Excerpt: “Learning the secrets of alternate molecular pathways could provide clues about how to use them to patients’ advantage, she said.”
“Mechanisms of epistasis are often best revealed through detailed examinations of interactions between amino acid mutations…”
See my comment: 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 adaptive evolution of GnRH pulse frequency-controlled LH secretion and 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). 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.
My review was published on the same day as this article in Science. See: Nutrient-dependent/pheromone-controlled adaptive evolution: a model.
So was Nei’s book: Mutation-Driven Evolution
The fact that scientists who study metabolism still cannot differentiate between mutations and amino acid substitutions attests to the overwhelming amount of ignorance among evolutionary theorists.
Mutations perturb protein folding.
Amino acid substitutions link metabolic networks to genetic networks in the organized genomes of all genera via the nutrient-dependent physiology of reproduction.
See also: The Human Condition—A Molecular Approach
Svante Pääbo includes discussion of the companion papers that link A single amino acid substitution to cell type differentiation in mice and in a modern human population, but fails to differentiate between the role of mutations and amino acid substitutions in the nutrient-dependent cell type differentiation of all cell types in all individuals of all species.