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Tuesday, September 05, 2023

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).

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 Harshman said...

One thing that becomes apparent: Mattick limits his source data to fully sequenced and annotated genomes. Thus he has a much smaller database to work with than Gregory, and one that's historically biased in favor of small genomes, with the major exceptions being humans, model organisms in genetics, and domesticated species. This bias is gradually being corrected as more and larger genomes are sequenced, but he doesn't seem to be adding them. And he won't make use of the genome size database because it doesn't differentiate between coding and non-coding fractions. Thus he can ignore most of the current data, presumably under the assumption, likely unstated, that large genomes have proportionately large coding fractions. Of course, based on current data, that's a poor assumption. The amount of coding sequence clearly varies much less than genome sizes do. Still, does Mattick understand anything about the biases in his data?

Donald Forsdyke said...

When reading John Mattick's elegant historical analysis paper some weeks ago, I was please - as a coauthor of Bateson's scientific biography (2008, 2022) - to see the Bateson and Pellew "rogue" reference (1915) that leads on to Brink's paramutation work. Furthermore, there was reference to Garrod and, as we relate in the biography, in the 1930s Garrod acknowledged his ideas as beginning with Bateson!

What may be missing from the Mattick analysis, is the early evolution of intracellular defenses against intracellular parasites. I was disappointed that, when pervasive transcription was described (circa 2002), there was not immediate recognition of this role. Adaptive advantages would have been conferred on antisense nucleic acid segments that happened to interact with corresponding parasite nucleic acid segments. This advantage might be called upon infrequently (not every generation). Yet infrequent usage would be sufficient to sustain its presence in the genome. As a general response to stress, it would be transcribed. In some generations it might seem to be "junk" but not in others. Likewise, in some generations some of the multiplicity of antibody V region genes might be expendable (not confer important adaptive advantages). Yet, generation after generation, they are carried forward in the genome.

As for the C-value so-called "paradox", in past decades I have drawn attention in Sandwalk - with a simple metaphor - to the general idea that different organism employ different evolutionary paths to attain the same goal, depending to the particular contingencies of their existence. Thus, to deal with a flat bicycle tyre, some organisms carry a simple puncture repair kit to repair the defective tyre. Others, carry a large collection of spare tyres. Both systems work quite well.

SPARC said...

I wonder if paradigm shifts can only recognized after they have taken place and by people who were not involved in what lead to the shift.
Mattick cannot wait that long. Him being his own most vocal proponent is at least bewildering and I might add Trumpian. Just repeat something mostly unproven and likely completely wrong often enough, don't mention or misrepresent your critics and attempt to dominate the discourse.