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Wednesday, March 30, 2022

John Mattick presents his view of genomes

John Mattick has a new book coming out in August where he defends the notion that most of our genome is full of genes for functonal noncoding RNAs. We have a pretty good idea what he's going to say. This is a talk he gave at Oxford on May 17, 2019.

Here are a few statements that should pique your interest.

  • (0:57) He says that his upcoming book is tentatively titled "the misunderstandings of molecular biology."
  • (1:11) He says that "the assumption has been very deeply embedded from the time of the lac operon on that genes equated to proteins."
  • (2:30) There have been three "surprises" in molecuular biology: (1) introns, (2) eukaryotic genomes are full of 'selfish' DNA, and (3) "gene number does not scale with developmental complexity."
  • (4:30) It is an unjustified assumption to assume that transposon-related seqences are junk and that leads to misinterpretation of neutral evolution.
  • (6:00) The view that evolution of regulatory sequences is mostly responsible for developmental complexity (Evo-Devo) has never been justified.
  • (8:45) A lot of obtuse theoretical discussion about how the number of regulatory protein-coding genes increases quadratically as the total number of protein-coding genes increase in a bacterial genome but at some point there has to be more protein-coding regulatory genes than total protein-coding genes so that limits the evolution of bacteria.
  • (13:40) The proportion of noncoding DNA increases with developmental complexity, topping out at humans.
  • (14:00) The vast majority of the genome in complex organisms is differentially transcribed in different cells and different tissues.
  • (14:15) The whole genome is alive on both strands.
  • (14:20) There are two possibilities: junk RNA or abundant functional transcripts and that explains complex organisms.
  • Mattick then takes several minutes to document the fact that there are abundant transcripts— a fact that has been known for the better part of sixty years but he does not mention that. All of his statements carry the implicit assumption that these transcripts are functional.
  • (20:20) He makes the boring, and largely irelevant, point that most disease-associated loci are located in noncoding regions (GWAS). He's responding to a critic who asked why, if these things (transcripts) are real, don't we see genetic evidence of it.
  • (24:00) Noncoding RNAs have all of the characteristics of functional RNAs with an emphasis on the fact that their expression is often only detected in specific cell types.
  • (31:50) It has now been shown that everything that protein transcription factors can do can be done by noncoding RNA.
  • (32:15) "I want to say to you that conservation is totally misunderstood." Apparently, lack of conservation imputes nothing about function.
  • (41:00) RNAs control phase separation. There's a whole other level of cell organization that we never dreamed of. (Ironically, he gives nucleoli as an example of something we never dreamed of.)
  • (42:36) "This is called soft metaphysics, and it's just come into biology, and it's spectacular in its implications."
  • (46:25) Almost every lncRNA is alternatively spliced in mice and humans.
  • (46:30) There's more alternative splicing in human protein-coding genes than in mice protein-coding genes but the extra splicing in humans is mostly in the 5' untranslated region. (I'm sure it has nothing to do with the fact that tons more RNA-Seq experiments have been done on human tissues.) "We think this is due to the increased sophistication of the regulation of these genes for the evolution of cognition."
  • (48:00) At least 20% of the human genome is evolutionarily conserved at the level of RNA structure and this does not require any assumptions.
  • (55:00) The talk ends at 55 minutes. That's too bad because I'm sure Mattick had a dozen more slides explaining why all of those transcripts are functional, as opposed to the few selected examples he picked. I'm sure he also had a lot of data refuting all of the evidence in favor of junk DNA but he just ran out of time.

I don't know if there were questions but, if there were, I bet that none of them challenged Mattick's main thesis.


14 comments :

  1. Won't ever pass our mutual friend T. Ryan Gregory's onion test

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  2. (13:40) The proportion of noncoding DNA increases with developmental complexity, topping out at humans.

    Wow! Somebody inform our lord and master, the lungfish!

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  3. That bar graph does remind me of .. what was it called? The infamous "dogleg graph" on the amount of DNA versus complexity? I thought even that was more than passe' by now. I did a bit of searching and found you had posted about this many years ago ( https://sandwalk.blogspot.com/2007/09/genome-size-complexity-and-c-value.html ). And guess who it came from?

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  4. I do believe the bar graph is assembled based on sequenced genomes, which of course are biased toward small ones. Hence the predominance of prokaryotes and the absence of genomes larger than the human one. Now why didn't he use T. Ryan Gregory's genome size database?

    Given all that, what correlation does it show. The vertical axis is genome size. The horizontal axis is also just an ordering of taxa by genome size. So we see that genome size is strongly correlated with genome size.

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    1. Yes, but is that statistically significant?

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    2. It's not genome size, but the fraction of the genome that is noncoding. You need to look at the colours (three orange vertebrates, three red invertebrates, etc) to see the 'developmental complexity'.

      It looks like we still have to worship lungfush and salamanders, but we get to look down on pufferfish.



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    3. It's not genome size, but the fraction of the genome that is noncoding.

      That amounts to the same thing, given that the coding part doesn't vary by that much. Huge genomes are mostly non-coding, small genomes mostly coding. And we also need to worship the ferns, which are evidently much more complex than mammals.

      Developmental complexity is defined by the number of cell types, and that depends on how closely you look and how finely you choose to divide them. Largely subjective.

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    4. "I do believe the bar graph is assembled based on sequenced genomes, which of course are biased toward small ones."

      If that's the case, it's quite out of date. There are plenty of assembled genomes that are larger than the human genome.

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    5. The slide is probably considerably older than the talk, and the talk is three years old.

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    6. Mattick surely knows about Ryan's database. He knows that most frogs and all salamanders have genomes larger than ours. He knows that there are several mammals with larger genomes. He knows that there are crustaceans and insects that have larger genomes than humans.

      It's hard to understand why he doesn't recognize these facts when he presents his data. Is it ignorance, or is he deliberately trying to deceive?

      I struggled with the question of motive when I was writing my book. It doesn't make sense to assume that all those supposedly successful scientists are stupid and it doesn't make sense to assume that they are deliberately lying.

      Is it some form of mass delusion?

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  5. "(6:00) The view that evolution of regulatory sequences is mostly responsible for developmental complexity (Evo-Devo) has never been justified."

    I didn't watch the video but if he really made a point of that then it is just weird. I think it's well known that most animals share the vast majority of their protein coding genes, so since cells by dry mass are mostly protein, the differences in complexity and anatomical characteristics more broadly must lie predominantly in the regulation of expression of those proteins.

    Organisms aren't made of up of bulk lncRNA, so whatever functional roles the different types of RNAs might have, that Mattick refers to to argue the genome is mostly functional, is almost exclusively regulatory. Those RNAs that really are functional do not form the bulk of muscle or brain tissue(and most of it is fleeting in nature and quickly broken down again), so excluding ribosomal and tRNA, the remaining functional RNA have functions in gene-regulation.

    Does Mattick even know what his own position is?

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    1. Mattick and several of the ENCODE researchers are convinced that the superiority of humans is due to their increased intelligence. They seem to believe that the evolution of brain complexity is somehow related to huge increases in the number of noncoding genes. They don't explain this connection very well but they are sure to mention that brain tissue has a lot of transcripts.

      So do spermatocytes but that doesn't get the same attention.

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