[HN Gopher] RNA-targeting CRISPR reveals that noncoding RNAs are...
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RNA-targeting CRISPR reveals that noncoding RNAs are not 'junk'
Author : PaulHoule
Score : 79 points
Date : 2024-11-29 17:10 UTC (7 days ago)
(HTM) web link (phys.org)
(TXT) w3m dump (phys.org)
| syntheticnature wrote:
| It seemed likely that the parts we don't understand likely served
| some purpose; assuming they were junk because we don't understand
| their function is like a user deleting random system files
| because they "don't use them."
| anotherhue wrote:
| https://en.m.wiktionary.org/wiki/Chesterton's_fence
| keepamovin wrote:
| Exactly
|
| it's so stupid to assume they were junk. but it's by no means
| lonely as an example.
|
| Merely limiting the tremendous stupidity of the human race (in
| the long run, collectively) to science (when there's plenty
| more in other fields), this is just more part of human
| arrogance that has brought us other myopic spectacular fuck ups
| as:
|
| Earth is the center of universe (at pain of death, no less); We
| can introduce a new predatory species to a virgin ecosystem to
| control an existing pest; Aliens can't possibly exist as we are
| clearly the best God could create; We understand all physics
| and all reality and therefore even if the incredible
| impossibility of aliens existing were true, they couldn't
| possible ever visit us from other solar systems because we
| can't figure out how their doing so could be consistent with
| the equations of physics we devised; ancient people's are so
| incredibly primitive compared to us today, they must of only
| had inferior methods of almost everything; despite being so
| inferior to us, they created multiple megalithic monuments
| (primitively, of course), because we are clearly so superior to
| anything else that could possibly exist there could never have
| been other human or non-human civilizations on this planet
| doing stuff we still can't...
|
| A disappointing collectivist conformity on hyperdrip into the
| mainline of what should be global creative scientific endeavor
| on this planet is instead a monument to our collective
| stupidity, ignorance and anthropocentric, self aggrandizing
| myopia.
|
| Hopefully that self-limiting arrogance is a genetic trait we
| will soon evolve out of....as long as people keep
| reproducing!!!
| schmidtleonard wrote:
| Another day, another person accusing scientists of arrogance
| without knowing shit about what they are talking about.
|
| > it's so stupid to assume they were junk.
|
| They didn't. "Everyone Thought X but actually Y" is popular
| science speak for "nobody thought X but we want to talk about
| Y so let's pretend for a moment."
|
| > A disappointing collectivist conformity
|
| Clickbait sucks, but I wouldn't call it collectivist, the
| opposite if anything.
|
| > self-limiting arrogance is a genetic trait we will soon
| evolve out of
|
| Eugenics? Really? Over _this_?
| keepamovin wrote:
| Lol this comment is so funny and exactly what I'm talking
| about. You're the one who has no idea what they're talking
| about - but congratulations for being the example. Hahaha!
| :)
| piva00 wrote:
| Can you explain exactly how that comment is an example of
| what you are talking about?
| trelliscoded wrote:
| That's interesting, it's like the difference between code used at
| runtime (protein coding DNA) and initialization code (lncRNAs).
| Both have to be there for the program to work, but the
| initialization code is only used at startup to look at the
| environment and set up flags and data structures for the rest of
| the code. There's probably signaling pathways that interact with
| the lncRNA genes which are part of cell differentiation.
| akira2501 wrote:
| > probably signaling pathways
|
| Check out Homeobox Proteins.
| _qua wrote:
| _Some_ non-protein coding DNA produces RNA which serves a
| purpose. We also know that there are large areas of non-coding
| DNA which are very important for transcriptional regulation.
|
| But it remains true that there are large amounts of non-coding
| junk DNA which is under no selection pressure. It may be
| important for spacing out sections of DNA or it may just be along
| for the ride after being incorporated by ancient splicing errors
| or viruses. It's just frustrating to keep reading this articles
| about how, "it's not junk after all," when it has been known for
| decades that DNA/RNA have many non-coding functions and it has
| also been known for decades that there truly is "junk" DNA.
| ilija139 wrote:
| Exactly! You make all the points. Nothing more left to say.
| bpodgursky wrote:
| > But it remains true that there are large amounts of non-
| coding junk DNA which is under no selection pressure
|
| For people who may not understand how we know this -- there are
| "conserved" sections of DNA which don't change much over time.
| Very similar in mice and humans for example, because it
| performs important regulatory work, and if it doesn't, the
| animal dies.
|
| There are other large sections where it can disappear and
| nothing of consequence seems to happen. And we know that,
| because some people have micro-deletions or other variants in
| the region and they are completely benign.
|
| We will eventually identify a better classification than
| "intron" and "exon" to sort through the "junk" from "critical
| junk" but we are really only starting to untangle the
| situation.
| causal wrote:
| > There are other large sections where it can disappear and
| nothing of consequence seems to happen.
|
| So then we don't know for sure? I thought surely we must have
| some more rigorous means of identifying junk for OP's comment
| to be true, but trial and error removal seems really weak.
| imoldfella wrote:
| It's benign in the tested environment. You can't really test
| every possible environment (diet, climate, etc), so it seems
| roughly comparable to the halting problem; Does there exist a
| micro-deletion that in some environment causes this life to
| halt? It's unsolvable at DNA scale.
| causal wrote:
| Yeah I feel pretty incredulous about this too. Surely you
| would want to see a few hundred generations reproducing
| with the change before you could begin to say with any
| confidence that it might not have an effect.
| bpodgursky wrote:
| "Benign" in a clinical genetics context means "the variant
| is not linked to observed phenotype in patients". Patient
| lives their life without disability, reproduces without
| issue.
|
| Not really productive to imagine scenarios to unlock some
| hidden use. Sometimes junk is junk. Evolution is not hyper-
| efficient in the short term, stuff happens.
| ackfoobar wrote:
| >> non-coding junk DNA which is under no selection pressure
|
| > "conserved" sections of DNA which don't change much over
| time
|
| I'm not a biologist. I imagine DNA that does nothing and is
| under no selection pressure should have a bunch of random
| mutation accumulated - the opposite of what you described.
| bpodgursky wrote:
| The two quoted statements aren't talking about the same
| thing.
| exe34 wrote:
| there's even the endogenous retroviruses that make up 5-8% of
| our DNA - including bits that just repeat over and over without
| every doing anything.
| causal wrote:
| Viral origin says nothing of how important its function is.
| exe34 wrote:
| https://sandwalk.blogspot.com/2018/03/whats-in-your-
| genome-p...
|
| We don't need 1M copies of Alu:
| https://en.wikipedia.org/wiki/Alu_element
|
| A lot of the sequences are defective copies. These are
| often how new genes arise, but they are not useful to the
| individual.
| moralestapia wrote:
| >But it remains true that there are large amounts of non-coding
| junk DNA which is under no selection pressure.
|
| Nope, you cannot ever assert that.
|
| Did you understand the article? What was once thought to be
| junk turned out not to be. Extrapolate from that.
| schmidtleonard wrote:
| Selection pressure can be measured. If a big chunk of DNA is
| missing from a third of a population with no apparent ill
| effects, the onus is on you to show that it was somehow
| important. Of course there is plenty of non-coding DNA which
| is under selection pressure and therefore does something
| important, but everyone has known this for decades.
|
| The single most common sin in all of science is to
| misrepresent the null hypothesis because it makes getting
| positive results easy. In article form, this translates to
| when you see a title "Everyone thought X but actually Y," 99%
| of the time nobody thought X and Y is otherwise unremarkable.
| They wanted to remark on Y, though, so they cooked up
| "Everyone Thought X" to facilitate the presentation.
| moralestapia wrote:
| >the onus is on you to show that it was somehow important
|
| What? Like ... not at all? Onus does not get assigned "by
| default" due the nature of things, lol. The onus falls on
| whoever comes up to propose an hypothesis.
|
| In this case that hypothesis is "all other DNA/RNA is
| junk", well, then "prove that thing is true", which is
| unfeasible and hence why one could not assert such thing.
| searine wrote:
| >In this case that hypothesis is "all other DNA/RNA is
| junk",
|
| Strawman.
|
| It is not as black and white as you think it is. Some
| non-coding DNA/RNA is functional. Some is not.
| Selection/conservation is often used as quick way to tell
| whether something is functional or not.
|
| Nobody actually in the field of genetics would say "all
| other DNA/RNA is junk". You'd get laughed out of the
| room, kind of in the same way if you said "all non-coding
| DNA is functional because 'epigenetics' ".
| gweinberg wrote:
| It's like this: now that full-genome sequencing is getting
| pretty cheap and common, you can tell how string the
| selection pressure is on a chunk of DNA just by looking at
| frequencies of variants. If it turns out there are very few
| variants, you can be confident the chunk is doing something,
| even if you don't know what. If the variation looks like
| random drift, you can be pretty confident it is.
| moralestapia wrote:
| No, you seem to only have a casual/superficial
| understanding of the field.
|
| There's an abysmal number of post-transcriptional effects
| that are functional. Start with something like [1].
|
| There's also plenty of evidence (like TFA and [2]) of
| "junk" DNA turning out to be functional through some
| contrived and completely unexpected mechanisms.
|
| Every time someone says something like "this is how Biology
| works" one can lmao all the way to the lab.
|
| 1: https://en.wikipedia.org/wiki/Epigenetics
|
| 2: https://pubmed.ncbi.nlm.nih.gov/36484387/
| _qua wrote:
| As others and I have mentioned above, there are
| absolutely parts of the genome that are functional
| despite being non-coding. There is no debate about this.
| You have shared links and arguments emphasizing that
| _there is function_ in these parts. However, you have not
| addressed the fact that there are large stretches of DNA
| that are not conserved across species, show no
| differential selection pressure compared to what would be
| expected from random genetic drift, and that there are
| hugely varying sizes of genome between species.
|
| From my reference below: "If most eukaryotic DNA is
| functional at the organism level, be it for gene
| regulation, protection against mutations, maintenance of
| chromosome structure, or any other such role, then why
| does an onion require five times more of it than a
| human?"
|
| Of course, one can always say, "How arrogant to think we
| know everything." But given our current understanding of
| evolution and genetic function, the specific identity of
| a genetic sequence correlates with its function. If that
| function is important, the sequence should be preserved
| to a degree better than random chance.
|
| To deny this is to suggest that any random sequence of
| genetic material can serve a vital purpose while being
| subject to endless mutation without consequence. This
| raises the question: What do we mean by a "specific
| sequence" if it isn't conserved and is constantly
| mutating?
|
| I assume you are familiar with the information I've just
| shared. I'm curious where we are diverging in our views
| because it feels like we are not discussing the same
| thing.
|
| This artcle fairly represents my understanding of what I
| mean when I say "junk DNA": https://journals.plos.org/plo
| sgenetics/article?id=10.1371/jo...
| gdavisson wrote:
| You're refuting a strawman. The junk DNA claim is not, and as
| far as I can see never had been, that _all_ non-coding DNA is
| junk. It 's that _most_ of our genome -- around 90% -- is
| junk[1][2]. But since the genome is over 98% non-coding, that
| implies that something like 8% is functional non-coding DNA,
| which is several times the amount of coding DNA. Finding
| small amounts of additional functional non-coding DNA does
| not significantly challenge this[3].
|
| [1] https://sandwalk.blogspot.com/2022/08/junk-dna-vs-
| noncoding-...
|
| [2] https://en.wikipedia.org/wiki/Junk_DNA#History
|
| [3] https://judgestarling.tumblr.com/post/154553548091/long-
| nonc...
| PaulHoule wrote:
| My understanding of it is that in eukaryotes the genome is
| folded up like the pages of a book and that one function of
| non-coding DNA is control of the opening up of these "pages"
| which in turn plays a major role. You are not just looking at
| RNAs being expressed but also sections of DNA that those RNAs
| bind to, pieces that bind to each other to keep pages shut,
| probably things like the hinges and springs in a pop-up book.
|
| Genetic engineering always had the problem that you just don't
| want to express a gene that makes a protein but you want to
| express that gene _a lot_. For instance the first version of
| _Golden Rice_ produced detectable but not nutritionally
| significant amounts of Vitamin A. It took them quite a few more
| years to get _Golden Rice 2_ which produces enough to matter.
|
| It's been known a long time that a lot of genes associated with
| diseases are non-coding, but looking at what my RSS reader
| shows me it seems that very rapid progress is being made right
| now on understanding these hidden regulatory networks.
| graypegg wrote:
| This is just pure assumption from my part, I know nothing about
| this. But extrapolating from your point:
|
| > It may be important for spacing out sections of DNA
|
| Is it possible that there IS selection pressure for unread DNA?
| I could imagine that cells with comparatively huge chromosomes
| last a bit longer, since you'd hope that some percentage of
| those pairs are just cannon fodder for the usual mutagenic
| sources. (energy, viruses, being a European king, etc) Like you
| can either make the bullseye on the target smaller, or spread
| out the points across the whole face of the target.
|
| Again, no idea what I'm talking about, but maybe the
| researchers here are seeing a breakdown in the "control
| characters" around these parts? Maybe there's a sort of null
| start/null terminate at both ends in the "real" DNA, and when
| it breaks down, these unintended sacrificial spacers get
| parsed.
| altruios wrote:
| That seems like a fallacy to claim to know that there is in
| fact junk dna. To know that: you need to iterate over every
| possible function for a section of dna could have and test
| against that.
|
| How is it known that there truly is junk dna?
| searine wrote:
| Most of the genome is non protein coding. Some is functional,
| most simply is not functional in any way. It is just empty
| space.
|
| Rates of mutation in these regions, and lack of conservation
| are hallmark clues which show that there isn't function in
| these regions. That doesn't mean totally useless, these non-
| functional regions provide the raw material for the creation
| of genes and functional elements. Its just that, right now,
| those regions aren't doing anything.
|
| No biologist calls it "junk DNA". That is just a simplified
| layman's term for media press releases.
| _qua wrote:
| I get the skepticism. There have been a lot of surprising
| revelations in biology and I don't think anyone would argue
| we have every angle nailed down. However, the idea that some
| DNA is genuinely "junk" is based on more than a hunch. It's
| from looking at patterns across species. If a sequence really
| mattered, then changing it should cause a problem. That would
| put pressure on the sequence to stay the same, generation
| after generation. Yet we see big stretches of DNA mutating
| freely, at rates that exactly match what would be expected
| from accumulation of random copying errors. That suggests
| these sequences aren't under selection for any important
| function.
|
| This isn't just "we don't know what it does, so it must be
| junk." It's more like, "We can't find any sign that it
| matters, and everything we know about evolution says if it
| mattered, we'd see fewer random changes there." Down the road
| we might uncover small roles for some of these regions, but
| at this point, calling them junk is just an honest read of
| the evidence we have.
| ddgflorida wrote:
| It's based on certain presuppositions but 1 thing is for sure
| - we'll know more in the future as more research is done.
| pinkmuffinere wrote:
| I understand that you say "junk" dna in the context of the
| individual, but I'm curious if there could still be some
| selection pressure on this "junk"? For instance, I can imagine
| that "junk" which has more variety in it may generally result
| in more useful mutations, and this could put pressure on our
| "junk" to have high entropy, almost providing a source of
| randomness. I know very little about the field though -- am i
| totally off base?
| w10-1 wrote:
| I don't think you have to argue for junk DNA to state that the
| article in question fails utterly to explain the findings
| except by way of not being the straw-man "junk".
|
| Yes, we find the significance of DNA by knocking it out and
| seeing what happens.
|
| Yes, crispr/cas-9 or /cas13 can be used for knocking out.
|
| Yes, it's interesting to compare across models to find
| relatively conserved behaviors.
|
| That's all known and done.
|
| What could be interesting about these results is exactly how
| they achieved scale and variety at reasonable time and cost.
| Labs typically build expertise in a particular model organism,
| and it's very hard to get things right in many cell types, no
| less to run essentially thousands of experiments. Developers
| have a vague sense of 3nm semiconductor process and the
| potential for on-chip memory (both yield/quality and
| potential), but we (I) have no sense how good the process is
| underlying findings like this.
| _qua wrote:
| I don't have an qualms with the research. I think it was
| shared on HN because of the never-ending articles about "it's
| not junk after all" which is what I was reacting to. The
| linked press release uses this term, but the original study
| does not. I agree with your points.
| readthenotes1 wrote:
| The article, unfortunately, repeats the 70-year debunked
| articulation of the "central dogma".
|
| Sad.
|
| https://en.m.wikipedia.org/wiki/Central_dogma_of_molecular_b...
| moralestapia wrote:
| The central dogma exists and is a thing, everyone in the field
| understands that.
|
| Also, "debunked" implies something was proven to be false,
| which is not the case with the central dogma.
| bglazer wrote:
| lncRNA are very weird and I think they challenge some of the
| common, traditional assumptions about how cells work. Basically,
| the traditional view of RNA was that it's a messenger between the
| DNA and proteins. That is, it _just_ functions a way to transfer
| genomic information to the protein factories (ribosomes). There
| were some widely known exceptions to this, like ribosomal RNA,
| which forms essential parts of the structure of ribosomes, so it
| 's not just a messenger, it actually has a functional role in
| building a key cellular machine. My sense was that was viewed as
| a weird edge case that ribosome biologists were concerned with.
|
| Anyways, there's been an explosion of different classes of RNA in
| the past decade or so. This has been driven by new techniques in
| RNA sequencing technology that allow us to detect and sequence
| RNA in a more unbiased and high-throughput way. What we saw was a
| _huge_ number and variety of RNA molecules in cells that don 't
| look like they encode any protein. So, this fundamentally breaks
| that assumption about RNA's role as "just" a messenger.
|
| The best characterized class of these weird new non-coding RNA's
| is probably micro-RNA. They're very short stretches of non-
| protein-coding RNA, and it seems that they bind to other
| sequences of RNA and prevent their translation to proteins. So,
| RNA has at least one layer of self-regulation. Then we see long
| non-coding RNA. They can act as "sponges" or buffers of microRNA
| by preferentially binding to miRNA, preventing the micro-RNA's
| interaction with their normal protein coding RNA targets. So,
| there's another layer: long non-coding RNA buffers microRNA which
| inhibits translation of messenger RNA. Further the long RNA can
| also condensate into these structures that are similar to
| droplets of oil in water. They're transitory structures that form
| and dissolve then reform quickly and repeatedly. What they do is
| still a bit vaguely understood but they seem to bring together
| very weakly interacting proteins and RNA in concentrations that
| wouldn't be possible just by diffusion within the cell. So,
| there's another layer of regulation: long coding RNAs form
| condensates to that allow interactions between _proteins_ that
| wouldn 't happen otherwise.
|
| All of this is complicated by the fact that these things have
| other weird properties. They aren't expressed very frequently, so
| they're hard to detect. They're not very well conserved
| evolutionarily, i.e. their sequences diverge rapidly between
| species. They don't really have fixed structures, they're more
| just like floppy, sticky noodles. This would typically indicate
| they're not functional or at least non-essential. How could this
| be important? It's an _RNA_ that doesn 't make a protein, isn't
| very abundant, has no defined shape, and evolution doesn't seem
| to care much about the details of its sequence.
|
| *But*, as this paper shows, they're absolutely essential for
| cellular function. If you take them out of cells, the cells die.
|
| So, all that to say that the idea of biology as working like a
| little computer; just a series of linear information transmission
| steps, is probably rather misleading in many cases. Instead it's
| a tangled mess of weak interactions that depends on subtle
| biochemical effects like condensation. It's noisy and imprecise
| at the molecular level, but all the self-interacting layers of
| regulation and interaction somehow give rise to remarkably
| precise and adaptive responses at the tissue and organismal
| level.
| webdoodle wrote:
| We know so little about DNA and RNA still, and yet we allow
| medical companies to make mRNA 'vaccines' that supposedly will
| working exactly as they say. How can that be possible when we
| don't even fully understand the system on which it is built?
|
| It's like trying to repair a sinking ship at sea without
| understanding how the planks and caulking displace water. Sure
| you might patch it temporarily, and might even keep it afloat,
| but what other problems are you creating that you literally don't
| know anything about...
| exe34 wrote:
| keeping it afloat is usually a good step towards limping back
| to dock! We're still trying to figure out where the dock is,
| but sinking in the meantime would not necessarily be an
| improvement.
| bglazer wrote:
| I mean you're getting the mRNA in your body one way or the
| other. One choice is to inhale someone else's cough droplets,
| then the self-replicating nano-machines inside the sputum drops
| take over the cells in your lungs, explode them and spread out
| of control until your immune system catches up and kills even
| more of your cells by just absolutely nuking everything around
| them. That's "natural immunity". You could also get a shot with
| a precisely controlled dose of one non-functional part of the
| virus that your immune system can then learn to recognize and
| destroy quickly. That's a vaccine. I know which I prefer.
| PaulHoule wrote:
| We can test the safety of these things the same way we test the
| safety of other drugs.
| akira2501 wrote:
| Safety tests really are the lowest level of engineering
| understanding you can have with a product. You give it to a
| bunch of people and not to a bunch of other people and check
| to see if things seem to be working without too much
| divergence on side effects.
|
| It leaves you with limited understanding of the mechanism,
| it's efficacy across different populations, the circumstances
| in which it fails, how bad those failures could get, or how
| to improve the product in any way whatsoever.
| webnrrd2k wrote:
| Staying with the sinking ship analogy, by patching your sinking
| ship you will avoid sinking, which is a _really big_ problem.
|
| I know what I'd choose givin the option of avoiding sinking,
| and possibly dealing with unknown and probably minor
| consequences later; or dealing with a potentially deadly
| sinking now, and avoiding unknown (and probably minor)
| consequences later.
| CodeWriter23 wrote:
| One would think by this stage of Science, when it comes to
| naturally occurring phenomena, there is only "yet to be
| understood" things and never "junk".
| dekhn wrote:
| For those who want to see a really fascinating argument that has
| lasted for a while, about junk DNA, functional selection, data,
| and models of evolution, start at
| http://cryptogenomicon.org/encode-says-what.html and then
| https://www.cell.com/current-biology/fulltext/S0960-9822%281...
| and https://www.nature.com/articles/d41586-024-00575-x
| (unfortunately paywalled).
|
| From what I can tell, ENCODE project collected a ton of data
| suggesting that large regions of DNA which are not under
| functional selection (to the extent that we can measure that) are
| actively transcribed. They released some press and papers
| suggesting this meant that "junk DNA was not actually junk",
| which led Eddy to have a rage fit and propose an experiment to
| support his beliefs.
|
| From what I can tell, we still don't have a great explanation for
| why large regions of DNA that are not under apparent functional
| selection are constantly being transcribed and what evolutionary
| impact that has on organisms. Personally I think Eddy greatly
| overplayed his claims, depending on some historical details in
| genome analysis that probably are dated and missing critical new
| biology, but honestly, these are areas where the theories and
| data are so ambigious, you can construct any number of narratives
| explaining the observed results.
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