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.
VARIANTS OF UNCERTAIN SIGNIFICANCE
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?
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.
In mice with WT mitochondria, stress significantly decreased circulating levels for 13 (65%) of the 20 amino acids investigated (Fig. S3).
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 methylation2.3 Chromatin remodelling2.4 Histone variants2.5 Noncoding RNAs – microRNAs2.6 Noncoding RNAs – piRNAs2.7 Noncoding RNAs – long noncoding RNAs introduction2.8 Long noncoding RNAs Xist and HOTAIR2.9 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.
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).
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
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’
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