Functional coding variants are not mutations

August 25, 2013 | James Kohl

Rare coding variants of the adenosine A3 receptor are increased in autism: on the trail of the serotonin transporter regulome

Conclusions: Our results validate the hypothesis that the SERT regulatory network harbors rare, functional variants that impact SERT activity and regulation in ASD, and encourages further investigation of this network as a site for additional functional variation that may impact ASD risk.”

My comment: This open access article mentions mutations, but the title and conclusion correctly infer that coding “variants” in a specific receptor are increased. In my model, epigenetically-effected coding variants cause the de novo creation of olfactory receptor genes, which are responsible for nutrient-dependent pheromone-controlled adaptive evolution.

De novo creation of olfactory receptor genes results in additional coding variants in unicellular and multicellular organisms, which enable organisms to adapt to the presence of novel nutrients via epigenetic effects on receptor-mediated protein biosynthesis and degradation. The epigenetic landscape becomes the physical landscape of DNA via physiological control of these coding variants.

The physiological processes of cellular metabolism of nutrients to pheromones that control reproduction in species from microbes are why Physiology is rocking the foundations of evolutionary biology. It is no longer possible to look at “coding variants” as uncontrolled mutations or to place them in the context of mutation-driven evolution because adaptive evolution is clearly nutrient-dependent and pheromone-controlled (sans mutations).

In mammals, for example, the trail of the serotonin transporter regulome is part of the clear evolutionary trail that can be followed from unicellular organisms to insects to humans via olfaction and odor receptors. It has been known for more than two decades that noradrenergic, dopaminergic, serotoninergic, and opiotergic pathways; inhibitory neurotransmitters (e.g., gamma aminobutyric acid) and excitatory amino acids (e.g., glutamic and aspartic acids); and other brain peptides including pineal secretions (melatonin) and corticotrophin releasing hormone, and the complex interactions among them are subtle but functional species-specific influences on the electrochemical transmission of neuronal signals that the hypothalamus translates to the chemical signal GnRH.

In my mammalian model, gondadotropin releasing hormone (GnRH) pulse frequency and amplitude link the epigenetic effects of nutrient uptake (e.g., glucose) and metabolism of the nutrients to species-specific pheromones directly to gene activation in hormone-secreting nerve cell tissue of the brain that is responsible for modulation of brain development and behavior throughout the lives of mammals whose behavior is hormone-organized and hormone-activated, as is the behavior of invertebrates and all other vertebrates. See for example our 1996 review article in Hormones and Behavior and extension of the model to invertebrates in Organizational and activational effects of hormones on insect behavior.

In the context of autism spectrum disorders, the failure to start from a model of receptor-mediated brain development and the placement of the serotonin transporter regulome into the context of mutations, obfuscates cause and effect. The serotonin transporter regulome does not automagically appear, nor is it manifested due to mutation-driven evolution. It is nutrient-dependent and pheromone-controlled, which may help to explain what is atypical during the development of autism spectrum disorders.

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James Vaughn Kohl

James Vaughn Kohl

James Vaughn Kohl was the first to accurately conceptualize human pheromones, and began presenting his findings to the scientific community in 1992. He continues to present to, and publish for, diverse scientific and lay audiences, while constantly monitoring the scientific presses for new information that is relevant to the development of his initial and ongoing conceptualization of human pheromones.