John Mattick's new paradigm shaft

John Mattick continues to promote the idea that he is leading a paradigm shift in molecular biology. He believes that he and his colleagues have discovered a vast world of noncoding genes responsible for intricate gene regulation in complex eukaryotes. The latest salvo was fired a few months ago in June 2023.

Mattick, J.S. (2023) A Kuhnian revolution in molecular biology: Most genes in complex organisms express regulatory RNAs. BioEssays:2300080. [doi: 10.1002/bies.202300080]

Thomas Kuhn described the progress of science as comprising occasional paradigm shifts separated by interludes of ‘normal science’. The paradigm that has held sway since the inception of molecular biology is that genes (mainly) encode proteins. In parallel, theoreticians posited that mutation is random, inferred that most of the genome in complex organisms is non-functional, and asserted that somatic information is not communicated to the germline. However, many anomalies appeared, particularly in plants and animals: the strange genetic phenomena of paramutation and transvection; introns; repetitive sequences; a complex epigenome; lack of scaling of (protein-coding) genes and increase in ‘noncoding’ sequences with developmental complexity; genetic loci termed ‘enhancers’ that control spatiotemporal gene expression patterns during development; and a plethora of ‘intergenic’, overlapping, antisense and intronic transcripts. These observations suggest that the original conception of genetic information was deficient and that most genes in complex organisms specify regulatory RNAs, some of which convey intergenerational information.

This paper is promoted by a video in which he explains why there's a Kuhnian revolution under way. This paper differs from most of his others on the same topic because Mattick now seems to have acquired some more knowledge of the mutation load argument and the neutral theory of evolution. Now he's not only attacking the so-called "protein centric" paradigm but also the Modern Synthesis. Apparently, a slew of "anomalies" are casting doubt on several old paradigms.

This is still a paradigm shaft but it's a bit more complicated than his previous versions (see: John Mattick's paradigm shaft). Now his "anomalies" include not only large numbers of noncoding genes but also the C-value paradox, repetitive DNA, introns, enhancers, gene silencing, the g-value enigma, pervasive transcription, transvection, and epigenetics. Also, he now seems to be aware of many of the arguments for junk DNA but not so aware that he can reference any of his critics.¹ His challenges to the Modern Synthesis include paramutation which, along with epigenetics, violate the paradigm of the Moden Synthesis because of non-genetic inheritance.

But the heart of his revolution is still the discovery of massive numbers of noncoding genes that only he and a few of his diehard colleague can see.

The genomic programming of developmentally complex organisms was misunderstood for much of the last century. The mammalian genome harbors only ∼20 000 protein-coding genes, similar in number and with largely orthologous functions as those in other animals, including simple nematodes. On the other hand, the extent of non-protein-coding DNA increases with increasing developmental and cognitive complexity, reaching 98.5% in humans. Moreover, high throughput analyses have shown that the majority of the mammalian genome is differentially and dynamically transcribed during development to produce tens if not hundreds of thousands of short and long non-protein-coding RNAs that show highly specific expression patterns and subcellular locations.

The figure is supposed to show that by 2020 junk DNA had been eliminated and almost all of the mammalian genome is devoted to functional DNA—mostly in the form of noncoding genes. There's only one very tiny problem with this picture—it's not supported by any evidence that all those functional noncoding genes exist. This is still a paradigm shaft of the third kind (false paradigm, false overthrow, false data).

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1. There are 124 references; Dawkins and ENCODE make the list along with 14 of his own papers. Most of the papers in my list of Required reading for the junk DNA debate are missing. The absence of Palazzo and Gregory (2023) is particularly noteworthy.

Palazzo, A.F., and Gregory, T.R. (2014) The Case for Junk DNA. PLoS Genetics, 10:e1004351. [doi: 10.1371/journal.pgen.1004351]>/p>

John Mattick's new dog-ass plot (with no dog)

John Mattick is famous for arguing that there's a correlation between genome size and complexity; notably in a 2004 Scientific American article (Mattick, 2004) [Genome Size, Complexity, and the C-Value Paradox ]. That's the article that has the famous Dog-Ass Plot (left) with humans representing the epitome of complexity and genome size. He claims that this correlation is evidence that most of the genomes of complex animals must have a function. He repeats this claim in a recent paper (see below).

Mattick, J.S. (2023) RNA out of the mist. TRENDS in Genetics 39:187-207. [doi: 10.1016/j.tig.2022.11.001,/p>

RNA has long been regarded primarily as the intermediate between genes and proteins. It was a surprise then to discover that eukaryotic genes are mosaics of mRNA sequences interrupted by large tracts of transcribed but untranslated sequences, and that multicellular organisms also express many long ‘intergenic’ and antisense noncoding RNAs (lncRNAs). The identification of small RNAs that regulate mRNA translation and half-life did not disturb the prevailing view that animals and plant genomes are full of evolutionary debris and that their development is mainly supervised by transcription factors. Gathering evidence to the contrary involved addressing the low conservation, expression, and genetic visibility of lncRNAs, demonstrating their cell-specific roles in cell and developmental biology, and their association with chromatin-modifying complexes and phase-separated domains. The emerging picture is that most lncRNAs are the products of genetic loci termed ‘enhancers’, which marshal generic effector proteins to their sites of action to control cell fate decisions during development.

John Mattick's paradigm shaft

Paradigm shifts are rare but paradigm shafts are common. A paradigm shaft is when a scientist describes a false paradigm that supposedly ruled in the past then shows how their own work overthrows that old (false) paradigm.¹ In many cases, the data that presumably revolutionizes the field is somewhat exaggerated.

John Mattick's view of eukaryotic RNAs is a classic example of a paradigm shaft. At various times in the past he has declared that molecular biology used to be dominated by the Central Dogma, which, according to him, supported the concept that the only function of DNA was to produce proteins (Mattick, 2003; Morris and Mattick, 2014). More recently, he has backed off this claim a little bit by conceding that Crick allowed for functional RNAs but that proteins were the only molecules that could be involved in regulation. The essence of Mattick's argument is that past researchers were constrained by adherance to the paradigm that the only important functional molecules were proteins and RNA served only an intermediate role in protein synsthesis.

Shanghai ranks oldest and wealthiest science research universities

The latest Shangai rankings can be found here.

These are the criteria used to determine the ranking.

As usual, American universities dominate the rankings taking eight of the top ten positions. (Cambridge and Oxford are the other two.) Most of the top schools are quite old so they are more likely to have had alumni who won Nobel Prizes and more likely to have had Nobel Laureates on staff. Many of the American universities are private and wealthy—they are able to attract the best scientists and the most funding for research.

My school, the University of Toronto (Toronto, Canada), comes in at #24 - far behind the top schools on the list.

It's important to note that the rankings have nothing to do with the quality of undergraduate education at these universities.

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What is the Modern Synthesis?

Serious criticisms of evolutionary theory have been floating around for half a century. The main focus is over the Modern Synthesis and whether it's the best explanation of evolution. That requires a throrough understanding of what the Modern Synthesis actually means and how it's understood by most evolutionary biologists.

One view is that the Modern Synthesis is almost exclusively about natural selection. If that's true, then Stephen Jay Gould makes a good case when he argues that the Modern Synthesis is effectively dead—it was killed off by the neutral theory and the recognition that random genetic drift is a major player in evolution [Is the Modern Synthesis effectively dead?].

Donald Voet (1938-2023)

I just learned that Don Voet died on April 11th, 2023. Don and Judy Voet were the authors of one of the most successful biochemistry textbooks of all time and for a long time they were the editors of the journal Biochemistry and Molecular Biology Education (BAMBED). I've known Don for over thirty years and we met often at conferences.

He will be greatly missed. Here's an excerpt from the obituary from the American Society for Biochemistry and Molecular Biology written by my old friend Charlotte Pratt who collaboated with me on my textbook and with Don and Judy Voet on theirs [Don Voet (1938-2023)].

Don’s work over the years demonstrated his conviction that biochemical knowledge has limited value unless it is transmitted fully and honestly to the next generation of scientists. His writing style was intentionally aimed at students of all levels, never dumbed down, and straightforward — a way to invite readers to enter a conversation among professional scientists.

Ever collegial, Don insisted on dropping names into the text, referring to the discoveries of specific researchers wherever possible and borrowing figures from the original publications rather than rendering simplified versions. In cases where visual information was lacking, Don created his own molecular graphics, at a time when modeling software was not accessible to amateurs.

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Help fix the Wikipedia article on evolution

The Wikipedia article on evolution [Evolution] is a "Featured article," which means two things: (1) it is one of the best articles Wikipedia has to offer, and (2) it was voted a featured article by Wikipedia editors and that means they will resist any changes.

You will be shocked to learn that the article isn't perfect. It could use some serious updating and revision but my first attempt was reverted by an editor named Efbrazil who has vowed to revert any edits I make unless I can get his approval. So I thought I'd give it a try and you can see the result on the Talk:Evolution pages. My intitial objective is to edit the introductory paragraphs in the lead to eliminate the reference to expression of genes and to introduce the term "allele," which is covered in the main part of the article. Here's the current opening paragraphs of the lead,

In biology, evolution is the change in heritable characteristics of biological populations over successive generations.[1][2] These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Genetic variation tends to exist within any given population as a result of genetic mutation and recombination.[3] Evolution occurs when evolutionary processes such as natural selection (including sexual selection) and genetic drift act on this variation, resulting in certain characteristics becoming more or less common within a population over successive generations.[4] It is this process of evolution that has given rise to biodiversity at every level of biological organisation.[5][6]

The theory of evolution by natural selection was conceived independently by Charles Darwin and Alfred Russel Wallace in the mid-19th century and was set out in detail in Darwin's book On the Origin of Species.[7] Evolution by natural selection is established by observable facts about living organisms: (1) more offspring are often produced than can possibly survive; (2) traits vary among individuals with respect to their morphology, physiology, and behaviour; (3) different traits confer different rates of survival and reproduction (differential fitness); and (4) traits can be passed from generation to generation (heritability of fitness).[8] In successive generations, members of a population are therefore more likely to be replaced by the offspring of parents with favourable characteristics for that environment. In the early 20th century, other competing ideas of evolution were refuted as the modern synthesis concluded Darwinian evolution acts on Mendelian genetic variation.[9]

I'm also thinking that we should modify the following sentences that don't seem to be appropriate in a "Featured article,"

According to the now largely abandoned neutral theory of molecular evolution most evolutionary changes are the result of the fixation of neutral mutations by genetic drift.[101] In this model, most genetic changes in a population are thus the result of constant mutation pressure and genetic drift.[102] This form of the neutral theory is now largely abandoned since it does not seem to fit the genetic variation seen in nature.[103][104]

Editor Efbrazil seems to be he only editor willing to discuss these problems and he is hard to convince. If anyone else is interested in improving this Wikipedia article, I invite you to participate in the discussion on the Talk pages.

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How could a graduate student at King's College in London not know the difference between junk DNA and non-coding DNA?

There's something called "the EDIT lab blog" written by people at King's College In London (UK). Here's a recent post (May 19, 2023) that was apparently written by a Ph.D. student: J for Junk DNA Does Not Exist!.

It begins with the standard false history,

The discovery of the structure of DNA by James Watson and Francis Crick in 1953 was a milestone in the field of biology, marking a turning point in the history of genetics (Watson & Crick, 1953). Subsequent advances in molecular biology revealed that out of the 3 billion base pairs of human DNA, only around 2% codes for proteins; many scientists argued that the other 98% seemed like pointless bloat of genetic material and genomic dead-ends referred to as non-coding DNA, or junk DNA – a term you’ve probably come across (Ohno, 1972).

You all know what's coming next. The discovery of function in non-coding DNA overthrew the concept of junk DNA and ENCODE played a big role in this revolution. The post ends with,

Nowadays, researchers are less likely to describe any non-coding sequences as junk because there are multiple other and more accurate ways of labelling them. The discussion over non-coding DNA’s function is not over, and it will be long before we understand our whole genome. For many researchers, the field’s best way ahead is keeping an open mind when evaluating the functional consequences of non-coding DNA and RNA, and not to make assumptions about their biological importance.

As Sandwalk readers know, there was never a time when knowledgeable scientists said that all non-coding DNA was junk. They always knew that there was functional DNA outside of coding regions. Real open-minded scientists are able to distinguish between junk DNA and non-coding DNA and they are able to evaluate the evidence for junk DNA without dismissing it based on a misunderstanding of the history of the subject.

The question is why would a Ph.D. student who makes the effort to write a blog post on junk DNA not take the time to read up on the subject and learn the proper definition of junk and the actual evidence? Why would their supervisors and other members of the lab not know that this post is wrong?

It's a puzzlement.

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What's in Your Genome?: 90% of Your Genome Is Junk

If you are interested in learning more about junk DNA here's some links to relevant information.

Prologue
Chapter 1: Introducing Genomes
Chapter 2: The Evolution of Sloppy Genomes
Chapter 3: Repetitive DNA and Mobile Genetic Elements
Chapter 4: Why Don't Mutations Kill Us?
Chapter 5: The Big Picture
Chapter 6: How Many Genes? How Many Proteins?
Chaper 7: Gene Families and the Birth and Death of Genes
Chapter 8: NoncodingGenes and Junk RNA
Chapter 9: The ENCODE Publicity Campaign
Chapter 10: Turning Genes On and Off
Chapter 11: Zen and the Art of Coping with a Sloppy Genome

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Zach Hancock interviews me on his YouTube channel

We had a good time talking about junk DNA, alternative splicing, and science misinformation.

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The evolution of genomic complexity explained by Zach Hancock

Zach Hancock has posted another YouTube video. This one is about the evolution of genomic complexity. Have you ever wondered why eukaryotic biochemistry is so much more complex than the same processes in bacteria? Maybe it's because bacteria have highy efficient biochemistry and eukaryotes have evolved bigger, more complex structures by accident. This is a video about evolution by accident and the evolution of complexity in the absense of positive Darwinian selection.

You can learn about constructive neutral evolution and the origin of introns and the spliceosome. You can learn why eukaryotic ribosomes are so much bigger and more complex than bacterial ribosomes. As a bonus, you can learn how structures showing irreducible complexity arose quite naturally in the absence of any supernatural intervention.

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James Shapiro doesn't like junk DNA

Shapiro doubles down on his claim that junk DNA doesn't exist.

It's been a while since we've heard from James Shaprio. You might recall that James A. Shapiro is a biochemistry/microbiology professor at the University of Chicago and the author of a book promoting natural genetic engineering. I reviewed his book and didn't like it very much—Shapiro didn't like my review [James Shapiro Never Learns] [James Shapiro Responds to My Review of His Book].

Gert Korthof reviews my book

Gert Korthof thinks that the current view of evolution is incomplete and he's looking for a better explanation. He just finished reading my book so he wrote a review on his blog.

Scientists say: 90% of your genome is junk. Have a nice day! Biochemist Laurence Moran defends junk DNA theory

The good news is that I've succeeded in making Gert Korthof think more seriously about junk DNA and random genetic drift. The bad news is that I seem to have given him the impression that natural selection is not an important part of evolution. Furthermore, he insists that "evolution needs both mutation and natural selection" because he doesn't like the idea that random genetic drift may be the most common mechanism of evolution. He thinks that statement only applies at the molecular level. But "evolution" doesn't just refer to adaptation at the level of organisms. It's just not true that all examples of evolution must involve natural selection.

I think I've failed to explain the null hypothesis correctly because Korthof writes,

It's clear this is a polemical book. It is a very forceful criticism of ENCODE and everyone who uncritically accepts and spreads their views including Nature and Science. I agree that this criticism is necessary. However, there is a downside. Moran writes that the ENCODE research goals of documenting all transcripts in the human genome was a waste of money. Only a relatively small group of transcripts have a proven biological function ("only 1000 lncRNAs out of 60,000 were conserved in mammals"; "the number with a proven function is less than 500 in humans"; "The correct null hypothesis is that these long noncoding RNAs are examples of noisy transcription", or junk RNA"). Furthermore, Moran also thinks it is a waste of time and money to identify the functions of the thousands of transcripts that have been found because he knows its all junk. I disagree. The null hypothesis is an hypothesis, not a fact. One cannot assume it is true. That would be the 'null dogma'.

That's a pretty serious misunderstanding of what I meant to say. I think it was a worthwhile effort to document the number of transcripts in various cell types and all the potential regulatory sequences. What I objected to was the assumption by ENCODE researchers that these transcripts and sites were functional simply because they exist. The null hypothesis is no function and scientists must provide evidence of function in order to refute the null hypothesis.

I think it would be a very good idea to stop further genomic surveys and start identifying which transcripts and putative regulatory elements are actually functional. I'd love to know the answer to that very important question. However, I recognize that it will be expensive and time consuming to investigate every transcript and every putative regulatory element. I don't think any lab is going to assign random transcripts and random transcription factor binding sites to graduate students and postdocs because I suspect that most of those sequences aren't going to have a function. If I were giving out grant money I give it to some other lab. In that sense, I believe that it would be a waste of time and money to search for the function of tens of thousands of transcripts and over one million transcription factor binding sites.

That not dogmatic. It's common sense. Most of those transcripts and binding sites are not conserved and not under purifying election. That's pretty good evidence that they aren't functional, especially if you believe in the importance of natural selection.

There's lot more to his review including some interesting appendices. I recommend that you read it carefully to see a different perspective than the one I adocate in my book.

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Chapter 11: Zen and the Art of Coping with a Sloppy Genome

In last chapter of my book I try to convince readers that biochemistry, molecular biology, and evolution are sloppy processes and the idea of a sloppy genome is a logical consequence of evolution. The chapter contains Chautauguas on genomics, the function wars, intelligent design creationists, and scientific controversies.

Click on this link to see more.
Chapter 11: Zen and the Art of Coping with a Sloppy Genome

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Chapter 10: Turning Genes On and Off

Francis Collins, and many others, believe that the concept of junk DNA is outmoded because recent discoveries have shown that most of the human genome is devoted to regulation. This is part of a clash of worldviews where one side sees the genome as analogous to a finely tuned Swiss watch with no room for junk and the other sees the genome as a sloppy entity that's just good enough to survive.

The ENCODE researchers and their allies claim that the human genome contains more than 600,000 regulatory sites and that means an average of 24 per gene covering about 10,000 bp per gene. I explain why these numbers are unreasonable and why most of the sites they identify have nothing to do with biologically significant regulation.

This chapter also covers the epigenetics hype and restriction/modification.

Click on this link to see more.
Chapter 10: Turning Genes On and Off

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