Ricki Lewis' Time Machine (4)

Variants near CHRNA3/5 and APOE have age- and sex-related effects on human lifespan

The signal we observe is driven by rs429358, a non-synonymous Cys112Arg variant, which defines the ε4 allele and which has not previously been shown to be the causal variant influencing lifespan.

See also: Gorilla Genome 2.0: Lessons for the Clinic?

With phrases such as “settled science” and “scientific proof” part of the lexicon, it’s little wonder that health care consumers expect medical test results to be yes or no, not maybe. Few clinical experiences are as unsettling as receiving a “VUS” – variant of uncertain (or unknown) significance – as a genetic test result. “Yes, your gene has an unusual DNA sequence, but we don’t know what it means.”
VUS arise from the informational nature of a gene. The hundreds of DNA building blocks can vary in ways that do not affect the structure or function of the encoded protein, a little like a typo in this sentence changing “blocks” to “blokks”. For example, the three “Ashkenazi” mutations in BRCA1 remove 2 bases or add or delete one – changes that disrupt the 3-base language of DNA, greatly altering protein structure. But some mutations don’t alter protein structure at all, or do so in a way that doesn’t appreciably impact the protein’s function.

My question and comments: Is there any reason to not report all causal variants, such as the Cys112Arg variant, in the context of nutrient-dependent RNA-mediated amino acid substitutions. I think some people may be confused by terms that link the mouse to human model of cell type differences in expression of the EDAR variant, rs3827760, which also is known as 1540T/C, 370A, EDARV370A or Val370Ala, which is a  single nucleotide polymorphism (SNP) in the ectodysplasin A receptor (EDAR) gene on chromosome 2?
See: Modeling Recent Human Evolution in Mice by Expression of a Selected EDAR Variant

The biochemical properties of 370A support the possibility that the variant directly causes the associated phenotypes. Structural models predict that V370A lies in the EDAR Death Domain (DD) required for interaction with the downstream signal transducer EDARADD (Sabeti et al., 2007). Moreover, overexpression of 370A has been reported to upregulate downstream NFkB signaling in vitro relative to 370V (Bryk et al., 2008; Mouet al., 2008). This finding suggested that a pre-existing mouse model, in which the ancestral 370V allele is overexpressed, might provide insight into 370A’s phenotypic consequences (Headon and Overbeek, 1999; Mou et al., 2008). Indeed, transgenic mice expressing multiple copies of 370V have thicker hair shafts as seen in humans with the 370A allele (Fujimoto et al., 2008a, 2008b; Mou et al., 2008). In addition, these animals exhibit increased mammary gland branching, enlarged mammary glands and hyperplastic sebaceous and Meibomian glands that secrete hydrophobic films as a barrier to water loss in the skin and eyes, respectively (Chang et al., 2009). These latter phenotypes led to the proposal that the 370A variant may have been selected in response to cold and arid environmental conditions (Chang et al., 2009).

My comment: The differences in the way causal variants are reported may have stalled the “Precision Medicine Initiative” because the differences are reported outside the context of environmental conditions. Obviously, a cold and arid environment could link ecological variation to nutrient-dependent ecological adaptation by everything currently known to serious scientists about the biophysically constrained physiology of reproduction in mice and humans.  Also, others are now linking metabolic networks to genetic networks and to differences in human behavior during life history transitions by fixation of single amino acid substitutions and supercoiled DNA that appears to protect all organized genomes from virus-driven entropy.
See for example: Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress

In mice with WT mitochondria, stress significantly decreased circulating levels for 13 (65%) of the 20 amino acids investigated (Fig. S3).

See also: Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity

Using both WT mice and a humanized mouse model of reduced BDNF function (Val66Met SNP), we found that the epigenetic activator of histone acetylation, P300, plays a pivotal role in the dynamic up- and down-regulation of mGlu2 expression in the hippocampus in response to chronic and acute novel and familiar stressors. This dynamic reaction of the hippocampus reveals a window of epigenetic plasticity, a temporary timeframe of dynamic neuroplasticity, in response to stress that could allow interventions to rapidly promote resilience through regulation of acetylation of histones.

See also: Epigenetic Modifications and Organisation of the Nucleus: Enrollment in this free course has ended. For future reference–when other courses become available, I include information on what is being presented during week 2 of the course.

Week 2 – Epigenetic Modifications and Organisation of the Nucleus

2.1 Introduction to histone tail modifications 2.2 Histone acetylation and histone methylation
2.3 Chromatin remodelling
2.4 Histone variants
2.5 Noncoding RNAs – microRNAs
2.6 Noncoding RNAs – piRNAs
2.7 Noncoding RNAs – long noncoding RNAs introduction
2.8 Long noncoding RNAs Xist and HOTAIR
2.9 3D organisation of the nucleus and summary of epigenetic marks

Anyone who is taking the course will be better prepared to help sort out the information about nutrient-dependent RNA-mediated amino acid substitutions and cell type differentiation in all living genera for comparison to the pseudoscientific nonsense that has been touted by neo-Darwinian theorists. There is no defined boundary between epigenetic and genetics, which means that use of de Vries 1904 definition of mutation may have led to the bastardization of every claim Darwin repeatedly made about his “conditions of life.”
See: What is life when it is not protected from virus driven entropy (6 minutes)
See for comparison: VIRUS EVOLUTION ( AMAZING DOCUMENTARY) At 32 minutes into this video, Larry Young discusses how viruses might have led to the emergence of love.

See also:
The 3.8 Å resolution cryo-EM structure of Zika virus
Excerpt 1)

It was shown recently that the coding region of this strain has >99.9% amino acid identity to the strain currently circulating in Latin America (21).

Excerpt 2)

The differences in E protein structure shown here between ZIKV and other flaviviruses may govern cellular tropism and contribute to disease outcome.

My comment: This was reported as: Structure of Zika virus determined

Starting from the four innermost letters and working to the outermost ring, this table shows shows which three-letter base sequence or codon encodes which amino acid. In the journal Angewandte Chemie International Ed., researchers from the US Department of Energy Joint Genome Institute (DOE JGI), a DOE Office of Science User Facility, and Yale University have discovered that microorganisms recognize more than one codon for the rare, genetically encoded amino acid selenocysteine. Credit: Wikimedia Commons, public domain image

My comment: I think that ignoring what is known about how virus-driven energy theft links angstroms to failed ecosystems will lead to the death of millions. Does anyone else agree with this claim?
Virus-driven energy theft and energy-dependent RNA-mediated amino acid substitutions in viruses should be viewed in the context of a terrorist threat. Viruses prevent DNA repair, cell type differentiation, and transgenerational epigenetic inheritance of supercoiled DNA in organized genomes.
If the ignorance of neo-Darwinian theorists who know nothing about energy-dependent cell type differentiation is not the biggest threat to humanity that has ever gone relatively unnoticed, what do you think will kill you?
See also: Substitutions Near the Receptor Binding Site Determine Major Antigenic Change During Influenza Virus Evolution
Author’s comment: The major antigenic changes of the influenza virus are primarily caused by a single amino acid near the receptor binding site.
See also: Zika Up Close

The detailed structure could help guide scientists performing site-directed mutagenesis on the viral genome to test whether changes at this site might attenuate the pathogenicity or ability of the virus to cause an infection of specific cell types, Diamond added.
“Now that we have the structure, there is a lot of work that we can start directed towards developing [prophylactic] vaccines and antiviral compounds and antibodies,” Rossmann told The Scientist.

See also my comment to The Scientist on the ever-present danger of not understanding virus-driven entropy. Neuroscience of Early-Life Learning in C. elegans’
I wrote:
See also:Pan-neuronal imaging in roaming Caenorhabditis elegans
Reported as: Watching sensory information translate into behavior

“We have long been recording behavior in worms, but we and others have concluded that, if you want to get physiologically relevant neural activity patterns, you have to look at neurons inside a behaving animal,” Samuel explained. “Only in that context are all feedback loops intact, where behavioral output modulates neural activity which, in turn, shapes behavior.”

As all serious scientists continue to link ecological variation to ecological speciation via nutrient-dependent pheromone-controlled reproduction in species from microbes to humans, my antagonists have all but disappeared.

Clearly, it is time to finally begin discussion of how virus-driven energy theft links hydrogen-atom transfer in DNA base pairs in solution from mutations to pathology instead of from nutrient-dependent RNA-mediated DNA repair via amino acid substitutions to supercoiled DNA, which protects organized genomes from virus-driven entropy.

My comment: I get the impression that no one wants to discuss the role of virus-driven energy theft in pathology because they realize it might force them to reconsider everything they were taught to believe in the context of ridiculous theories that some people still think may link virus-driven energy theft from mutations to evolution.

For an example of someone who ignores everything known to serious scientists about Gorilla Genome 2.0, see Perry Marshall’s Evolution 2.0: Breaking the Deadlock Between Darwin and Design

See also:

Perry Marshall says:

March 19, 2016 at 10:04 am

James, you are one step away from being banned because of your disingenuous comments, your accusations, and your unnecessary combativeness. I am getting tired of it. People accuse you of being a troll for a reason.This is your final warning.

Perry Marshall says:

March 22, 2016 at 5:39 pm

To all reading this post:Mr Kohl does not seem to understand that to solve the origin of information problem, you can’t start with DNA or blood or anything else biological.I have asked him to stop posting here because the negative nature of some of his communications. You are welcome to pursue his writings at his blog

My additional comments have been blocked: Perry Marshall does not want others to learn that the origin of the DNA code has been detailed in the context of my works, and that his opinions are becoming more ridiculous each week.

See for example: Genetic circuit design automation


Genetic circuit design is challenging for several reasons (37, 38). First, circuits require precise balancing of regulator expression (22, 39). Second, many parts are combined to build a circuit and their function can vary depending on genetic context, strain, and growth conditions (40–46). Third, circuits are defined by many states (their response to different inputs or how they change over time), and this can be cumbersome to characterize (15, 47–49). Finally, many regulators are toxic when overexpressed, and even mild effects can combine to drive negative selection against the circuit (50).

My comment: Gene circuit design is not possible outside the context of the origin of information manifested as the de novo creation of nucleic acids. Nucleic acids, such as ribonucleic acid (RNA),  links the anti-entropic virucidal energy of the sun on contact with water to all RNA-mediated morphological and behavioral biodiversity via what is currently known about olfaction and how the innate immune systems links what organisms eat to their physiology of reproduction.

Perry Marshall and other like him may claim that “…you can’t start with DNA or blood or anything else biological” but their claims are based on ignorance. All serious scientists know that you must start from what is known about quantum physics and link it from classical physics to chemistry and the conserved molecular mechanisms of all RNA-mediated cell type differentiation that links atoms to ecosystems via the physiology of reproduction and supercoiled DNA.

Without supercoiled DNA that protects all organized genomes, there is only virus-driven entropy. Virus-driven entropy is typically not considered by theorists.

Perry Marshall is simply another one of the theorists who think they can challenge serious scientists without learning anything about how Feedback loops link odor and pheromone signaling with reproduction.


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