn out to be true but the experiment required to prove that thesis would require closely observing a biological systems evolution and disease evolution for some length of time, with "junk" DNA somehow removed and repressed. It may turn out to be a sort of filler with certain characteristics that work out to have repercussions for longer term genetic dynamics, and it may not. Since we cant tell yet, the name for it is very presumptive.

> But junk is perjorative word which suggests that it is entirely disposable even desirable to remove

That's subjective.

> It may turn out to be a sort of filler

Yes, that's understood and recognized in every analysis.

> the name for it is very presumptive.

Naming is hard. The lowest common denominator (least amount of thought/simplest concept) will almost always persist. It's not like someone is wringing their hands in the background imagining they have fooled the scientific community.

Junk (and/or noncoding) DNA provides necessary structure for our chromosomes, spacing for transcription, and some defensive properties.

There are many benefits beyond just that of coded information storage, which people are focused on here in this thread.

As far as I can tell, the preferred scientific term is "non-coding DNA," with "junk DNA" being a sensational term that gets more traction in the media.

Here’s the Wikipedia quote:

> When there is much non-coding DNA, a large proportion appears to have no biological function, as predicted in the 1960s. Since that time, this non-functional portion has controversially been called "junk DNA".[1]

It’s not all non-coding DNA that is “junk”, just the stuff that “has no purpose”.

I’m arguing that it is much more likely that we don’t understand its purpose and should treat it as such rather than dismissing it as “junk”.

I like the use of “junk” DNA only because it reminds people how much we don’t know. It wasn’t that long ago the term was used because that’s DNA was assumed to be useless.

Personally I think it's both naive and arrogant to assume that because something is called "junk DNA", that means that the scientific community as a whole have decided to never consider whether it has any impact. There are all sorts of weird terms-of-art in science and I find it quite frustrating that armchair-scientists think they know better purely based on the words that happen to be used.

Actually, “junk DNA” was assumed to have no function decades ago. That’s why it got the name. That’s what I was taught in college 15 years ago.

Subsequently it was discovered it does have a very important function.

Scientific understanding evolves.

What you were taught in college 15 years ago is still correct. Junk DNA does not have “a very important function”. The “subsequent discoveries” were, by and large, just a failure in science communication. Junk DNA is still non-functional, very little has changed. We know this because it’s not preserved evolutionarily. By contrast, “important” DNA is preserved from mutation (this is called “negative” or “purifying” selection) because mutating it is almost always bad for the individual. What has changed is twofold:

* We have a better handle on what constitutes noncoding, non-junk DNA. The proportion of DNA thus labelled has grown slightly (but only slightly!). We were always aware of its existence but we previously couldn’t study it easily. There are very good reasons to think that the proportion won’t grow much further. The rest is still junk DNA.

* We know more about how new genetic function can evolve using the raw genetic material in junk DNA, and how junk DNA might interfere with the proper function of cells, in particular in the presence of pathogens. But, again, the principle of this was already known (or, partially, at least strongly suspected) decades ago. It was just not studied, and we’re now able to study it better.

But our fundamental understanding of junk DNA hasn’t changed.

Many noncoding DNA sequences must have some important biological function. This is indicated by comparative genomics studies that report highly conserved regions of noncoding DNA, sometimes on time-scales of hundreds of millions of years. This implies that these noncoding regions are under strong evolutionary pressure and positive selection.[47] For example, in the genomes of humans and mice, which diverged from a common ancestor 65–75 million years ago, protein-coding DNA sequences account for only about 20% of conserved DNA, with the remaining 80% of conserved DNA represented in noncoding regions.[48]

Noncoding DNA ≠ junk DNA! In fact, the latter is a subset of the former. Confusing the two is understandable since even scientists occasionally play fast and loose with the terms but scientists nevertheless understand that they are different. To cite from the same article you’ve cited:

And this is by no means a new discovery, functional noncoding DNA has been known for as long as junk DNA.

Maybe my wording wasn’t clear. I never implied that everyone is ignoring non coding DNA. My point was that it seems naive or arrogant to label something as “not useful” rather than “use unknown”. It makes it less likely that a larger amount of people will investigate it.

I think you should also use some data to back up your point because it’s my understanding that the majority of DNA sequencing ignores non coding DNA and the article makes the same point. You also have no idea what field I work in so I’d suggest perhaps asking before coming to the conclusion without any data.

The word junk does not appear in this paper. They talk about noncoding regions, noncoding mutations, and noncoding genome.

More generally, the term "junk DNA" was coined to refer to a specific type of noncoding DNA. These two articles give the historical background for the term:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014423/

https://judgestarling.tumblr.com/post/64504735261/the-origin...

Agreed, maybe I misspoke but I wasn’t aware of any place I said it did.

“Junk DNA” is a well accepted term by the scientific community and public.

https://www.scientificamerican.com/article/what-is-junk-dna-...

Humorous take on my point: https://www.amazon.com/Junk-DNA-Journey-Through-Matter/dp/02...

I think my main point was missed which is: “labeling something as non useful and leaving it out of the majority of DNA sequencing as a result has made large swathes of the scientific community unaware of how non coding DNA works within the DNA ecosystem”. I think it’s unfortunate that the community doesn’t label this as “exciting area of unknown science” which would encourage investigation.

> labeling something as non useful and leaving it out of the majority of DNA sequencing as a result has made large swathes of the scientific community unaware of how non coding DNA works within the DNA ecosystem

This is simply not true. Noncoding RNA and in particular regulatory regions have been known and studied for many decades. The reason we know less about them than about genes has multiple reasons, foremost the difficulty in studying them (large-scale studies have only recently become possible). But it has nothing to do with “ignorance”, or with the label “junk DNA” (the SciAm article you link to is utterly wrong to claim otherwise).

Furthermore, although I also think the name has issues (but mostly in science communication), scientists don’t just “assume” that intergenic, non-regulatory DNA regions are unimportant. They have good reasons, backed by evidence, to think so. I’m actually in the camp that thinks that stochastic biochemical function is potentially important (and I used to study repeat elements) but even so there’s almost certainly very little “exciting … unknown science” in junk DNA.

I have to disagree. Whole genome sequencing has only been prevalent in the past few years. I can agree that much of this has to do with the cost and complexity involved and the rise of new techniques and more computing power has opened up whole genome sequencing which has only been around since 2003 (1) and has been highly expensive and not used frequently until recently (2).

The majority of research I’ve come across in the past decade has been still focusing on DNA microarrays and qPCR which are focused on coding DNA. Perhaps I’m not seeing all the papers published for the studies you are familiar with and as such have a bias to believe that only a small portion of research is using NGS and is focused on non coding DNA.

1 https://www.yourgenome.org/facts/timeline-history-of-genomic... 2 https://academic.oup.com/hmg/article/25/R2/R157/2198171

Well my own research has focused completely on noncoding DNA. So yes. It exists.

Ok, we'll replace junk with noncoding above.

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/ in the last one, the 5yo started speaking after diet switch

> 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

This theory doesn't stand in face of science. However: some autistic people have food allergies and comorbid metabolic problems; addressing those will usually alleviate suffering-caused problematic behaviors, and thus make communication easier. This doesn't mean it was "autism treatment" or "autism diet"; you'd get the same effect if you treated a toothache in a nonverbal autistic child.

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