Simply put all aspects of biophysically constrained energy-dependent cell type differentiation must first be linked from the physiology of reproduction to ecological adaptations, or they must be linked from energy theft to the evolution of pathology.
See for contrast and comparsion: Finding your diagnosis in the brave new world of genetics-based medicine by John Hewitt
- Typically all they have is a stack of diffuse paper reports and xeroxed publications from the primary medical literature with no clear explanation to tie everything together.
- This current state of affairs is not the direct fault of anybody in particular, but rather a side effect of an incomplete and evolving body of knowledge that necessarily contains significant ambiguity in its presentation.
- Having a ‘genomic sequencing’ reference (g.) would be a little more informative here for many reasons, namely, the presence of multiple transcription initiation sites (promoters), alternative splicing, the use of different poly-A addition signals, multiple translation initiation sites (ATG-codons), and the occurrence of length variations. Potentially, if exome sequencing draws on mRNAs after they are edited, (either in nucleus-specific or cytosol-specific editing), this would be an issue too, although RNA editing (post-transcriptional modification of bases, mostly A to G or A to I substitutions in humans) is quite rare.
- An important related question here is what tissue source got sequenced in the exome analysis—was it blood, skin, or epithelium? Because the same gene is typically spliced differently in different tissues it would also give different cDNAs in exome analysis of different tissues.
- Isoleucine is a hydrophobic amino acid and serine is a polar and uncharged amino acid. These are fairly different animals altogether and it is normally assumed that this kind substitution should have some significant effect on protein structure or function. The question is what effect?
- I will not delve much further into the other variants found in the genetic testing other than to note that the one for PGAP1 has a slightly different notation from the others, given as c.2525+4C>T. This annotation c.2525+4C>T appears to suggest that this variant is located +4 nucleotides apart from the last exonic nucleotide. This variant is predicted to be a “splice donor” which means that can alter the length of the resulting protein, a different transcript. PGAP1 has 22 exons and at least 11 splice variants. This variant has a mutation in the intron downstream of nucleotide position 2525. This creates a splice junction failure where the intron will not be spliced out and thus the variant will include protein sequence corresponding to the intron.
Thanks to John Hewitt for calling attention to this at a time when others are beginning to realize there is no such thing as “genetics-based” medicine. Personalized species-specific treatments across different human populations must link nutrient energy-dependent changes from angstroms to ecosystems.
All serious scientists will continue to attest to that fact. Even the best science journalists may not be able to cross disciplines and report on what is already known. For example, John Hewitt comes up short.
Excerpt (I paraphrase to reiterate):
I will not delve much further into the other variants found in the genetic testing other than to note that … [one variant] …. is predicted to be a “splice donor” which means that can alter the length of the resulting protein, a different transcript. PGAP1 has 22 exons and at least 11 splice variants. This variant has a mutation in the intron downstream of nucleotide position 2525. This creates a splice junction failure where the intron will not be spliced out and thus the variant will include protein sequence corresponding to the intron.
My comment: There is no need to delve any further into the differences in the splice variants. The differences link natural selection for energy-dependent codon optimality to the RNA-mediated fixation of amino acid substitutions in supercoiled DNA. Supercoiled DNA links chromosomal rearrangements to the physiology of reproduction, which prevents most of the transgenerational epigenetic inheritance of virus-driven energy theft. Virus-driven energy theft links negative supercoiling in DNA to all pathology in all living genera.
Until more people understand that fact, even the best science journalists are not likely to escape from the pseudoscientific nonsense touted by theorists who fail to link energy to healthy longevity and/or fail to link virus-driven energy theft to all pathology.
No one gets out of this alive who cannot understand that the splice variants are energy-dependent, which is why no one lives for ever. Eventually, the viruses steal too much energy and use it for their genomic stability.
Not only does that fact limit the life expectancy of all humans but the limits are predictably linked from nutrient stress and/or social stress to everything known about energy-dependent amino acid substitutions in the context of life history transitions, which link the energy-dependent differences in archaea to humans via differences in base pairs and amino acid substitutions.