Epigenetic pharmacology and RNA-mediated transciptional landscapes

By: James V. Kohl | Published on: November 26, 2014

Last year, Vosshall’s group eliminated ideas about the involvement of beneficial mutations in the nutrient-dependent cell type differentiation of mosquitoes. orco mutant mosquitoes lose strong preference for humans and are not repelled by volatile DEET. This year her group showed that nutrient-dependent amino acid substitutions clearly are involved in cell type differentiation. Evolution of mosquito preference for humans linked to an odorant receptor
RNA-mediated events have since been linked to sexual dimorphism in mosquitoes. Examination of the genetic basis for sexual dimorphism in the Aedes aegypti (dengue vector mosquito) pupal brain
Excerpt: “Transcripts (2,527), many of which were linked to proteolysis, the proteasome, metabolism, catabolic, and biosynthetic processes, ion transport, cell growth, and proliferation, were found to be differentially expressed in A. aegypti female vs. male pupal heads.”
My comment: The authors address the complexity of cell type differentiation in the context of sex differences. Nutrient-dependent RNA-mediated events, which are linked from the de novo creation of olfactory receptor genes in mosquitoes, can now be linked via their pheromone-controlled physiology of reproduction via RNA-mediated events that link morphological and behavioral diversity in species from microbes to man via conserved molecular mechanisms.
The idea that cell type differentiation could arise via mutations and natural selection or somehow evolve has been subjected to scrutiny by serious scientists for more than 18 years. For example, we started from sex differences in cell types of yeasts, worms, and flies. “Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation…”  Our model of nutrient-dependent RNA-mediated cell type differentiation and pheromone-controlled reproduction was extended to insects and subsequently to the life history transitions of the honeybee model organism.
No matter how many times I have mentioned these facts, or included comments that the same model applies to differences of cell types that vary with sexual orientation, other researchers have consistently focused on attempts to find genes that can somehow be linked to cell type differentiation. They have ignored the fact that “…even the yeast Saccharomyces cerevisiae has a gene-based equivalent of sexual orientation (i.e., a-factor and alpha-factor physiologies). These differences arise from different epigenetic modifications of an otherwise identical MAT locus (Runge and Zakian, 1996; Wu and Haber, 1995).”
They have ignored thermodynamic cycles of protein biosynthesis and degradation that lead from glucose uptake to pheromone-controlled cell type differentiation via RNA-mediated events in all species, from yeasts to other mammals via amino acid substitutions.
Gene duplication as a mechanism of genomic adaptation to a changing environment
Comparison of the transcriptional landscapes between human and mouse tissues
For the role of amino acid substitutions in comparisons of the transcriptional landscapes between human and mouse tissues see Nutrient-dependent/pheromone-controlled adaptive evolution: a model.

Excerpt: “High excretion rates of trimethylamine-associated odor in humans cause ‘fish odor syndrome’. The aversive body odor has been attributed to a mutation (Dolphin, Janmohamed, Smith, Shephard, & Phillips, 1997). This attribution is not consistent with the portrayal of synergy in the mouse model, which enables both the production of the odor and the response to the odor.

This synergy requires at least two things to happen simultaneously: for example, (1) natural selection for nutrient chemicals and (2) sexual selection for odor production. Sexual selection for nutrient-dependent odor production is not likely to be achieved via one mutation involved in nutrient acquisition and another mutation that is involved in odor production because two mutations are not likely to simultaneously occur.”

My comment: Clear links from genetic networks to metabolic networks have been used to develop pharmacogenomic profiles that predict how patients with different genotypes will manifest differences in their phenoytpes via examples of enymatically metabolized therapeutic drugs that link RNA-mediated amino acid substitutions to tissue-specific differences in cell types and behavior.
Clinically Actionable Genotypes Among 10,000 Patients With Preemptive Pharmacogenomic Testing
Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults
Cell Context Dependent p53 Genome-Wide Binding Patterns and Enrichment at Repeats
An integrative analysis of DNA methylation and RNA-Seq data for human heart, kidney and liver
circRNA Biogenesis Competes with Pre-mRNA Splicing
Excerpt: “…canonical pre-mRNA splicing can compete with circularization of exons. Mechanisms of this competition are tissue specific and conserved from flies to humans.
Evolutionary biologists, human ethologists, and other social scientists continue to claim that mutations somehow lead to the evolution of biodiversity when no experimental evidence of biologically-based cause and effect suggests that is possible. I reiterate: “Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation…” — and to cell type differentiation of all cells in all individuals of all species. If not for the ridiculous claims of pseudoscientists, serious scientists might have convinced everyone to quit funding the pseudoscientific nonsense of evolutionary theory. Instead, works are funded that have no benefit whatsoever, while those that link the epigenetic landscape to the physical landscape of DNA in the organized genomes of microbes to man fall short of what would otherwise be remarkable progress.

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