Disruption of "Autism Gene" Alters Hippocampal Identity

[Cryptid]

Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity

Abstract

Chromatin regulation plays a pivotal role in establishing and maintaining cellular identity and is one of the top pathways disrupted in autism spectrum disorder (ASD). The hippocampus, composed of distinct cell types, is often affected in patients with ASD. However, the specific hippocampal cell types and their transcriptional programs that are dysregulated in ASD are unknown. Using single-nucleus RNA sequencing, we show that the ASD gene, lysine demethylase 5A (KDM5A), regulates the development of specific subtypes of excitatory and inhibitory neurons. We found that KDM5A is essential for establishing hippocampal cell identity by controlling a differentiation switch early in development. Our findings define a role for the chromatin regulator KDM5A in establishing hippocampal cell identity and contribute to the emerging convergent mechanisms across ASD.

Read the Complete and Unabridged Research Paper HERE

 

[Tom]

Interesting, but Wow, this is technically so over my head.

 

[Alexej]

...we show that the ASD gene, lysine demethylase 5A (KDM5A), regulates the development of specific subtypes of excitatory and inhibitory neurons.

only one gene responsible for autism? - I doubt it

 

[Cryptid]

"the ASD gene, lysine demethylase 5A (KDM5A), regulates the development of specific subtypes of excitatory and inhibitory neurons" -- it's been called "The ASD Gene" because its disruption more strongly correlates with the presence of ASDs than the disruption, presence, or absence of other genes.

You need to understand that the research is ongoing, and that other similar genetic effects may more strongly relate to ASDs.

In science, 'fact' can only mean "confirmed to such a degree that it would be perverse to withhold provisional assent". And by 'provisional', I mean to remain skeptical about the absolute nature of a claim, because another experiment might prove the claim at least partially incorrect -- that's science.

 

[Magna]

only one gene responsible for autism? - I doubt it

I thought there were many genes potentially responsible for autism.

 

[Tom]

In science, 'fact' can only mean "confirmed to such a degree that it would be perverse to withhold provisional assent". And by 'provisional', I mean to remain skeptical about the absolute nature of a claim, because another experiment might prove the claim at least partially incorrect -- that's science.

That's a good way to look at it.

 

[Hypnalis]

Interesting article. It's been clear for a long time that there's a significant genetic factor in ASD susceptibility (40%-80% according to the article I linked below), but that it's not simple.

The article Cryptid linked seems to explain some of the mechanisms, so it's probably a step forward towards full understanding.

The "ASD gene" name looks to be too broad though.

Calling it the "ASD gene" seems to be a "marketing trick". Remember that scientists who work on this kind of thing have to "sell" their projects to e.g. a Government or other research-supporting organization). There's always a marketing element to the documentation of any good project, and that means simplified terminology.
(See "Funding" at the end of the paper for the organizations that paid for this project.)

So calling it "the ASD Gene" has to be somewhat true, but not necessary the full picture.

In this case it's something that affects how genes are "expressed"

Epigenetics - Wikipedia

en.wikipedia.org

So it's an influencer, but:
* It's not the only one that affects gene expression in ways that correlate with ASD
* It's not a simple "1-1" relationship between these genes and ASD

I looked at a couple of other articles, but they're all fairly heavy going.
FWIW this one has good overview sections about 1/3 of the way in:

Genetic Causes and Modifiers of Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is one of the most prevalent neurodevelopmental disorders, affecting an estimated 1 in 59 children. ASD is highly genetically heterogeneous and may be caused by both inheritable and de novo gene variations. In the past decade, ...

www.ncbi.nlm.nih.gov

Personally I think it's interesting, but IMO it's not relevant to most of us.
It's already clear that ASD is genetic (which means it can't be changed by modern medicine), and I'm way to old even if it could be changed very early in the human life cycle.

So I'm happy the research is being done, but even if the science was complete, it wouldn't change anything for me.

I'm also very happy I'll never have to be involved in any discussion about applying medical tech to human DNA early enough to "remove the risk of genetic disorders".

 

[Neonatal RRT]

Just to add some clarity and context here because I think some of you either did NOT read the article or do not understand what the study was about:

1. lysine demethylase 5A (KDM5A) is a single gene that, in turn, up regulates or down regulates thousands of other genes. It is absolutely true there are thousands of ASD-associated genes, but if there are a few KEY genes that up regulate or down regulate all these other genes, then is good progress in our understanding.
2. They studied this in the hippocampus of mice. We are not mice, but we both are mammalian, so sometimes these murine studies are compatible with humans, sometimes they are not. Think Venn diagram. At some point, other studies with a primate model will be needed before looking at the human brain.
3. This diagram from the study helps us visualize and explain the role of KDM5A in gene transcription the hippocampus:

 

[Magna]

Personally I think it's interesting, but IMO it's not relevant to most of us.
It's already clear that ASD is genetic (which means it can't be changed by modern medicine), and I'm way to old even if it could be changed very early in the human life cycle.

So I'm happy the research is being done, but even if the science was complete, it wouldn't change anything for me.

I'm also very happy I'll never have to be involved in any discussion about applying medical tech to human DNA early enough to "remove the risk of genetic disorders".

Eugenics...here we come.

 

[Neonatal RRT]

Eugenics...here we come.

Well, it may get there, but not any time soon, and when I say this, knowing what I have experienced first hand working in a referral center for any and all genetic diseases across the US,...there are a "LOT bigger fish to fry" than autism. Some the these genetic conditions you've never heard of, as even these are so rare, and yet some are rather common on the spectrum and definitely familial,...cystic fibrosis, as an example. There are terrible, devastating, horrific, and lethal genetic conditions out there being passed along family lines, that frankly, we would all like to eliminate. I have seen some "really nasty stuff" in my day.

This field of using CRISPR and stem cell manipulation is a branch of biomedical engineering (genetic engineering), one of the most highly demanded degrees in 2023, and is still in its infancy. My son is a biomedical engineer and professor, so I do have a limited understanding of it from our conversations, despite him signing NDAs not to talk about it. My interpretation is that they have made some interesting breakthroughs, like reverse-engineering of stem cells (human embryonic tissue is no longer needed), but actual genetic manipulation, itself, remains extremely limited to very specific animal and plant models. Regulations are in place when it comes to human embryo genetic manipulation, cloning, etc. The mountain of government red tape you have to go through to even consider making this a "viable" or "acceptable" medical therapy is often prohibitive. One thing government is good at, slowing things down. Even if your "hot shot" genius biotech company did come up with something worth while, you've still got to contend with all the regulations, not to mention the "court of public opinion". We aren't there yet. Not even close. Regardless, I think eugenics, the way most people think of it, is generations of us away, even considering our exponential learning curve and AI technologies. This is all highly complex, and given the thousands of associated genes associated with autism, even if we could somehow narrow it down to a handful of key genes, any sort of genetic manipulation would be orders of magnitude more difficult than say, my example of cystic fibrosis.

The bottom line here, I don't think we need to be concerned about autism being used within the same sentence as eugenics. I don't think it will ever be a reality in our lifetimes.

 

[Magna]

Well, it may get there, but not any time soon, and when I say this, knowing what I have experienced first hand working in a referral center for any and all genetic diseases across the US,...there are a "LOT bigger fish to fry" than autism. Some the these genetic conditions you've never heard of, as even these are so rare, and yet some are rather common on the spectrum and definitely familial,...cystic fibrosis, as an example. There are terrible, devastating, horrific, and lethal genetic conditions out there being passed along family lines, that frankly, we would all like to eliminate. I have seen some "really nasty stuff" in my day.

This field of using CRISPR and stem cell manipulation is a branch of biomedical engineering (genetic engineering), one of the most highly demanded degrees in 2023, and is still in its infancy. My son is a biomedical engineer and professor, so I do have a limited understanding of it from our conversations, despite him signing NDAs not to talk about it. My interpretation is that they have made some interesting breakthroughs, like reverse-engineering of stem cells (human embryonic tissue is no longer needed), but actual genetic manipulation, itself, remains extremely limited to very specific animal and plant models. Regulations are in place when it comes to human embryo genetic manipulation, cloning, etc. The mountain of government red tape you have to go through to even consider making this a "viable" or "acceptable" medical therapy is often prohibitive. One thing government is good at, slowing things down. Even if your "hot shot" genius biotech company did come up with something worth while, you've still got to contend with all the regulations, not to mention the "court of public opinion". We aren't there yet. Not even close. Regardless, I think eugenics, the way most people think of it, is generations of us away, even considering our exponential learning curve and AI technologies. This is all highly complex, and given the thousands of associated genes associated with autism, even if we could somehow narrow it down to a handful of key genes, any sort of genetic manipulation would be orders of magnitude more difficult than say, my example of cystic fibrosis.

The bottom line here, I don't think we need to be concerned about autism being used within the same sentence as eugenics. I don't think it will ever be a reality in our lifetimes.

I feel for humanity in the future if humanity gets to a point where it "cures"/prevents autism through gene therapy because of the undeniably large number of autistic people through the course of history who have made positive discoveries and advancements that have benefitted humanity in general.

Not that all autistic people are highly intelligent and also, not that NT people can't be highly intelligent, but the idea of "curing"/preventing autism in the future would in my opinion be like humanity preventing anyone being born with a high IQ. How logical would that be? Future humanity: Have fun with that....

 

[Ken]

I saw this article on Science.org and have been reading it. A fairly long read, especially when I have to stop frequently to research terms I'm unfamiliar with.Thanks for posting it here.

I don't know the actual goal of this research, but it seems that many people assume it is to find a way to treat, cure or market a treatment or cure. I find this sort of research very interesting for the sole purpose of knowledge and understanding. The simple discovery that I am autistic was a revelation to me, dramatically improving my life, just from that knowledge. But, regardless of what the studies intent is, I do welcome the pure knowledge it can result in.

I believe if autism was widely understood and autistic people were not discriminated against or forced to endure sensitivities, that life would be far better than any form of treatment. I know that my life would have been far better. I could have gotten along with a very happy life if I had not been forced into societies and traumatic environments and situations. All that is simply a matter of knowledge and understanding.

 

[Ronald Zeeman]

Bottom line nobody is screwing with my gifts . My wife just told me the only thing that needed fixing was the cats. when we got them.

 

[Neonatal RRT]

undeniably large number of autistic people through the course of history who have made positive discoveries and advancements that have benefitted humanity in general.

Not that all autistic people are highly intelligent and also, not that NT people can't be highly intelligent, but the idea of "curing"/preventing autism in the future would in my opinion be like humanity preventing anyone being born with a high IQ. How logical would that be? Future humanity: Have fun with that....

This was the conclusion of the autism genetics project, that statistically, compared to the general population, more autistic children were born to educated, high-achieving mothers, and even within mixed families of NTs and autistic children, the autistic children were more likely to also be of higher academic achievement. The commentary from the researchers were (paraphrasing) quite similar to yours.

So again, I don't think the researchers are looking at this from a "cure" standpoint, but rather quite the opposite, that perhaps a little bit of autism is good to have.

Having said that, as we all know, autism does run that spectrum of variants and hypothetically, if, in some distant future, the light was shown on autism, I think it may be more the folks with the more debilitating variants of our condition, especially those where there is an identified familial marker.

 

[Ronald Zeeman]

My older brother was on the spectrum, my sister probably also is and a younger brother We have all made significant contributions to society.

 

[Cryptid]

My older brother was on the spectrum, my sister probably also is and a younger brother We have all made significant contributions to society.

"Because Of" or "In Spite Of" autism?

 

[Cryptid]

I have often said that my successes arose from a deep, burning desire to spite those who reacted negatively to my autistic traits -- to spite my "detractors", if you will. Them saying that I was too stupid to ever amount to anything just fueled my fire.

This was even before I was officially diagnosed. I just knew I had to prove them all wrong, and I did!

Now, if an effective treatment had been available about 40 years ago, and had I accepted it, I would likely be just another ordinary, average man with no drive or ambition in life.

Then again, who is to say for certain?

Anyway, I posted the article to help put away some of the false beliefs regarding ASDs. I hope it helps.

 

[Alexej]

Anyway, I posted the article to help put away some of the false beliefs regarding ASDs. I hope it helps.

Thank you @Cryptid for posting the article.
This has been one of the better threads where there has been, IMHO, good respectful discussion around a topic.

 

[Ronald Zeeman]

"Because Of" or "In Spite Of" autism?

There is not much doubt we are on the spectrum, combined with being brighter than typical our behaviors are not typical.

 

[Tom]

"Disruption of "Autism Gene" Alters Hippo camp al Identity"​

Btw, who's Hippo camp Al?

I didn't even know they had Hippo Camps, not to mention they got caught up in the identity stuff.

I'm guessing he's a counselor. Hands out volleyballs, etc.