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MiRNAs methylation and ecological adaptation sans mutations

MiRNAs methylation and ecological adaptation sans mutations
 Our 2003 Molecular and Cellular Biology paper …opened the mechanistic ‘black box’ of the developmental origins of adult disease susceptibility, and firmly placed the word, epigenetics, in the vernacular of this research field.”  — Randy Jirtle (2009)
Our 1996 Hormones and Behavior paper included a section on molecular epigenetics with evidence that attested to the involvement of epigenetics in the context of olfactory/pheromonal input and the developmental origins of hormone-organized and hormone-activated adult sexual behavior. — James V. Kohl (2014)
Our model was extended to invertebrates in 2000 and to the life history transitions of honeybees in 2005. The model now links the experience-dependent RNA-mediated induction of olfactory receptor gene expression from nutrient-dependent pheromone-controlled ecological adaptations to the creation of species biodiversity in species from microbes to man via conserved molecular mechanisms, which also are linked to perturbed protein folding and the developmental origins of disease. For example see 1, 2, & 3 below with my comments.
1) Odor memories regulate olfactory receptor expression in the sensory periphery. “…olfactory receptor expression is experience-dependent and modulated by scent conditioning…”
Scent conditioning of olfactory receptor (OR) expression  is clearly linked from invertebrates to vertebrates via nutrient uptake in:
2) A Cluster of Olfactory Receptor Genes Linked to Frugivory in Bats.
The authors addressed the experimental “… evidence for ecological niche specialization linked to the evolution of the OR gene repertoire across all major clades of eutherian mammals.”
Taken together with this report:
3)  Large Numbers of Novel miRNAs Originate from DNA Transposons and Are Coincident with a Large Species Radiation in Bats,
these articles conclusively link the epigenetic landscape of invertebrates to the physical landscape of DNA in the organized genomes of invertebrates and vertebrates via the nutrient-dependent assembly of “…functional miRNAs…” that “…influenced the diversification of Vespertilionidae [mammals].”
Thus, the link from food odors to miRNAs and to protein folding required for the de novo creation of OR genes in invertebrates and vertebrates is perfectly clear in the context of conserved molecular mechanisms that link the biophysically constrained nutrient-dependent pheromone-controlled physiology of reproduction to species diversity in species from microbes to man.
Academically irresponsible suppression of accurate representations that detail biophysically-constrained biologically-based cause and effect may continue to delay scientific progress, which might otherwise be made via use of a model that links ecological variation from atoms to ecosystems. Clearly, those who Dobzhansky (1964) labeled ‘bird watchers’ and ‘butterfly collectors’ will continue to tout their pseudoscientific nonsense.
However, they can now be categorized as modern-day antagonists who are still living in an era of ignorance. They continue to ignore the basic principles of biology and levels of biological organization required to link the sensory environment directly to behavior.  That leaves them to tout theories about mutation-initiated natural selection or mutation-driven evolution, which gained popularity despite the lack of experimental evidence to support them.

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Pheromone-controlled thermodynamics and cancer

If you learnt evolutionary biology and genetics a decade or more ago you need to be aware that those debates have moved on very considerably, as has the experimental and field work on which they are based.” — Denis Noble

Can thermodynamics help us better understand human cancers?

Excerpt: “In a new study, UCLA researchers analyzed the gene-expression profiles of more than 2,000 patients and were able to identify cancer-specific gene signatures for breast, lung, prostate and ovarian cancers. The study applied an innovative approach to gene-array analysis known as “surprisal analysis,” which uses the principles of thermodynamics—the study of the relationship between different forms of energy—to understand cellular processes in cancer.”
My comment: This article “miRNA and mRNA cancer signatures determined by analysis of expression levels in large cohorts of patients” integrates what is known about RNA-directed DNA methylation and the RNA-mediated DNA/RNA protein synthesizing system and biological information with the thermodynamics of intercellular interactions. A robust microRNA/messenger RNA (miRNA / mRNA) balance exemplifies a finely tuned, calibrated, and standardized reference state. Deviation from the finely tuned miRNA / mRNA balance exemplifies the cancer-specific disease pattern. The deviation is “…a signature comprised of unique mRNAs and miRNAs capable of distinguishing diseased patient samples from normal controls.” Thus, the importance of Nutrient-dependent / Pheromone–controlled thermodynamics and thermoregulation to distinguishing between an atypical or typical miRNA / mRNA balance becomes more important to the diagnosis and treatment of cancer, or to prevention. For example, I wrote: “Disease is associated with mutations exemplified in cancer where perturbations of the glucose-dependent thermodynamic/thermoregulatory equilibrium are equally clear (Locasale, 2012).”
However, it is simply not possible to differentiate bottom-up nutrient-dependent epigenetic effects on thermodynamics and stochastic gene expression from top-down pheromone-controlled epigenetic effects on organism-level thermoregulation until others realize that common molecular mechanisms are involved across species and that only one neuronal signaling pathway is required in mammals. The gonadotropin releasing hormone (GnRH) neuronal system is responsible for thermodynamically controlled organism-level thermoregulation in mammals. Yet the origins of this neuronal system can be traced back to single-celled yeasts at the advent of sexual reproduction that predicts sex differences in hormone-linked cancers and other disease states. This means thermodynamics alone cannot help us better understand human cancers. Cancer must be understood in the context of organism-level thermoregulation and adaptive evolution by differentiating it from theories that incorporate mutation-initiated natural selection. Mutations perturb the thermodynamics of intercellular signalling, and no organism naturally selects for anything involved in cancer.

Researchers must begin to popularize biological facts and continue to fight against the popularity of mutations theory. We can then better teach others to understand the epigenetic effects of nutrient stress and social stress on cancer, which is not adaptive, and also help others to begin to better understand many things about adaptive evolution. See, for example, this 5.5 minute video representation from my 2013 International Society for Human Ethology Summer Institute Poster presentation:  “Nutrient-dependent / pheromone-controlled adaptive evolution: (a mammalian model of thermodynamics and organism-level thermoregulation)”


 
 

diseases-disorders

Functional coding variants are not mutations

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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A thought experiment

I may be confused about proximate and ultimate cause, especially if the role of transgenerational epigenetic inheritance is not central to the extended evolutionary synthesis. Isn’t transgenerational epigenetic inheritance the problem that led Dickins and Rahman to suggest a thought experiment; one where epigenetic mechanisms introduce shifts in learning bias for certain associations as would endocrine functioning? If so, my model (Kohl, 2012), which combines the epigenetic effects of nutrient chemicals and pheromones with biased endocrine functioning and adaptive evolution, may help move the modern synthesis forward.
I tried this before, but the evolutionary continuum from microbes to man (Kohl, 2007) seems too much to grasp in the context of biased endocrine functioning. However, the honeybee has since emerged as a model organism to exemplify nutrient chemical and pheromone-dependent epigenetic alterations in endocrine functioning. These epigenetic effects that bias endocrine functioning are required for the adaptive evolution of reproduction.
Reproduction is required for transgenerational epigenetic inheritance and species diversity, which is perhaps better represented in the threespine stickleback vertebrate model organism. However, in all invertebrate and vertebrate model organisms, nutrient chemicals establish the ecological niche of individuals, and the presence of conspecifics establishes their social niche (as also occurs with microbial species).
The honeybee best exemplifies how  ecological and social niches contribute to the hypothalamic gonadotropin releasing hormone (GnRH) neurogenic niche that is responsible for the adaptive evolution of the human brain. Simply put, what the queen eats determines her pheromone production and everything else about the social interactions in the colony, including the required epigenetic effects of pheromones on the neuroanatomy of the worker bee’s brains during the development of their diverse behaviors that change with exposure to different chemical input associated with a variety of other sensory input of lesser importance / salience.
Of course, that sounds too simple in the context of the extended evolutionary synthesis and human brain evolution. But the molecular biology is conserved across species, which is helpful for proof of concept. In placental mammals, for example, in utero nutrient chemical transfer is responsible for organization of the brain’s postnatal activation by nutrient chemicals and pheromones. The proper GnRH-driven behavioral response of the infant to activation by these chemicals ensures its survival, just as the proper response of the honeybee worker bee’s brain to nutrient chemicals and pheromones ensures its survival and helps to ensure the colony’s survival via changes in the neuroanatomy of its brain. (Parenthetically, spectral input may or may not be correlated with direct epigenetic effects on the brain, but it is not causal to brain development.)
Model organisms have their RNA-mediated molecular biology in common with all other organisms. No organism survives in the absence of sufficient nutrient chemicals. Ecological niches contract. And no species survives in the absence of reproduction controlled by pheromones. I think that’s why we are now seeing more reports on transgenerational epigenetic inheritance, with causal links to speciation via ecological and social niches in all species. We should soon see the addition of neurogenic niches in many others.
What I don’t see is anyone who is integrating the ecological, social, and neurogenic niches and considering the epigenetic effects of nutrient chemicals and pheromones in the context of endocrine disruption and transgenerational epigenetic inheritance. Nutrient chemicals and pheromones promote homeostasis and also allow adaptive evolution, including adaptive evolution of the human brain. Endocrine disruption causes atypical development of the brain and the body.
Isn’t that the apparent design we might all someday see in biology? Isn’t seeing the apparent design required to move forward from the Modern Synthesis to the Extended Evolutionary Synthesis?
Jim Kohl
www.pheromones.com
On 5/27/2012 3:26 AM, R.J.King@lse.ac.uk wrote:

jvkohl:
I fear that you may have confused proximate and ultimate. Easily done. Epigenetics, while fascinating, has no impact on the central doctine of genes as the sole information carriers. Epigenetics are just one more set of mechanisms by which genes achieve their ultimate aim of replication. I.e. they are part of the suite of adaptations. The University of Utah has an excellent site detailing this
http://learn.genetics.utah.edu/
May I particularly recommened this page which beautifully illustrates the way in which behaviours and epigenetics intereact in this way to calibrate personality to environment?
http://learn.genetics.utah.edu/content/epigenetics/rats/
My suspicion  is that the folk biology concept of "biology=fixed at birth" dies very very hard and keeps recurring in odd forms in even the best and brightest of us.