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Wednesday, March 30, 2022

John Mattick's new book

John Mattick and Paulo Amaral have written a book that promotes their views on the content of the human genome. It will be available next August. Their main thesis is that the human genome is full of genes for regulatory RNAs and there's very little junk. A secondary theme is that some very smart scientists have been totally wrong about molecular biology and molecular evolution for the past fifty years.

I pretty much know what's going to be in the book [see John Mattick presents his view of genomes]. I also know that most of his claims don't stand up to close scrutiny but that's not going to prevent it from being touted as a true paradigm shift. (It's actually a paradigm shaft.) I suspect it's going to get favorable reviews in Science and Nature.

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.

Saturday, March 26, 2022

Science communication in the modern world

Science editors asked young scientists to imagine what kind of course they would have created if they could go back to a time before the pandemic [A pandemic education]. Three of the courses were about science communication.

COM 145: Identification, analysis, and communication of scientific evidence

This course focuses on developing the skills required to translate scientific evidence into accessible information for the general public, especially under circumstances that lead to the intensification of fear and misinformation. Discussions will cover the principles of the scientific method, as well as its theoretical and practical relevance in counteracting the dissemination of pseudoscience, particularly on social media. This course discusses chapters from Carl Sagan’s book The Demon-Haunted World, certain peer-reviewed and retracted papers, and materials related to key science issues, such as the anti-vaccine movement. For the final project, students will comprehensibly communicate a scientific topic to the public.

Camila Fonseca Amorim da Silva University of Sao Paulo, Sao Paulo, Brazil

COM 198: Everyday science communication

As scientific discoveries become increasingly specialized, the lack of understanding by the general public undermines trust in scientists and causes the spread of misinformation. This course will be taught by scientists and communication specialists who will provide students with a toolset to explain scientific concepts, as well as their own research projects, to the general public. Upon completion of this course, students will be able to explain to their grandparents that viruses exist even though they can’t see them, convince their neighbors that vaccines don’t contain tracking devices, and explain the concept of exponential growth to governmental officials.

Anna Uzonyi Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

COM 232: Introduction to talking to regular people

Communicating science is difficult. Many scientists, having immersed themselves in the language of their field, have completely forgotten how to talk to regular people. This course hones introductory science communication skills, such as how to talk about scary things without generating mass panic, how to calmly discourage the hoarding of paper hygiene products, and how to explain why scientific knowledge changes over time. The final project will include cross examination from law school faculty, who are otherwise completely uninvolved with the course and possess minimal scientific training. Recommended for science majors who are unable to discuss impactful scientific findings without citing a P value.

Joseph Michael Cusimano Bernard J. Dunn School of Pharmacy, Shenandoah University, Winchester, VA, USA.

They sound like interesting courses but my own take on science communication is somewhat different. I think it's very difficult for practicing scientists to communicate effectively with the general public so I tend to view science communication at several different levels. My goal is to communicate with an audience of scientists, science journalists, and people who are already familiar with science. The idea is to make sure that this intermediate group understands the scientific facts in my field and to make sure they are familiar with the major controversies.

My hope is that this intermediate group will disseminate this information to their less-informed friends and relatives and, more importantly, stop the spread of misinformation whenever they hear it.

Take junk DNA for example. It's very difficult to convince the average person that 90% of our genome is junk because the idea is so counter-intuitive and contrary to the popular counter-narratives. However, I have a chance of convincing the intermediate group, including science journalists and other scientists, who can follow the scientific arguments. If I succeed, they will at least stop spreading misinformation and false narratives and start presenting alternatives to their sudiences.

Monday, March 14, 2022

Junk DNA

My book manuscript has been reviewed by some outside experts and they seem to have convinced my editor that my book is worth publishing. I hope we can get it finished soon. It would be nice to publish in in September on the 10th anniversary of the ENCODE disaster.

Meanwhile, I keep scanning the literature for mentions of junk DNA to see if scientists are finally coming to their senses. Apparently not, and that's a good thing because it means that my book is still needed. Here's the opening paragraph from a recent review of lncRNAs. The authors are in the Department of Medicine at the Medical College of Gerogia, in Augusta, Georgia (USA).

Ghanam, A.R., Bryant, W.B. and Miano, J.M. (2022) Of mice and human-specific long noncoding RNAs. Mammalian Genome:1-12. [doi: 10.1007/s00335-022-09943-2]

Approximately ninety-eight percent of our genome is noncoding. Contrary to initial descriptions of this vast sea of sequence comprising “junk DNA” (Ohno 1972), comparative genomics and various next-generation sequencing studies have revealed millions of transcription factor binding sites (TFBS) (Vierstra et al. 2020) and tens of thousands of noncoding genes, most notably the class of long noncoding RNAs (LncRNAs), defined currently as processed transcripts of length > 200 base pairs with no protein-coding capacity (Rinn and Chang 2020; Statello et al. 2021). The widespread transcription of LncRNAs and abundance of regulatory sequences such as enhancers support the concept of a genome that is largely functional (ENCODE Project Consortium 2012). Such a dynamic genome should not be surprising given the complex nature of gene expression and gene function necessary for embryonic and postnatal development as well as disease processes.

  • No reasonable scientist, especially Susumu Ohno, ever said that all noncoding DNA was junk.
  • There are millions of transcription factor binding sites but most of them are spurious binding sites that have nothing to do with regulation. They simply reflect the expected behavior of typical DNA binding proteins in a large genome full of junk DNA.
  • Nobody has demonstrated that there are tens of thousand of noncoding genes. There may be tens of thousands of transcripts but that's not the same thing since you have to prove that those transcripts are functional before you can say that they come from genes.
  • There is currently no evidence to support the concept of a genome that is largely functional in spite of what the ENCODE researchers might have said ten years ago.
  • Such a genome would be very surprising, if it were true, given what we know about genomes, evolution, and basic biochemistry.

Except for those few minor details—I hope I'm not being too picky—that's a pretty good way to start a review of lncRNAs. :-)