Bringing RNA back to epigenetics (20 years later)

By: James V. Kohl | Published on: February 19, 2016

Has Contemporary Academia Outgrown the Carl Sagan Effect?  [Subscription required]
Excerpt (with my emphasis):

[Sean Carroll] offered 13 pieces of advice…: “Do good research; Make an impact in the field; Bring in grant money… Don’t be too well known outside the field; Don’t write a book; Choose your hobbies wisely.” Carroll argued that academics look askance at colleagues that have too high of a public profile. Not out of envy—but because they worry that public scientists care more about their media presence than about discovery.


…institutions must find new incentives for dissemination, and the Royal Society has recommended the implementation of “a more effective support system” and “the introduction of significant departmental rewards” (Royal Society, 2006) for those who communicate. These are worthwhile goals, but more pressing perhaps is the need to overcome lingering ambivalence toward engagement in public discourse.

My comment: The book I wrote and published in 1995 with co-author Robert T. Francoeur is available here in an updated paperback from 2002. See: The Scent of Eros: Mysteries of Odor in Human Sexuality.  With other co-authors, I subsequently linked the nutrient-dependent physiology and behavior of species from microbes to humans via RNA-mediated events.
Metabolic networks and genetic networks are RNA-mediated. The networks link atoms to ecosystems in all living genera via the physiology of reproduction. Supercoiled DNA in organized genomes protects all genera against virus-driven pathology. Examples that link virus-driven pathology from bacteria to plants and animals have since repeatedly confirmed the links from atoms to ecosytems in the context of energy-dependent hydrogen-atom transfer in DNA base pairs in solution that link nutrient energy-dependent reproduction to RNA-mediated amino acid substitutions and all biomass and all biodiversity.
For comparison, see: 
RNA Epigenetics January 1, 2016

New RNA letter regulates gene expression: Discovery brings RNA to the fore of epigenetics February 16, 2016
My comment: RNA has been at the fore of epigenetics since our 1996 Hormones and Behavior review. In our section on molecular epigenetics, we wrote:

Yet another kind of epigenetic imprinting occurs in species as diverse as yeast, Drosophila, mice, and humans and is based upon small DNA-binding proteins called “chromo domain” proteins, e.g., polycomb. These proteins affect chromatin structure, often in telomeric regions, and thereby affect transcription and silencing of various genes (Saunders, Chue, Goebl, Craig, Clark, Powers, Eissenberg, Elgin, Rothfield, and Earnshaw, 1993; Singh, Miller, Pearce, Kothary, Burton, Paro, James, and Gaunt, 1991; Trofatter, Long, Murrell, Stotler, Gusella, and Buckler, 1995). Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation in at least two species, Drosophila melanogaster and Caenorhabditis elegans (Adler and Hajduk, 1994; de Bono, Zarkower, and Hodgkin, 1995; Ge, Zuo, and Manley, 1991; Green, 1991; Parkhurst and Meneely, 1994; Wilkins, 1995; Wolfner, 1988). That similar proteins perform functions in humans suggests the possibility that some human sex differences may arise from alternative splicings of otherwise identical genes.

Among other published works, we cited:

Adler, B. K., and Hajduk, S.L. (1994). Mechanisms and origins of RNA editing. Curr. Opin. Genet. Dev. 4, 316-322.

Clemson, C. M., and Lawrence, J. B. (1996). Multifunctional compartments in the nucleus: Insights from DNA and RNA localization. J. Cell. Biochem. 62, 181-190.

Green, M. R. (1991). Biochemical mechanisms of constitutive and regulated pre-mRNA splicing. Annu. Rev. Cell Biol. 7, 559-599.

Guthrie, K. M., Anderson, A. J., Leon, M., and Gall, C. (1993). Odor-induced increases in c-fos mRNA expression reveal an anatomical “unit” for odor processing in the olfactory bulb. Proc. Natl. Acad. Sci. USA 90, 3329-3333.

Schneider-Gadicke, A., Beer-Romero, P., Brown, L. C., Mardon, C., Luoh, S. W., and Page, D. C. (1989). Putative transcription activator with alternative isoforms encoded by human ZFX gene. Nature 342, 708 -711.

Our focus was on sex differences in cell types. Others have since linked RNA-mediated events from the epigenetic landscape to the physical landscape of DNA in all living genera via the physiology of reproduction.
See for example:

  1. Sex-specific Patterns of the Epigenome as a Putative Mechanism in Fear-related Memory
  2. Exploring the role of histone demethylase, UTX, in mediating sex differences in fear-related learning and memory
  3. From Toxins to Culture: How Environment Shapes the Infant Brain
  4. En’Cas’ing The Stress: Engineering a Human Cell Line Knockout of Heat Shock Response Genes

See also: The Bull Sperm MicroRNAome and the Effect of Fescue Toxicosis on Sperm MicroRNA Expression
My comment: Science news outlets appear to be following my series of more that 600 blog posts and my FB group posts at RNA-mediated. If I were following reports from other news services I would not already have linked: Watson–Crick Base Pairing Controls ExcitedState Decay in Natural DNA, which was reported as: Base-pairing protects DNA from UV damage, from microbes to mammals.
See for example: Applying humanized mouse models to immune therapy research

Mouse models have been a mainstay in biomedical research for decades. As these models have become more sophisticated, their application has grown and now includes a wide variety of immunodeficient strains that can be used to examine the in vivo growth of human tumors and to test new cancer treatments.

My comment: I linked the mouse model organism to humans via one base pair change and one amino acid substitution in my 2013 review: Nutrient-dependent/pheromone-controlled adaptive evolution: a model

The recently detailed mouse model (Li et al., 2013) builds on what is known about olfactory/pheromonal communication in species from microbes to man and incorporates works from mammals that elucidate the molecular mechanisms that are clearly involved. Sex-dependent production of a mouse ‘chemosignal’ with incentive salience appears to have arisen de novo via coincident adaptive evolution that involves an obvious two-step synergy between commensal bacteria and a sex-dependent liver enzyme that metabolizes the nutrient chemical choline.

See also: U of Chicago Researchers Discover Novel Polymorphisms Associated With VTE in African Americans


They identified a link between VTE and three variants in a chromosome — rs2144940, rs2567617, and rs1998081 — associated with decreased expression of thrombomodulin, a protein that regulates clotting. Approximately 36 percent of American Americans have at least one of these variants, however, these variants were found in much lower frequency in other ethnicities from previous studies.
“This study not only brings us closer to understanding the cause of VTE in African Americans,” Perera said in a statement, “it demonstrates the importance of conducting populations-specific research in precision medicine.

My comment: Do neo-Darwinian theorists think that these variants are mutations?  Are they claiming that 36 percent of African Americans are mutants? If so, what are they claiming about the other 64 percent of African Americans who do not have these three variants in a chromosome?
See also: Transposons, and why you should love them

Although TEs can have deleterious effects, in higher animals they have become essential contributors to evolution, and have been described as the “motors of evolution”. By carrying out processes such as gene rearrangement, mutation of gene and regulatory sequences, genomic recombination, gene duplication, and other types of rearrangements, TEs have provided the adaptive benefit of increased genetic diversity and plasticity for their host species. TEs and their hosts have been forced to coevolve, and have achieved a fine balance between the potentially damaging and potentially beneficial effects of TEs.

My comment: They seem to be claiming that mutants co-evolved with organisms that ecologically adapted in the context of their nutrient-dependent physiology of reproduction, which is linked to the supercoiled DNA that protects all organisms from virus-driven entropy. Others have yet to link the virucidal effects of sunlight from hydrogen-atom transfer in DNA base pairs in solution to the physiology of nutrient-dependent pheromone-controlled RNA-mediated cell type differentiation in soil microbes to the cancer treatment “taxol.” When someone else finally does that, their report will be a follow-up to this one: Discovery brings RNA to the fore of epigenetics.
Until then, see: Delving into dark matter

Bhardwaj added, “The ncRNAs in cancers where odd RNAs were being activated and transcribed had unusual patterns that were similar to some pathogens, and this causes them to stimulate an innate immune response.”
“All in all, we believe these ncRNAs may play a significant role in mediating immune responses against cancer, but much work remains to describe their precise interactions,” said Greenbaum. “If we could characterize the ncRNA and link it with specific pathways, we could understand its role in the tumor environment and determine how it can be utilized for patient therapy.”

My comment: They fail to recognize the difference between nutrient-dependent microRNAs and viral microRNAs, which is why they cannot categorize the difference in pathways that lead to nutrient-dependent healthy longevity, which could be compared to virus-driven pathology. Instead, most researchers are still trying to determine how what they once called “Junk DNA” and now call “dark matter” links metabolic networks from genetic networks to supercoiled DNA that typically protects all organized genome from virus-driven entropy.
A new kind of periodic table

According to Marsh, researchers are still very interested in trying to understand the evolutionary pathways of protein complexes, in particular heteromeric complexes. “We are currently doing some work on how the assembly pathways of heteromers are related to their evolution. Now that I’ve started my own research group in Edinburgh, one of my main focuses is on understanding how pathogenic mutations can disrupt the assembly of protein complexes, and how protein complex assembly and quaternary structure can influence the phenotypic impacts of mutations.”

See also: How to Build Life in a Pre-Darwinian World Perhaps chemistry played a more instrumental role in the origin of life than scientists thought.

Conclusion: Hud and his collaborators propose that RNA and proteins evolved in tandem, and those that figured out how to work together survived best. This idea lacks the simplicity of the RNA world, which posits a single molecule capable of both encoding information and catalyzing chemical reactions. But Hud suggests that facility might trump elegance in the emergence of life. “I think there’s been an overemphasis on what we call simplicity, that one polymer is simpler than two,” he said. “Maybe it’s easier to get certain reactions going if two polymers work together. Maybe it’s simpler for polymers to work together from the start.”

My comment: They fail to link sunlight and gravitational waves from hydrogen-atom transfer in DNA base pairs in solution and claim emergence and evolution. Since our 1996 review brought RNA to the fore of epigenetics, please return to this blog site to find information that others may still be missing during the next 20 years, or if I gave up trying to tell them anything more about about the obvious links from angstroms to ecosystems.

See also:  Nutrient-dependent pheromone-controlled ecological adaptations: from atoms to ecosystems


This atoms to ecosystems model of ecological adaptations links nutrient-dependent epigenetic effects on base pairs and amino acid substitutions to pheromone-controlled changes in the microRNA / messenger RNA balance and chromosomal rearrangements. The nutrient-dependent pheromone-controlled changes are required for the thermodynamic regulation of intracellular signaling, which enables biophysically constrained nutrient-dependent protein folding; experience-dependent receptor-mediated behaviors, and organism-level thermoregulation in ever-changing ecological niches and social niches. Nutrient-dependent pheromone-controlled ecological, social, neurogenic and socio-cognitive niche construction are manifested in increasing organismal complexity in species from microbes to man.

See for comparison: Evolution silences harmful mutations

…researchers looked more closely at four synonymous but costly mutations in the gene for a ribosomal protein. They observed that the main problem with these mutations was that they caused a decrease in production of the mutated ribosomal protein. The cells entered into a vicious circle in which low protein levels resulted in defective ribosomes that in turn caused further problems with protein synthesis. By allowing these low fitness bacteria to grow for many generations it was possible to see that evolution solved the problem of synonymous mutations by creating compensatory mutations that restored the level of ribosomal protein to normal. In this way, the researchers have gained a greater understanding of why silent mutations might reduce fitness was and how bacteria could compensate for them.
My comment: Organisms that have enough food can reproduce. Successful reproduction links nutrient-dependent pheromone-controlled ecological adaptations to supercoiled DNA in species that control the replication of viruses and virus-driven genomic entropy.

See also: U of Chicago Researchers Discover Novel Polymorphisms Associated With VTE in African Americans


They identified a link between VTE and three variants in a chromosome — rs2144940, rs2567617, and rs1998081 — associated with decreased expression of thrombomodulin, a protein that regulates clotting. Approximately 36 percent of American Americans have at least one of these variants, however, these variants were found in much lower frequency in other ethnicities from previous studies.
“This study not only brings us closer to understanding the cause of VTE in African Americans,” Perera said in a statement, “it demonstrates the importance of conducting populations-specific research in precision medicine.

See also: The mid-developmental transition and the evolution of animal body plans

Embryos in a particular phylum of the animal kingdom tend to most resemble one another at a stage in the middle of embryogenesis known as the phylotypic period; a transcriptional analysis of embryogenesis from single embryos of ten different phyla reveals that the transcripts expressed at the phylotypic stage (or mid-developmental transition) differ greatly between phyla, and a ‘phylum’ may be defined as a set of species sharing the same signals and transcription factor networks during the mid-developmental transition.

My comment: All development transitions are nutrient-dependent and RNA-mediated. Other variants in chromosomes are reported in terms that link energy-dependent hydrogen-atom transfer in DNA base pairs to phenotypic changes in the mouse model that clearly are linked from amino acid substitutions to morphological and behavioral phenotypes via the physiology of nutrient-dependent phermone-controlled reproduction.
Again, see: Nutrient-dependent/pheromone-controlled adaptive evolution: a model

Two additional recent reports link substitution of the amino acid alanine for the amino acid valine (Grossman et al., 2013) to nutrient-dependent pheromone-controlled adaptive evolution. The alanine substitution for valine does not appear to be under any selection pressure in mice. The cause-and-effect relationship was established in mice by comparing the effects of the alanine, which is under selection pressure in humans, via its substitution for valine in mice (Kamberov et al., 2013).

These two reports (Grossman et al., 2013; Kamberov et al., 2013) tell a new short story of adaptive evolution. The story begins with what was probably a nutrient-dependent variant allele that arose in central China approximately 30,000 years ago. The effect of the allele is adaptive and it is manifested in the context of an effect on sweat, skin, hair, and teeth. In other mammals, like the mouse, the effect on sweat, skin, hair, and teeth is due to an epigenetic effect of nutrients on hormones responsible for the tweaking of immense gene networks that metabolize nutrients to pheromones. The pheromones control the nutrient-dependent hormone-dependent organization and activation of reproductive sexual behavior in mammals such as mice and humans, but also in invertebrates as previously indicated. That means the adaptive evolution of the human population, which is detailed in these two reports, is also likely to be nutrient-dependent and pheromone-controlled, since there is no other model for that.

Multiple Instances of Ancient Balancing Selection Shared Between Humans and Chimpanzees
Functional characterisation of a SNP in the ABCC11 allele—Effects on axillary skin metabolism, odour generation and associated behaviours
Odor perception between heterosexual partners: its association with depression, anxiety, and genetic variation in odorant receptor OR7D4

Genetic variants in OR7D4 receptor can modify the detection of the steroids androstenone and androstadienone, two pheromones that have the potential to evoke behavioral changes in many mammals, including humans, including mood changes (Kohl et al., 2001) and inter-sex communication (Kohl et al., 2001).


…it was observed that the rating of partner odor was significantly associated with rs8109935 genotypes suggesting that genetic variability in the OR7D4 might have a role in the odor perception between partners. In fact, the data of this study replicate, for the first time, the results of Keller et al. (2007) about the influence of genotype variations in OR7D4 on odor perception.

See also:  Why Do Floral Perfumes Become Different? Region-Specific Selection on Floral Scent in a Terrestrial Orchid
Reported as: Orchid’s scent stronger in Swiss lowlands than mountains

The difference in pollinator communities between regions may indicate that different pollinators select for differences in floral scent chemicals, but further experiments would be required to test this theory. Nonetheless, the authors state their study is the first to find consistent regional differences in selection on floral scent, showing that this could be one mechanism behind geographical floral chemical scent divergence.
Karin Gross notes: “The observed regional differences in selection are an important evolutionary force contributing to divergence in floral fragrances. Other traits such as plant height were also affected by selection, but in a more uniform way.”

My comment: The changes in the orchid’s scent link ecological variation in the soil bacteria to the nutrient-dependent pheromone-controlled physiology of reproduction in mammals.
Epistasis Among Adaptive Mutations in Deer Mouse Hemoglobin
Repeated elevational transitions in hemoglobin function during the evolution of Andean hummingbirds
Evidence from cyclostomes for complex regionalization of the ancestral vertebrate brain
Reported as: Reported as: Jawless fish brains more similar to ours than previously thought
See also:  Distinct Circuits for the Formation and Retrieval of an Imprinted Olfactory Memory
Reported as: Neuroscience of Early-Life Learning in C. elegans
See alsoThe Bull Sperm MicroRNAome and the Effect of Fescue Toxicosis on Sperm MicroRNA Expression
The information that connects all of the above from ecological variation to ecological adaptation in all living genera via hydrogen-atom transfer in DNA base pairs in solution arrives so quickly that biologists must look at conference abstracts to stay current and they must also pay attention to advice like this:
Biologists urged to hug a preprint

Both Vale and Vosshall think that preprints will become widely accepted only if the life-sciences community develops a consensus that preprint publication establishes a priority for any discovery.

See my invited review of nutritional epigenetics, which was published as a preprint when it was returned without review. Note, however, that Vosshall has referred to all my works as pseudoscience that she will not address. Nutrient-dependent pheromone-controlled ecological adaptations: from atoms to ecosystems. I would value her opinion if I thought she was a serious scientist. Instead, she is trying to genetically engineer mosquitoes to prevent the transmission of pathogens. Obviously, she doesn’t know enough about RNA-mediated cell type differentiation to predict that the pathogens will adapt faster than the organisms she genetically engineers.

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