RNA-directed gene choice

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March 2015: ChemoSense; see Timothy S. McClintock: “Odorant Receptor Gene Choice”

He concludes: “The epigenetic control of OR gene expression through repression and de-repression is a remarkable story, and as a fundamental mechanism intimately associated with the random differentiation of a neural progenitor cell into multiple neuronal subtypes, one wonders whether it might be a framework for understanding other instances of differentiation of neural subtypes (Lyons and Lomvardas, 2014).”

My comment: The epigenetic control of OR gene expression is RNA-directed via DNA methylation. RNA-mediated events link food odors and pheromones from nutrient-dependent amino acid substitutions to the pheromone-controlled physiology of reproduction.

McClintock places these facts into the theoretical context of random differentiation of all cell types. He begins with a reference to Nobel Laureates from 2004, but does not seem to know that one of them co-authored “Feedback loops link odor and pheromone signaling with reproduction.” (2005) In the article co-authored by Linda Buck, they claim “Indications that GnRH peptide plays an important role in the control of sexual behaviors suggest that pheromone effects on these behaviors might also involve GnRH neurons” (p 683).

In our 1996 Hormones and Behavior review article From Fertilization to Adult Sexual Behavior, we linked RNA-mediated cell type differentiation from microbes to mammals via GnRH.

Excerpt: “For instance, a yeast pheromone, the alpha-mating factor, is very similar in structure to mammalian gonadotropic releasing hormone (GnRH). When injected into rats, this chemical binds to pituitary GnRH receptors and brings about the release of LH. Loumaye, Thorner, and Catt (1982) note: “GnRH and the yeast alpha-mating factor appear to represent a highly conserved effector system which includes the peptide ligand, the cell-surface receptor, and the physiological regulation of reproductive function” (p. 1325).

This puts Timothy S. McClintock more than a decade behind the experimental evidence that now links RNA-mediated amino acid substitutions and chromatin loops to the pheromone-controlled physiology of reproduction in species from microbes to man.  For example: Molecular ruler sets bacterial needle length reports findings that link nutrient-dependent RNA-mediated amino acid substitutions to the finely-tuned development of the bacterial flagellum, which enables movement towards a food source across a chemical gradient. Evolutionary theorists attribute the development of this extremely complex functional structure to mutations and evolution.

See also: Bacteria ‘hotwire their genes’ to fix a faulty motor.  Evolutionary theorists link the re-evolution of the bacterial flagellum, which occurs “over-the-weekend,” to mutations and amino acids with no mention of how the amino acid substitutions are fixed in the organized genomes of  species from microbes to man. Fixation of amino acid substitutions occurs via the pheromone-controlled physiology of their nutrient-dependent reproduction.  Perhaps there is no mention of how mutations are fixed in the organized genomes of microbes because no experimental evidence suggests that mutations are ever fixed in populations of any species.

For mutations to be fixed, the biophysical constraints on the chemistry of protein folding must first be removed. Obviously, the only way to remove the links from physics to chemistry and the conserved molecular mechanisms that link metabolic networks and genetic networks to cell type differentiation in all genera is to invent a theory and convince others that it explains the evolution of biodiversity. See Masatoshi Nei’s conclusion in Mutation-Driven Evolution. “…genomic conservation and constraint-breaking mutation is the ultimate source of all biological innovations and the enormous amount of biodiversity in this world” (p. 199).

Is Timothy S. McClintock claiming that mutations and evolution lead to “Odorant Receptor Gene Choice”? Not necessarily. He puts the role of mutations into the following context.

A link between homeodomain transcription factor stimulation of OR expression and OR gene choice is supported by evidence that deletion of Emx2, or mutation of homeodomain sites in both OR promoters and enhancers, alters the frequencies of OR expression rather than the amount of OR mRNA per OSN (Khan et al., 2011; McIntyre et al., 2008; Vassalli et al., 2011). These findings suggest that OR gene repression and the singularity of OR allele de-repression might be sensitive to the effects of positively acting transcription factors on OR genes.

That links nutrients and amino acid substitutions to the de novo creation of odorant receptor genes. It also links the fixation of the amino acid substitutions to the stability of protein folding in the organized genomes of species from microbes to man. Indeed, McClintock even mentions the obvious epigenetic link from yeasts to mammals.

Yeast one-hybrid assays using OR promoters as bait captured 10 homeodomain transcription factors from olfactory epithelium cDNA expression libraries (Hirota and Mombaerts, 2004; Hoppe et al., 2003). Of these, Lhx2 and Emx2 have expression patterns most consistent with the control of OR transcription because they are strongly expressed in immature OSNs and basal progenitor cells but are also expressed at lower levels in mature OSNs. In E18.5 mouse embryos, germline deletion of Emx2 decreased the frequency of expression of dozens of OR genes but also increased the frequency of more than 20 OR genes (McIntyre et al., 2008).

He just linked nutrient-dependent pheromone-controlled feedback loops to the chromatin loops and honeybee model organism of nutrient-dependent pheromone-controlled morphological and behavioral phenotypes via cell type differentiation in all cells of all individuals of the colony.  See: Genes associated with ant social behavior show distinct transcriptional and evolutionary patterns.

…after finding non-significant overlap in lists of genes associated with queen- and worker-caste development in paper wasps and honey bees, Berens et al. (2014) recently invoked a ‘looser’ version of the genetic toolkit hypothesis by examining the overlap of inferred functional enrichment of gene lists (i.e., via gene ontology analysis). Focus on co-expressed modules may actually improve the feasibility of inferring the function of co-expressed genes based on observed expression patterns together with standard functional information inferred from the subset of conserved annotated genes with identifiable orthologs from model systems.

How can McClintock not recognize the pattern that epigenetically links the RNA-mediated nutrient-dependent de novo creation of odorant receptor genes to the pheromone-controlled behavior of all animals via amino acid substitutions? For example, see Kohl, 2013:

The honeybee already serves as a model organism for studying human immunity, disease resistance, allergic reaction, circadian rhythms, antibiotic resistance, the development of the brain and behavior, mental health, longevity, diseases of the X chromosome, learning and memory, as well as conditioned responses to sensory stimuli (Kohl, 2012).

Perhaps McClintock knows nothing about the biophysically constrained chemistry of protein folding. Perhaps he doesn’t want others to know that it refutes his theoretical approach to explanations of biologically-based cause and effect.

It doesn’t matter why he appears to have learned nothing about molecular epigenetics in the past two decades. The problem is that he insists on putting what others have learned into the context of evolution. That’s why others are Combating Evolution to Fight Disease. Olfactory researchers link Timothy S. McClintock seem to be touting the evolutionary theories that serious scientists are fighting against. See also: Scientists find DNA is packaged like a yoyo

Excerpt: “There are many good studies that show that if you change the sequence of the gene, then it will affect other things. Different proteins may be created because they require certain sequences for binding and so on,” said Ha. “But no one had really thought about sequence changes having an effect on DNA physics, which in turn cause changes in the biology.”

My comment: The creation of different proteins is RNA-mediated. Perhaps the systems complexity of the nutrient-dependent de novo creation of odorant receptor genes and their fixation in the organized genomes of invertebrates and vertebrates cannot be addressed by people like McClintock. But that doesn’t mean they should continue to place the complexity of ecological variation and ecological adaptation into their ridiculous theories about evolution.

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