Base pairs, amino acids and phenotypes

(click to enlarge)

Holliday junction trap shows how cells use recombination and a junction-guardian role of RecQ helicase

DNA repair by homologous recombination (HR) underpins cell survival and fuels genome instability, cancer, and evolution.

Autophagy is the established link from energy-dependent changes in base pairs and RNA-mediated amino acid substitutions to DNA repair in the context of polycombic ecological adaptations that prevent the hecatombic evolution of virus-driven pathology. Inventing new detailed models of DNA repair serves only to confuse those who have already linked energy-dependent changes from angstroms to ecosystems via the physiology of reproduction, which links the innate immune system to supercoiled DNA and all biodiversity in all living genera.
See for comparison. This is another confusing attempt to link energy-dependent autophagy via the physiology of pheromone-controlled reproduction from changes is base pairs to RNA-mediated amino acid substitutions, which differentiate all cell types in all living genera in the context of polycombic ecological adaptations.
Very few published works use the term RNA regulons for comparison to energy-dependent changes in microRNAs in the context of hydrogen-atom transfer in DNA base pairs in solution. The changes in base pairs must be linked to the post-transcriptional events via biophysically constrained RNA-mediated protein folding chemistry, which links metabolic networks to genetic networks in all living genera.
RNA regulons: coordination of post-transcriptional events (2007)

Here I describe several recently discovered examples of RNA operons in budding yeast, fruitfly and mammalian cells, and their potential importance in processes such as immune response, oxidative metabolism, stress response, circadian rhythms and disease. I close by considering the evolutionary wiring and rewiring of these combinatorial post-transcriptional gene-expression networks.

The claims about RNA regulons in the context of the innate immune system and claims about a model of biologically-based cause and effect were included in this model.
See: Nutrient-dependent/pheromone-controlled adaptive evolution: a model. My model is a refutation of the neo-Darwinian nonsense about beneficial mutations, natural selection and evolution. Natural selection for energy-dependent codon optimaility links the pheromone-controlled physiology of nutrient-dependent reproduction to all biodiversity in all living genera via polycombic ecological adaptations.
The refutation of neo-Darwinian nonsense is supported by experimental evidence from many different published works that link energy-dependent changes in base pairs to fixation of RNA-mediated amino acid substitutions in organized genomes. The ~55,000 indexed published works on nutrient energy-dependent microRNAs and virus-driven energy theft can now be place into these claims about the hecatombic evolution of all virus-driven pathology
See: ‘Freeze-frame’ proteins show how cancer evolves: Researchers capture elusive clues about cells’ path to cancer.

“The intermediate molecules are the most important parts of biochemical reactions,” said Rosenberg… “They define what the reaction is and how it will proceed. But because they are transient and elusive, it’s really difficult to study them, especially in living cells.

The “intermediate molecules” are energy-dependent microRNAs. They link hydrogen-atom transfer in DNA base pairs in solution to all cell type differentiation in all genera via microRNA flanking sequences.
See: The phylogenetic utility and functional constraint of microRNA flanking sequences

Both miRNAs and their flanking sequences provide phylogenetic signals suitable for the inference of phylogeny with high levels of accuracy, when sufficient numbers of this type are concatenated. As detailed here, the clear identity and easy alignment of these sequences makes them good candidates for estimating phylogeny, and they can reliably be found and identified across all members of a clade of interest. Their relatively slow evolution [3] also means that they can easily be identified in de novo assemblies of genomes.

There is no such thing as the de novo assemblies of genomes or relatively fast or slow evolution. Cell type differentiation is energy-dependent and biophysically constrained. Energy-dependent changes in the microRNA/messenger RNA balance are required to link the epigenetic landscape to the physical landscape of supercoiled DNA.
Everything known about energy-dependent biophysically constrained RNA-mediated protein folding chemistry was placed into the context of Combating Evolution to Fight Disease.  Simply put, the innate immune system defends all cell types against the virus-driven evolution of cancer and all other pathology.

As predicted in “The Darwin Code,” That fact has forced A radical revision of human genetics

“…geneticists don’t have an accurate understanding of how mutations behave in people who are not obviously sick. “This is a fascinating flashpoint in the field right now,” says Robert Green, a geneticist at Brigham and Women’s Hospital in Boston, Massachusetts. “Many people are deeply concerned that widespread screening of ostensibly healthy people could actually lead to harm.”

The harm comes from not knowing how nutrient energy-dependent RNA-mediated cell type differentiation occurs. The availabiity of nutrients varied in the ancestors of people from Asian, African, Latino and other non-European ancestries. That is why…

…failing to include people from Asian, African, Latino and other non-European ancestries is holding back understanding of how genes influence disease by limiting the view of human genetic diversity.

Natural selection of food for energy-dependent codon optimality links base pairs and amino acid substitutions to sex specific cell type differences and all other RNA-mediated cell type differences.

See for example: Gender-Specific Association of Galanin Polymorphisms with HPA-Axis Dysregulation, Symptom Severity, and Antidepressant Treatment Response (2010)

Human galanin (GAL) is a 30 amino-acid neuropeptide, proteolytically processed from preprogalanin (PPGAL) (Evans and Shine, 1991; Schmidt et al, 1991). PPGAL is a single-copy gene located on chromosome 11q13.3–13.5, spanning over 6 kb of genomic DNA and organized into six exons (Rokaeus and Brownstein, 1986; Vrontakis et al, 1987).

Single-nucleotide polymorphism rs948854 in human galanin gene and multiple sclerosis: a gender-specific risk factor (2017)

Although it remains to be demonstrated whether A-to-G substitution in rs948854 leads to an increased or decreased transcriptional activity of the GAL gene, functional studies suggest a decrease of galanin level in the minor G allele carriers. It has been shown that reduction in galanin level leads to or exacerbates neurodegeneration, whereas an increased galanin level has neuroprotective effects (Hobson et al., 2008; Elliott-Hunt et al., 2011; Liu et al., 2013). Furthermore, galanin may exhibit anti-inflammatory effects, possibly via inhibition of excitatory neurotransmitter release and/or regulation of cytokine production by activated microglia (Hokfelt et al., 1987; Su et al., 2003; Elliott-Hunt et al., 2004). The associations between rs948854 variants and MS demonstrated in the current study support our hypothesis that polymorphism in the promoter region that are likely to change expression level of the GAL gene affect the cause and the outcome of MS, shifting the balance in favor of either neuroprotection or neurodegeneration.

Modeling Recent Human Evolution in Mice by Expression of a Selected EDAR Variant (2013)

Alternatively, it could be precisely the pleiotropic nature of 370A that allowed multiple distinct selective forces to act on this variant over its long history, when many of the postulated selective pressures such as temperature and humidity changed dramatically. The fact that EDAR acts mostly on ectodermal appendages and that the phenotypic effects of the 370A allele are not extreme reduces the costs of pleiotropy and would facilitate this process. Thus, what were initially neutral changes in some appendages driven by 370A would gain adaptive significance in the face of new selective pressures. It is worth noting that largely invisible structural changes resulting from the 370A allele that might confer functional advantage, such as increased eccrine gland number, are directly linked to visually obvious traits such as hair phenotypes and breast size. This creates conditions in which biases in mate preference could rapidly evolve and reinforce more direct competitive advantages. Consequently, the cumulative selective force acting over time on diverse traits caused by a single pleiotropic mutation could have driven the rise and spread of 370A.

My comment: 370 A exemplifies an energy-dependent change in rs3827760, which is also known as 1540T/C, 370A or Val370Ala. It is a single nucleotide polymorphism (SNP) linked from a base pair change to an amino acid substitution in the ectodysplasin A receptor EDAR gene on chromosome 2.
A genome-wide analysis of putative functional and exonic variation associated with extremely high intelligence (2015)

One SNP rs4713668 (P=4.62 × 10−4) identified in our study, was in LD (r2=0.65) with rs3227, which is one of the three variants recently reported with genome-wide significant evidence of association with educational attainment.46

A genetic basis of variation in eccrine sweat gland and hair follicle density (2015)
rs3827760 appears to have become En1 [Engrailed-1), and modulation of En1 levels became a driver of natural differences in eccrine gland and hair follicle density between mouse strains. Previously, those differences were linked to a single energy-dependent base pair change and one amino acid substitution.

This finding not only provides insight into a distinct molecular program that promotes increased eccrine gland density, but also reveals that this effect on eccrine development occurs at the expense of hair follicles in a tissue where the two appendage types are naturally interspersed.

The link to behavior via visually obvious traits such as hair phenotypes and breast size is missing. That means there is no link to sex differences and biases in mate preference via rs948854. That means everything known to serious scientists about biophysically constrained RNA-mediated amino acid substitutions and cell type differentiation in all individuals in all living genera may continue to be ignored.
See for instance: Nutrient-dependent/pheromone-controlled adaptive evolution: a model

Two additional recent reports link substitution of the amino acid alanine for the amino acid valine (Grossman et al., 2013) to nutrient-dependent pheromone-controlled adaptive evolution. The alanine substitution for valine does not appear to be under any selection pressure in mice. The cause-and-effect relationship was established in mice by comparing the effects of the alanine, which is under selection pressure in humans, via its substitution for valine in mice (Kamberov et al., 2013).

These two reports (Grossman et al., 2013; Kamberov et al., 2013) tell a new short story of adaptive evolution. The story begins with what was probably a nutrient-dependent variant allele that arose in central China approximately 30,000 years ago. The effect of the allele is adaptive and it is manifested in the context of an effect on sweat, skin, hair, and teeth. In other mammals, like the mouse, the effect on sweat, skin, hair, and teeth is due to an epigenetic effect of nutrients on hormones responsible for the tweaking of immense gene networks that metabolize nutrients to pheromones. The pheromones control the nutrient-dependent hormone-dependent organization and activation of reproductive sexual behavior in mammals such as mice and humans, but also in invertebrates as previously indicated. That means the adaptive evolution of the human population, which is detailed in these two reports, is also likely to be nutrient-dependent and pheromone-controlled, since there is no other model for that.

The fact that there is no other model of energy-dependent biophysically constrained cell type differentiation that also links virus-driven energy theft to all pathology has not escaped the attention of those who might wish they had a model. Because they don’t, all they can do is claim that no model refutes their ridiculous theories about evolution.

For a failed discussion attempt of everything known to serious scientists about energy-dependent base pair changes, RNA-mediated amino acid substitutions and cell type differentiation, see Creationism May 22, 2016

Energy-dependent base pair changes are the only known link from RNA-mediated amino acid substitutions to cell type differentiation via supercoiled DNA and protection from virus-driven energy theft. The energy-dependent base pair changes prevent the entropy of organized genomes.
The focus of my 2013 model was on the RNA-mediated amino acid substitutions that differentiate all cell types in all individuals of all living genera. The focus of theorists has been to obfuscate what is known about the links from energy-dependent base pair changes to RNA-mediated amino acid substitutions and cell type differentiation, which is the only way to explain biologically-based cause and effect. It also explains why some species survived and others became extinct during the past ~6000 years.
See for example:
Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants
Genome divergence and diversification within a geographic mosaic of coevolution
Difference in Plumage Color Used in Species Recognition between Incipient Species Is Linked to a Single Amino Acid Substitution in the Melanocortin-1 Receptor
Substitutions Near the Receptor Binding Site Determine Major Antigenic Change During Influenza Virus Evolution
Identification of amino acid substitutions supporting antigenic change of influenza A(H1N1)pdm09 viruses.
The fact that all divergence and diversification in all living genera must be energy-dependent and the fact that virus-driven energy theft causes all pathology must be ignored by those whose financial support for their research comes from the evolution industry or the big bang cosmology industry. We cannot expect much scientific progress until the financial constraints are broken and the biophysical constraints on energy-dependent RNA-mediated cell type differentiation are addressed at every level from angstroms top ecosystems after starting from quantized energy-dependent changes in base pairs.
See for comparison: Lineage-Specific Genome Architecture Links Enhancers and Non-coding Disease Variants to Target Gene Promoters
Re: “…the interactomes of 31,253 annotated promoters in 17 human primary blood cell types.”
Excerpt:

Here, we link thousands of GWAS SNPs to their putative target genes and prioritize more than 2,500 potential disease-associated genes, three-quarters of which were not previously implicated.

Reported as: Researchers identify missing links that connect human DNA variation with disease
All “missing links” are nutrient energy-dependent and biophysically constrained by the physiology of reproduction. They link RNA-mediated amino acid substitutions to cell type differentiation in all cell types of all living genera via the innate immune system and supercoiled DNA. Mathematical models are useless in that context. They are based on inferences and assumptions.
It’s time to finish this blog post. I linked energy-dependent changes in SNPs from amino acid substitutions to cell type differentiation via a model of biologically-based cause and effect, and the “science” news is still reporting biologically-based cause and effect in the context of their pseudoscientific nonsense about mathematical models of inferences and assumptions.

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