Epistasis among adaptive mutations? Is there a model for that?

Epistasis among adaptive mutations? Is there a model for that?

A Face Book friend (B.C.) wrote: “One of my pet peeves about science writing is the ease with which we state that the underlying mechanism of X is “unknown”, when in fact usually quite a bit is known. It’s a crutch used to justify almost everything.

Agreed. What we know is that nutrient-dependent pheromone-controlled alternative splicings are responsible for adaptive evolution in species from microbes to man and that the molecular mechanisms of thermodynamic alternatives and organism-level thermoregulation are the constraints. But the mere mention of mutations theory and what is not known tosses all that is known about cause and effect into the trash, so that even today many researchers are forced to explain their works in terms of theory and unknown natural mechanisms that they think include adaptive mutations. Instead of natural selection for food and sexual selection for nutrient-dependent species-specific pheromone production, mutations are somehow selected — as if that were likely given the constraints required for epistasis.

For example, see the recent report: Epistasis Among Adaptive Mutations in Deer Mouse Hemoglobin [subscription required].

Abstract excerpt: “Amino acid mutations increased or decreased Hb-O2 affinity depending on the allelic state of other sites. Structural analysis revealed that epistasis for Hb-O2 affinity and allosteric regulatory control is attributable to indirect interactions between structurally remote sites.”

My comment to the Science site: In my model species-specific epistasis is nutrient-dependent and pheromone-controlled. An additional example of this showed up earlier this week in the context of the epigenetically-effected microRNA/messenger RNA balance: “miR-124 controls male reproductive success in Drosophila” miR-14 acts in neurosecretory cells in the adult brain to control metabolism and miR-124 acts in the context of brain-directed neuroendocrine control of sexual differentiation and male pheromone production, which is controlled in mammals by gonadotropin-releasing hormone (GnRH) neurosecretory cells of the hypothalamus.

We can anticipate extension to mammals of the Drosophila model from the abstract of a forthcoming Science article: “MiR-200b and miR-429 Function in Mouse Ovulation and Are Essential for Female Fertility.” Given our earlier work in the context of molecular epigenetics and the concept of alternative splicings and sexual differentiation in Drosophila and C. elegans, I suspect we will see evidence for nutrient-dependent pheromone-controlled adaptive evolution of GnRH pulse frequency-controlled LH secretion and nutrient-dependent pheromone-controlled female fertility in mice.

If I’m correct, this evidence will link glucose and pheromones to feedback loops that control reproduction in invertebrates and vertebrates. (See Nutrient–dependent / pheromone–controlled adaptive evolution: a model, also published on June 14, 2013). Model organisms exemplify these feedback loops in microbes, nematodes, insects, and other mammals. The mouse to human example that Kamberov et al., and Grossman et al., detailed is the most telling.

A single amino acid substitution appears to result in what seem to be nutrient-dependent changes in the thermodynamics of intracellular signaling, intranuclear interactions, stochastic gene expression, and selection for phenotype via organism-level thermoregulation in a human population that arose in what is now central China during the past ~30K years. 

Using a model that integrates what is known about the common molecular mechanisms may help establish whether adaptive mutations lead to thermodynamic effects on organism-level thermoregulation and epistasis, or whether epigenetic effects of nutrients and their metabolism to species-specific pheromones that control reproduction via changes in the microRNA/messenger RNA balance are the driving force behind adaptive evolution in species from microbes to man. 

Author: James Kohl

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