Mutations in a non-coding gene associated with intellectual disability
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Fascinating. For reference, the mutated U4 spliceosome RNA is involved in splicing of all expressed genes. Doubtless, given its conservation, there are innumerable mutations that are simply incompatible with life - screw up splicing in any but the most subtle ways, and the results will be early embryonic lethality. To me it's most remarkable that there's a conserved region where mutations "only" affect the development and function of the brain. In the scale of life to not life, that's a "mild" phenotype, though certainly profound for the affected individuals and families.
The authors barely speculate about a mechanism, and I don't know enough to speculate further myself. Follow up studies will be interesting, to see if there are specific subsets of neuronal target transcripts that are misspliced, and figure out why they're the ones that are perturbed.
I've studied some of the mechanism behind neurodevelopmental and neurodegenerative disorders in my career, and the number of ways that a nervous system can go wrong without affecting the rest of a body is bewildering. With apologies to Douglas Adams, I'm sympathetic to the opinion that we've all made a big mistake by growing a brain in the first place. And maybe no one should ever have bothered with a nervous system.
The authors barely speculate about a mechanism, and I don't know enough to speculate further myself. Follow up studies will be interesting, to see if there are specific subsets of neuronal target transcripts that are misspliced, and figure out why they're the ones that are perturbed.
I've studied some of the mechanism behind neurodevelopmental and neurodegenerative disorders in my career, and the number of ways that a nervous system can go wrong without affecting the rest of a body is bewildering. With apologies to Douglas Adams, I'm sympathetic to the opinion that we've all made a big mistake by growing a brain in the first place. And maybe no one should ever have bothered with a nervous system.
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Which would, of course, be a disservice to probably a large segment of the Ars readership.
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Actually, I had heard of introns and exons (and understand what they are at a basic level). But I had never heard of "spliceosome", had to look it up.
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So, if I am reading this correctly the defect codes bad copies of an RNA component that is required for proper function of the spliceosome?
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While RUN4-2 (which is the small nuclear RNA referred to here) is not a “normal” protein coding gene - it certainly is included as a gene in the human genome annotation. So when one looks for mutations that could cause a disorder, we do look at these already. It makes an RNA which gets expressed- so it’s important. The interesting part here is that most of these are short (this RUN4-2 is only 141 bps) and incredibly conserved in mammals, so it is surprising that mutations can be found within humans in these genes that are very important (and so short on average maybe 200 mutations occur across 6B base pairs- so hitting this 141 is pretty rare anyway).
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yes they found 2 areas which had increased numbers of mutations in the disease affected individuals. These mutations don’t change the protein from run4-2, since it itself is not translated to a protein, however these mRNAs get bound into the splicesome complex and provide variation and binding to facilitate splicing. In this case run4-2 At least that is my take- hopefully a splicesome expert can comment since the process is fairly complicated. In his case run4-2 is heavily active in brain and lungs, these mutations degrade performance within the splicesome and cause the disease phenotype.
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I can't say I recall hearing the term "spliceosome" before, though of course I've heard about introns and exons and mRNA splicing. Looking up the google ngram frequency, it's not a new term but definitely not super common either. Maybe just very domain specific in genetics?
The breathless tone of the article seems a little unnecessary. We've known for a long time mRNA works as a regulator and signaling molecule, and I believe there are known RNA-based enzymes in humans, too. Proteins don't do everything.
The breathless tone of the article seems a little unnecessary. We've known for a long time mRNA works as a regulator and signaling molecule, and I believe there are known RNA-based enzymes in humans, too. Proteins don't do everything.
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I can't figure out what the heck this article is trying to tell me. What is "obviously called the spliceosome"?
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A great video from CSHL :
View: https://m.youtube.com/watch?v=aVgwr0QpYNE
It’s short and easy to see what the splicesome does.
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Yeah, that struck me too. Kinda pointless and a little misleading.
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chaos215bar2
Ars Praefectus
But they aren’t, strictly speaking, coded by DNA either, are they? I would expect that what’s coded in DNA are the proteins that produce these molecules.
Sorry, I know this is totally off topic. But it’s such a weird quip, I had to ask. What’s the problem with calling someone who… engineers software a “software engineer”?
(I mean, obviously there’s programming involved, but there’s also all the planning required before you actually get to that point. Turns out that just sitting down at a computer and writing code doesn’t tend to turn out all that well for all but the simplest projects.)
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Thank you. This was an egregious error coming from an Ars article contributor.
Authors, please be careful making positive assertions outside your expertise, especially as throwaway asides. In particular, calling steroid hormones, all of which are synthesized from cholesterol, "proteins", is an elementary error.
One should probably also specify estrogens, plural. There is no exact molecule that corresponds to "estrogen", it's a blanket term for usually related molecules that exert a particular kind of hormonal effect.
The nomenclature is very befuddled, unfortunately, due to having a long history. Usually what is meant by estrogen is either beta-estradiol (E2), or one of the four primary "estrogens" in mammals (e.g. estriol, estrone).
But then there are phytoestrogens, xenoestrogens, metalloestrogens, and so on, and all of these diverge farther and farther from specific molecular descriptions.
Also, compare "estrogen" to testosterone and the androgens, which are more cleanly separated despite suffering from similar historical ambiguities.
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So the result of this as far as the cells are concerned would be when the cell gets around to building the amino acid production center, the blueprints for the factory are wrong. So in a spot of the factory where some important chemical gets assembled, the factory floorplan has all the machinery upside down or going the wrong direction. The factory doesn't fail to produce every chemical; but whatever chemical that part of the factory would normally assemble doesn't end up with productive chemicals (maybe even detrimental chemicals).
Cool.
Next question is "Can CRISPR fix something like this?"
Cool.
Next question is "Can CRISPR fix something like this?"
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Just want to help explain why this is significant. Some RNAs form structural motifs called pseudoknots, which are made up of hairpin like structures (aka stem-loop). Such motifs are important for the interaction between these RNA molecules and other RNAs/proteins. In turn, such interactions are critical for the downstream activities of the RNA/protein complex. In this study, the authors identified sequence variants in two contiguous regions of the U4 snRNA. According to the authors:
"Analysis of published secondary structure data of the U4 snRNA revealed that one region maps to a quasi-pseudoknot interaction between U4 and U6 while the other maps to an interaction between U4 and U6 called stem III..."
So this is likely the underlying mechanism for spliceosome dysfunction, and a wide range of human diseases can be linked to improper splicing.
"Analysis of published secondary structure data of the U4 snRNA revealed that one region maps to a quasi-pseudoknot interaction between U4 and U6 while the other maps to an interaction between U4 and U6 called stem III..."
So this is likely the underlying mechanism for spliceosome dysfunction, and a wide range of human diseases can be linked to improper splicing.
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An infinite number of monkeys are outside. They'd like a word.
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That first sentence really puts things in perspective.
1500 genes is something like 1/20th of the total number in the human genome — with that amount of vulnerability, it’s almost miraculous that everything goes right so often.
Techniques like genome-wide association studies have made it quantitatively and molecularly clear what biologists have known for ages — that everything is connected to most everything else. AI tools like AlphaFold should be able to show what a single one of those 1500 genes does, but techniques that can map individual genes to individual aspects of brain function that lead to specific intellectual deficits, much less combinations of genes, seems far beyond anyone’s ability to imagine. I hope that there are some grand challenge programs in the works to make progress on the methodological issues.
In any particular case, with 1500 genes possibly involved, looking for the cause, or even a handful of causes, is probably a hopeless dream. Now there’s an entire new class of genetic factors to add to that count of possibilities. There may be a few critical genes in rare cases, but in most of them, the disability is more likely to arise from the interaction of scores or hundreds of genetic variants.
1500 genes is something like 1/20th of the total number in the human genome — with that amount of vulnerability, it’s almost miraculous that everything goes right so often.
Techniques like genome-wide association studies have made it quantitatively and molecularly clear what biologists have known for ages — that everything is connected to most everything else. AI tools like AlphaFold should be able to show what a single one of those 1500 genes does, but techniques that can map individual genes to individual aspects of brain function that lead to specific intellectual deficits, much less combinations of genes, seems far beyond anyone’s ability to imagine. I hope that there are some grand challenge programs in the works to make progress on the methodological issues.
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?As someone who only had a vague idea of what isn't expressed as being something like an appendix to the expressed stuff, I found the explanation in the article educational. Yes, being introduced to the terms may have sent me to Google - if they had sparked my mind in the same way as this explanation did, but that isn't the best way of communicating.
I've done a bit of web writing at work to explain technical issues to laypeople. I suppose that helps me see how difficult it can be to make effective communication as simple and digestable as most Ars coverage manages to be while still giving an accurate picture. Consistently acheiving that at the pace of a news magazine is impressive.
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This type of research is reassuring at a high level - I was ways frustrated reading the term "junk DNA", with the assumption/hubris that we understand all the machan isms of gene expression so perfectly as to dismiss the vast majority of our genome as vestigial.
I feel like there's a huge difference between this statement of saying that the commonly described scientific consensus in this area felt naive and, say covid denialism, though both seem on the surface similar. how does one express relief that one obvious oversimplification is starting to be rectified without justifying every other attack on scientific credibility?
I feel like there's a huge difference between this statement of saying that the commonly described scientific consensus in this area felt naive and, say covid denialism, though both seem on the surface similar. how does one express relief that one obvious oversimplification is starting to be rectified without justifying every other attack on scientific credibility?
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Recommended reading: What's In Your Genome by Laurence A. Moran, ISBN: 9781487508593
It is very odd that you feel the scientific consensus "felt naive," when it is based on solid experimental results, and your intuition is not.
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See maparent above for an obvious solution to this false choice. Also, re-read my original comment and realize that the false choice is yours, not mine.
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Strongly conserved in mammals doesn't mean mutations don't occur. Mutations occur in every sequence. It means it's rare for mutations in the sequence to result in a viable animal.
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I think the snark got you the reaction it did. If you'd just explained the terms in terms of how they relate to that text, we'd all be quite happy with your post.
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TFA:
Well, that explains the college students of today, here's hoping for the next generation
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Yes it means that over something like 100-125 million years of evolutionary tuning did not provide alternatives to these base pairs - so the chance that they have major effects when mutated is very high. The identified changes were denovo mutations which occurred in individuals independently.
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Always remember, genetic material that is currently "unused" by an organism serves as a library of potentially beneficial mutations should their environment throw a curveball at them. So the term "junk" DNA is only a bit of a misnomer if your rig never needs parts from the junkyard.
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I agree with maparent's solution and I'm not suggesting the article is perfect, a factual error has already been pointed out. Your original post was not offering a reasonable solution, it was just poorly thought out snark.
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HuntingManatees
Ars Centurion
I recall spliceosomes briefly being a topic in my intro cellular biology course -- the material covered very little about them, just that they splice -- but I think there are other requirement-fulfilling intro bio, uh, sub-subjects for non-bio majors that maybe don't have a granular focus on cells and would omit something that specific?
Anywho, all you really need to know, as Loverboy tells us, is that pig and elephant DNA just won't splice:
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