Saturday, September 09, 2017

Cold Spring Harbor tells us about the "dark matter" of the genome (Part I)


This is a podcast from Cold Spring Harbor [Dark Matter of the Genome, Pt. 1 (Base Pairs Episode 8)]. The authors try to convince us that most of the genome is mysterious "dark matter," not junk. The main theme is that the genome contains transposons that could play an important role in evolution and disease.

Here's a few facts.
  • A gene is a DNA sequence that's transcribed. There are about 20,000 protein-coding genes and they cover about 25% of the genome (including introns). It's false to say that genes only occupy 2% of the genome. In addition to protein-coding genes, there are about 5,000 noncoding genes that take up about 5% of the genome. Most of them have been known for decades.
  • It has been known for many decades that the human genome has no more than 30,000 genes. This fact was known by knowledgeable scientists long before the human genome sequence was published.
  • It has been known for decades that about 50% of our genome is composed of defective bits and pieces of once-active transposons. Thus, most of our genome looks like junk and behaves like junk. It is not some mysterious "dark matter." (The podcast actually say that 50% of our genome is defective transposons but they claim this is a recent discovery and it's not junk.)
  • The evidence for junk DNA comes from many different sources. It's not a mystery. It's really junk DNA. The term "junk DNA" was not created to disguise our ignorance of what's in your genome.
  • In addition to genes, there are lots of other functional regions of the genome. No knowledgeable scientists ever thought that the only functional parts of the genome were the exons of protein-coding genes.
There's much value in research on ALS but does it have to be coupled with an incorrect view of our genome? How many errors can you recognize in this podcast? Keep in mind that this is sponsored by one of the leading labs in the world.
Most of the genome is not genes, but another form of genetic information that has come to be known as the genome’s “dark matter.” In this episode, we explore how studying this unfamiliar territory could help scientists understand diseases such as ALS.


43 comments :

  1. No doubt Sal Cordova will be along soon to tell you how you're just one of those "theoreticians" and the CSH guys are all "hard working lab researchers" at a "highly prestigious" institute doing "cutting edge" research. Or something along those lines.

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  2. Dark matter of the genome refers to genes that can't be found/sequenced but there is evidence they exist because they leave their "footprints", so to speak. They must be functional.

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    1. I'm confused. Why can't they be found/sequenced, and what are their "footprints"?

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    2. The "footprints" referred to are probably the results of "phylogenetic footprinting", which is use of molecular phylogenies to find regions of the genome that are actively conserved. Alas for Jass, these make up only a small fraction of the noncoding DNA.

      There is also the delicious irony that to find the "phylogenetic footprint" you need to use molecular phylogeny methods. And I suspect Jass does not think that those methods are valid, when they infer phylogenies.

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    3. Some nonfunctional DNA should be expected as our genomes appear to be decaying rather than evolving.

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    4. Some nonfunctional DNA should be expected as our genomes appear to be decaying rather than evolving.

      Decaying with respect to what?

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    5. Joe,

      But those "footprints" are sequences that can be found and sequenced, so how could that be what Jass was talking about?

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    6. It depends on what that slash in "found/sequenced" means. I'm sure Jass will clarify the matter. I interpret "found" in the sense of "gene-finding".

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    7. How do you know that the gene, let's say for a hormone, that the body is producing exists, even if the genome sequencing revealed nothing?

      You got the footprints--the hormone--where are the boots then?

      While there could be more than one answer to this issue, one should be pretty clear, I think...

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    8. I for one have no clue what Jass is trying to say. Anyone?

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    9. Is he somehow trying to ask how we know that proteins are encoded in DNA? That is the only way I can make sense of his question.

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    10. I for one have no clue what Jass is trying to say.
      Really? Shocka...

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    11. I was gonna tell you but now I changed my mind...waiting for Larry to write the book first...

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    12. I suspect Jass has no clue what Jass is trying to say.

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    13. This article should give you an idea what I was talking about:

      Part I 'Dark DNA' could change how we think about evolution

      "DNA sequencing technology is helping scientists unravel questions that humans have been asking about animals for centuries. By mapping out animal genomes, we now have a better idea of how the giraffe got its huge neck and why snakes are so long. Genome sequencing allows us to compare and contrast the DNA of different animals and work out how they evolved in their own unique ways.

      But in some cases we’re faced with a mystery. Some animal genomes seem to be missing certain genes, ones that appear in other similar species and must be present to keep the animals alive. These apparently missing genes have been dubbed “dark DNA”. And its existence could change the way we think about evolution.

      My colleagues and I first encountered this phenomenon when sequencing the genome of the sand rat (Psammomys obesus), a species of gerbil that lives in deserts. In particular we wanted to study the gerbil’s genes related to the production of insulin, to understand why this animal is particularly susceptible to type 2 diabetes.

      But when we looked for a gene called Pdx1 that controls the secretion of insulin, we found it was missing, as were 87 other genes surrounding it. Some of these missing genes, including Pdx1, are essential and without them an animal cannot survive. So where are they?

      The first clue was that, in several of the sand rat’s body tissues, we found the chemical products that the instructions from the “missing” genes would create. This would only be possible if the genes were present somewhere in the genome, indicating that they weren’t really missing but just hidden.

      The DNA sequences of these genes are very rich in G and C molecules, two of the four “base” molecules that make up DNA. We know GC-rich sequences cause problems for certain DNA-sequencing technologies. This makes it more likely that the genes we were looking for were hard to detect rather than missing. For this reason, we call the hidden sequence “dark DNA” as a reference to dark matter, the stuff that we think makes up about 25% of the universe but that we can’t actually detect.

      By studying the sand rat genome further, we found that one part of it in particular had many more mutations than are found in other rodent genomes. All the genes within this mutation hotspot now have very GC-rich DNA, and have mutated to such a degree that they are hard to detect using standard methods. Excessive mutation will often stop a gene from working, yet somehow the sand rat’s genes manage to still fulfil their roles despite radical change to the DNA sequence. This is a very difficult task for genes. It’s like winning Countdown using only vowels.

      This kind of dark DNA has previously been found in birds. Scientists have found that 274 genes are “missing” from currently sequenced bird genomes. These include the gene for leptin (a hormone that regulates energy balance), which scientists have been unable to find for many years. Once again, these genes have a very high GC content and their products are found in the birds’ body tissues, even though the genes appear to be missing from the genome sequences.

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    14. Part II

      Shedding light on dark DNA
      Most textbook definitions of evolution state that it occurs in two stages: mutation followed by natural selection. DNA mutation is a common and continuous process, and occurs completely at random. Natural selection then acts to determine whether mutations are kept and passed on or not, usually depending on whether they result in higher reproductive success. In short, mutation creates the variation in an organism’s DNA, natural selection decides whether it stays or if it goes, and so biases the direction of evolution.

      But hotspots of high mutation within a genome mean genes in certain locations have a higher chance of mutating than others. This means that such hotspots could be an underappreciated mechanism that could also bias the direction of evolution, meaning natural selection may not be the sole driving force.

      So far, dark DNA seems to be present in two very diverse and distinct types of animal. But it’s still not clear how widespread it could be. Could all animal genomes contain dark DNA and, if not, what makes gerbils and birds so unique? The most exciting puzzle to solve will be working out what effect dark DNA has had on animal evolution.

      In the example of the sand rat, the mutation hotspot may have made the animal’s adaptation to desert life possible. But on the other hand, the mutation may have occurred so quickly that natural selection hasn’t been able to act fast enough to remove anything detrimental in the DNA. If true, this would mean that the detrimental mutations could prevent the sand rat from surviving outside its current desert environment.

      The discovery of such a weird phenomenon certainly raises questions about how genomes evolve, and what could have been missed from existing genome sequencing projects. Perhaps we need to go back and take a closer look.

      http://www.businessinsider.com/dark-dna-could-change-how-we-think-about-evolution-2017-8

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    15. That article is a case of sensationalism about something hat has been known to be a fact for over a decade at least. Mutational hotspots aren't news to anyone but people who are completely ignorant about molecular biology. And they don't change anything about natural selection or evolution.

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    16. I think this is the part Harshman and Felseintein were talking about:

      "But when we looked for a gene called Pdx1 that controls the secretion of insulin, we found it was missing, as were 87 other genes surrounding it. Some of these missing genes, including Pdx1, are essential and without them an animal cannot survive. So where are they?

      The first clue was that, in several of the sand rat’s body tissues, we found the chemical products that the instructions from the “missing” genes would create. This would only be possible if the genes were present somewhere in the genome, indicating that they weren’t really missing but just hidden.

      ALSO

      The DNA sequences of these genes are very rich in G and C molecules, two of the four “base” molecules that make up DNA. We know GC-rich sequences cause problems for certain DNA-sequencing technologies. This makes it more likely that the genes we were looking for were hard to detect rather than missing. For this reason, we call the hidden sequence “dark DNA” as a reference to dark matter, the stuff that we think makes up about 25% of the universe but that we can’t actually detect.

      By studying the sand rat genome further, we found that one part of it in particular had many more mutations than are found in other rodent genomes. All the genes within this mutation hotspot now have very GC-rich DNA, and have mutated to such a degree that they are hard to detect using standard methods. Excessive mutation will often stop a gene from working, yet somehow the sand rat’s genes manage to still fulfil their roles despite radical change to the DNA sequence. This is a very difficult task for genes. It’s like winning Countdown using only vowels.

      This kind of dark DNA has previously been found in birds. Scientists have found that 274 genes are “missing” from currently sequenced bird genomes. These include the gene for leptin (a hormone that regulates energy balance), which scientists have been unable to find for many years. Once again, these genes have a very high GC content and their products are found in the birds’ body tissues, even though the genes appear to be missing from the genome sequences.
      "

      Obviously ignorant people like Rum wouldn't know what issue has been discussed because he didn't read the thread or as usual has a selective cognitive inconvenience disorder common among select group of people...

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    17. I read the thread, I know the context, I read your linked articles. My statement still stands. The incidental fact that some genes might be technically difficult to sequence due to GC content has nothing to do with evolution. What a load of complete hogwash.

      It's a challenge for sequencing technology, not a problem with evolutionary theory, or the actual process of evolution. '

      The and the fact that some sequences are hard to detect due to GC content, and that GC content owes to a high rate of GC producing mutations at some particular mutational hotspot is also not a problem for evolution. Heck, it would seem the explanation FOR the phenomenon of high GC content is evolution.

      So please explain to me what you think the problem is?

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    18. So that's it? The fact that genes with high GC content are hard to sequence (and hard to amplify, and hard to find good primers for)? That's the big revelation? Yep, Jass doesn't know what Jass is trying to say.

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    19. Another one:

      Scientists shed light on the 'dark matter' of DNA
      January 17, 2013

      Research Institute of Molecular Pathology
      In each cell, thousands of regulatory regions control which genes are active at any time. Scientists
      have now developed a method that reliably detects these regions and measures their activity.
      FULL STORY
      Fluorescence image of ovarian tissue of the fruit fly. DNA is
      stained in blue, the activity of enhancers is represented by the
      green colour.
      Credit: Copyright IMP
      In each cell, thousands of regulatory regions control which genes are active at any time.
      Scientists at the Research Institute of Molecular Pathology (IMP) in Vienna have
      developed a method that reliably detects these regions and measures their activity.
      Information on the new technology was just published online in the journal Science.
      Genome sequences store the information about an organism's development in the DNA's four-letter alphabet.
      Genes carry the instruction for proteins, which are the building blocks of our bodies. However, genes make up only
      a minority of the entire genome sequence -- roughly two percent in humans. The remainder was once dismissed
      as "junk," mostly because its function remained elusive. "Dark matter" might be more appropriate, but gradually
      light is being shed on this part of the genome, too.
      Far from being useless, the non-coding part of DNA contains so-called regulatory regions or enhancers that
      determine when and where each gene is expressed. This regulation ensures that each gene is only active in
      appropriate cell-types and tissues, e.g. hemoglobin in red blood cell precursors, digestive enzymes in the stomach,
      or ion channels in neurons. If gene regulation fails, cells express the wrong genes and acquire inappropriate
      functions such as the ability to divide and proliferate, leading to diseases such as cancer.
      9/15/2017 Scientists shed light on the 'dark matter' of DNA -- ScienceDaily
      https://www.sciencedaily.com/releases/2013/01/130117142432.htm 2/3
      Cite This Page:
      Research Institute of Molecular Pathology. "Scientists shed light on the 'dark matter' of DNA." ScienceDaily.
      ScienceDaily, 17 January 2013. .
      Despite the importance of gene regulatory regions, scientists have been limited in their ability to study them on a
      genome-wide scale. Their identification relied on indirect means, which were error prone and required tedious
      experiments for validating and quantifying enhancer activities..
      Alexander Stark and his team at the IMP in Vienna now closed this gap with the development of a new technology
      called STARR-seq (self-transcribing active regulatory region sequencing), published online by Science this week.
      STARR-seq allows the direct identification of DNA sequences that function as enhancers and simultaneously
      measures their activity quantitatively in entire genomes.
      Applying their technology to Drosophila cells, the IMP-scientists surprisingly find that the strongest enhancers
      reside in both regulatory genes that determine the respective cell-types as well as in broadly active
      "housekeeping" genes that are required for basic cell survival in most or all cells. In addition, they find several
      enhancers for each active gene, which might provide redundancy to ensure robustness of gene regulation.
      The new method combines advanced sequencing technology and highly specialized know-how in bio-computing. It
      is a powerful tool which, according to Alexander Stark, will prove immensely valuable in the future. "STARR-seq is
      like a magic microscope that lets us zoom in on the regulatory regions of DNA. It will be crucial to study gene
      regulation and how it is encoded in the genome -- both during normal development and when it goes wrong in
      disease."

      https://www.sciencedaily.com/releases/2013/01/130117142432.htm

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    20. Seem Rum and Harshman belong to the same category of The Intelligencia...

      You'd better get that QM for Dummies book because it looks like your evolutionary nonsense based on random genetic changes is going to fall apart very soon.

      If I were Larry, I'd get into it to before writing the breakthrough book on j-dna...lol

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    21. Hey, Larry, did you read that thing Jass just posted? This bit jumped out at me: "The remainder was once dismissed as "junk," mostly because its function remained elusive." The rest isn't much better.

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    22. John, yes I read it. It's old news (2013) but science writers are still writing today about "dark matter" as if most of our genome was some mysterious bunch of hidden functions. Most science writers aren't comfortable with the concept of junk DNA because hey don't understand evolution.

      Jass doesn't understand evolution but that's not surprising because he doesn't understand science.

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    23. "...remainder was once dismissed as "junk," mostly because its function remained elusive."

      Isn't this what the whole kerfuffle has been with ENCODE?
      Isn't this what Larry has been saying all along that it is up to ENCODE to find function for their claims that 80% plus of genome is functional?

      Or, has it changes already?

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    24. "John, yes I read it. It's old news (2013) but science writers are still writing today about "dark matter" as if most of our genome was some mysterious bunch of hidden functions.

      Dark matter is a fairly new term. It relates to dark matter in the universe, where cosmologists and physicists agree there has to be some kind of matter holding galaxies together and preventing them from wild spins, but they have not been able to prove it exists although they know it is there...

      It accounts for about 23% of the total mass of the universe.

      It used be called "junk DNA" when 98% of human genome was supposed to be useless "dark matter"...

      Now former junk 8-15% or even 25%, as per Graur's current estimates or possibilities, junk DNA/Dark Matter is called functional genome...

      I know that knowledgeable scientists like you, Harshman, Felseinstain, Graur knew that 98% human genome was't junk, you just kept it to yourself until others discovered it...;-)

      Most science writers aren't comfortable with the concept of junk DNA because hey don't understand evolution.

      I've heard this many times and "...if ENCODE is right about 80% genome functionality, then evolution is wrong...

      I hope whoever said that is still around to hear he was wrong...

      I hope you are ready to accept it too just in case it happens soon...

      Jass doesn't understand evolution but that's not surprising because he doesn't understand science.

      Actually Larry, it's the other way around...

      Because I understand science enough i.e. quantum physics, I can't accept evolution; at least the way you, Harshman and Felseinstein, Graur see it...

      It is just not possible to know what I know and accept evolution (whatever your current view of what it is) as a 100% random process...

      I would be lying to myself if I accepted it...

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    25. Jass-
      Good news- evolutionary theory does not imply evolution is a 100% random process.
      So it is possible you could understand and agree with evolutionary theory without having to disregard any of your foundational premises about the universe.
      Keep trying.

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    26. "Because I understand science enough i.e. quantum physics, I can't accept evolution; at least the way you, Harshman and Felseinstein, Graur see it..."

      If your understanding about QP is like your understanding about how others view evolution, I doubt there's any understanding to talk about.

      "It is just not possible to know what I know and accept evolution (whatever your current view of what it is) as a 100% random process..."

      Jass, if you know what you know as well as your description of evolution as a 100% random process, then maybe you don't know what you think you know.

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    27. Because I understand science enough i.e. quantum physics, I can't accept evolution

      I understand the branch of physics known as "crank magnetism," which teaches us that cranks who don't understand a given well settled scientific theory such as evolution, but think they do, will also believe they understand at least one other well settled scientific theory, such as quantum physics, but won't understand that one any better than the first.

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    28. judmarc-
      Since evolution is a ‘well settled scientific theory’ perhaps you could tell me what the definition of ‘evolution’ is.
      http://sandwalk.blogspot.ca/2013/10/the-many-definitions-of-evolution.html

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    29. The definitions Larry quotes with approval in his "What is Evolution" article seem quite workable to me.

      I did want to mention I also liked, in the article you cited, Joe Felsenstein's discussion of whether arriving at a definition of evolution is necessary to research interesting scientific questions in evolution, as well as Georgi Marinov's take on the great importance of drift in looking at the evolution of multicellularity.

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    30. judmarc-
      I agree the definition of evolution given is acceptable. (I prefer ‘change in alleles…’).
      But I think the ‘well settled’ version is ‘Survival of the fittest’.
      In fact, I would wager the majority of scientists would agree that evolution is about ‘survival of the fittest’ aka ‘adaptationism’.
      That’s my complaint about your description.

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    31. That’s my complaint about your description.

      Nuthin' I can do about that. :-)

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  3. There are genes in the genome that are in stretches of the genome that can be sequenced but where gene-finding programs do not successfully recognize that there is a gene there.

    Folks who want to believe that all the junk DNA is "dark matter of the genome" which is functional will take the presence of some DNA in which there are genes that are not successfully annotated as validation of their view.

    Such folks include creationists who are unhappy with the idea that there is junk in the genome. It also, alas, includes a noticeable percentage of molecular biologists who do not understand the evidence for the existence of junk DNA, because they do not understand molecular evolution. They are also encouraged by all the grants that they could apply for to get money to work on elucidating the function of this DNA.


    That is silly.

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  4. Mikkel,

    Decaying with respect to what?

    To accumulating mutations etc.

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    1. Evolution includes the accumulation of mutations, so your previous comment is nonsensical.

      -jaxkayaker

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    2. Evolution includes the accumulation of mutations, so your previous comment is nonsensical.

      -jaxkayaker

      Junk DNA is at least partially an accumulation of mutations, as per current dogma, so your answer is worst than newbies

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    3. Junk DNA is absolutely an accumulation of mutations, and therefore is also the result of evolution. The fact that you think my answer is "worst" (sic) than that of newbies is irrelevant, given your obvious ignorance.

      -jaxkayaker

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    4. Junk DNA is absolutely an accumulation of mutations, and therefore is also the result of evolution. The fact that you think my answer is "worst" (sic) than that of newbies is irrelevant, given your obvious ignorance.

      -jaxkayaker


      Really? How does't this apply to organisms without Junk? They are done evolving?

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    5. Really? How does't this apply to organisms without Junk? They are done evolving?

      Presumably, you meant "does". I don't think does't is a word. And no, species lacking junk DNA (if there are any) are not done evolving. Such populations will usually still have variation in their genes and promoter sequences, and evolution can still occur. Although junk DNA is the result of mutations and can change in frequency in a population over generations, meaning the population's genome is evolving, it's important to remember that not all mutations are junk. Not to mention, even if one found a population lacking genetic variation and without junk DNA, that would not preclude new mutations from occurring.

      What do you think the definition of evolution is? It seems that you have a distorted view of what is or isn't considered evolution. One might even conclude you're a dishonest commenter here.

      -jaxkayaker

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  5. If someone wants to study the role of transposons in ALS, that seems fine. If there is a role, though, why would you describe that as part of the genome? It is clearly not something that happens to most people, and is clearly not something desirable or advantageous. It would be something potentially dangerous lurking in the junk DNA of a small percentage of humans.

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    Replies
    1. Is this what you were referring to?

      https://www.cshl.edu/news-a-features/storm-of-awakened-transposons-may-cause-brain-cell-pathologies-in-als-other-neurodegenerative-ill.html

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  6. One might even conclude you're a dishonest commenter here.

    It is an interesting philosophical question whether a commenter can be so clueless as to be incapable of dishonesty.

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