Nelly Furtado Mash-Up
Who do you look like?
Genotypically and phenotypically, which relative (or mailman) do you resemble? Like our DNA, we're mash-up expressions of our ancestral pasts... My Taiwanese relatives tell me I physically resemble my maternal grandmother, yet my youngest sister is an uncanny amalgamation of my paternal grandmother and my dad's older sisters.
In Advanced Bio in high school, our prof taught us how to extract DNA using high tech equipment from Cetus (bought out by Chiron, later bought out by Roche) and protocols from Cold Spring Harbor. Funny how technology merges or gets hijacked. My teacher was Mr. D and was the coolest because he gave us the key to the lab (and yes, we goofed around like all seniors).
Science can make indelible impressions, no?
How to Extract DNA 101
Here is a low tech home science project which is incrediblyfun and easy to do. DNA is the language of life -- 4 letters (A T G C) in a pair linked helix translate proteins to organs to life. Extract it from anything (bananas, beans, etc) with a little clear soap (EDTA -- an organic molecule which chelates and sequesters trace and heavy metals). The end step involves swirling the DNA 'snot' onto a glass rod or q-tip.
o Learn Genetics (Univ of Utah) How to Extract DNA From Anything Living
o PBS Nova Extract DNA From a BANANA Recipe (example HERE)
o Scientific American: Find DNA in a BANANA (see picture)
[Great U of Utah resources here: Evolution starts with DNA and Ingredients for evolution: variation, selection and time]
DNA Flow = Gene Flow (e.g. s*xxx)
In 99% of flora and fauna on earth, gene flow is carried forward via the confluence of events known as fertilization by the combination of an egg and sperm. Rare exceptions include slime molds, asexual fungi and 'immaculate conception'.
Researchers can now trace the ancestral carriage of certain genes by examining the frequence of polymorphisms in expressed proteins like ACE, APOE and APOB. APOE (apolipoprotein E) has been particularly interesting to me because of its role in immunity, neurobiology, and lipoprotein/fat/cholesterol metabolism. Modern medicine ignores the role of Apo E and its impact on lab metrics. Many in the paleosphere appear to *LOVE* calculating their LDL using the Iranian formula, however like Friedewald this metric is highly flawed. Not only is the premise for the LDL-heart hypothesis inherently incorrect, humans and other mammalian species do not conform to uniform cookie-cutter lipoprotein patterns.
See prior nephropal: Apo E4, Highest LDL Expression
Human DNA Migration (mtDNA)
Let's return briefly to Douglas Wallace, one of the originators of the mitochondrial medicine model (Wallace DC. Am J Hum Genet. 57:201-223, 1995. Free PDF). The above diagram traces the path of mtDNA following human migration since leaving Africa over 100,000 years ago. I think it will be quite neat later when they can include mtDNA data from the skeletal remains of neanderthals, H. heidelbergensis and H. erectus, our other ancestors.
Apo E4 = Ancestral Allele
(above diagram, see Luduc et al) Apo E4 not only is associated with higher Triglycerides (TG) and LDL cholesterol, but also aboriginal and ancestral hunter-gatherer societies. It is argued but widely accepted that apo E4 is the ancestral allele associated with the far past tightly evolved from our 200,000 YBP (years before present) to 4 million YBP hominid ancestors. Apo E3 showed up and evolved at least 300,000 year ago (found also in Neanderthals, Luduc et al), however apo E2 has only appeared recently according to scientific estimates. Rarely does any Amerindian culture exhibits apoE2 without obvious agrarian European gene flow.
Climate: Hot and Cold Extremes Selected ApoE4
The recipe for evolution and the excelling domination of a certain characteristic (phenotype/genotype) are: variation, time and selection. An increasing frequency of apoE4 has been witnessed along a south-to-north gradient in Europe (e.g.increasing with cold and fatty acid requirements for thermogenesis BAT). For equatorial cultures, on the other hand, a north-to-south contrasting pattern has been fully elucidated (increasing with heat and salt/mineral requirements with losses in sweat). Eisenberg et al (see below diagrams) hypothesizes that extreme climates which require higher cholesterol requirements and temperature regulation contributed to the higher apoE4 incidence. Agrarian practices appear to have initiated the latest allele appearance, apo E2, which is associated with less carbohydrate toxicity/sensitivities and an apparent buffer to modern SAD chronic conditions (mental, metabolic, autoimmunity).
Apo E4 Global Distribution
Carriers of apoE4 are 'survivors' since the dawn of time. In the medical literature, apo E4 has had a lot of attention because of its association with Alzheimer's, dementia, autoimmune disorders, Western SAD chronic conditions and obesity/metabolic syndrome/T2DM.
Highest allele frequency observed in:
--northern Europe (e.g. my hypothesis, Neanderthal clades)
--northern China (Mongolia, ancestral Han)
--southern India (equatorial)
Purpose and Role of ApoE4
Apo E has been associated with protection from infectious disease (diarrhea, viral, bacterial) and perhaps survival in select climate extremes (cold/harsh and hot/equatorial). E4 carriers (2/4, 3/4 or 4/4) exhibit heightened absorption of fat-soluble nutrients and cholesterol from the gut. Singh et al describes apoE4 'has also been proved to be a useful marker for evaluation of biological carriers are more responsive to dietary fats and this could be an advantage when food supplies are scarce or irregular. It is associated with better intestinal absorption of lipids including the fat-soluble vitamins A, D, E and K. This may be the reason that APOE E4 appears to be more common in hunters–gatherers than the long-established agricultural communities, e.g. southern Europe, Southeast Asia and Central America (Gerdes et al. 1996a; Corbo and Scacchi 1999) (Singh et al. Annals of Human Biology, 2006).' ApoE4 guards against cholesterol loss and maintains cholesterol homeostasis and cholinergic integrity in the central nervous system (e.g. brain).
In New Zealand, researchers found a correlation between apoE4, heavy metal toxicity and chronic diseases (chronic fatigue, western diseases, heart disease). After chelation of metals, chronic disease status improved. In the ApoE4 protein structure at position 112 (see Luduc diagram above), arginine occupies the site. In E3 and E2 however cysteine has evolved to occupy position 112. Cysteine has advantages in metal dominant environments.
Godfrey et al explain the variance on heavy metal accumulation by the influence of apoE4 v. E3 v. E2, below.
Isomer ε2 has two cysteineConceivably, IMHO, the ancestral allele allowed hominids and mammals to evolve away from rich marine-mineral sources to northern latitudes and above-sea-level altitudes which were physical terrains and landscapes devoid of and lacking brain/body nutrients: minerals (iodine, mag/calcium, zinc), omega-3 and UVB radiation for skin-synthesized vitamin D3. Our DNA mash-ups and heterogeneity explain not only our current health status but can illuminate the path to physiological recovery of neolethal damage and full health optimization.
amino-acids in its structure, ε3 has one cysteine and
one arginine, and ε 4 has two arginine amino-acids and
no cysteine . Cysteine, with its sulphydryl (-SH)
bonds, is potentially able to bind to, and remove metals
(e.g., mercury and lead) from tissues, whereas arginine,
lacking the -SH bonds, would be unable to do this.
Apo-E genotyping therefore becomes relevant once it
is acknowledged that prolonged exposure to mercury
has been associated with neurotoxicity, including the
pathological histology unique to Alzheimer’s senile
dementia, namely, ﬁbrillary tangles, amyloid plaques and
increased phosphorylation of tau protein [12,27,28,32].
See prior nephropal: Survival of the PHAT-est
1. Influence of apolipoprotein E genotype on the reliability of the Friedewald formula in the estimation of low-density lipoprotein cholesterol concentrations.
Tremblay AJ, Bergeron J, Gagné JM, Gagné C, Couture P.
Metabolism. 2005 Aug;54(8):1014-9.
** Iranian (for apoE2, inherently low TGs) v. Friedwald (for wildtype apoE3). See resource. **
2. The apolipoprotein E polymorphism: a comparison of allele frequencies and effects in nine populations. Free PDF.
Hallman DM, Boerwinkle E, Saha N, Sandholzer C, Menzel HJ, Csázár A, Utermann G.
Am J Hum Genet. 1991 Aug;49(2):338-49.
3. The effect of apoE genotype and sex on ApoE plasma concentration is determined by dietary fat in healthy subjects. (Email me for PDF)
Moreno JA, Pérez-Jiménez F, Moreno-Luna R, Pérez-Martínez P, Fuentes-Jiménez F, Marín C, Portugal H, Lairon D, López-Miranda J.
Br J Nutr. 2009 Jun;101(12):1745-52.
4. Apolipoprotein E isoform phenotype and LDL subclass response to a reduced-fat diet. Free PDF. [Higher LDL-IVb 'death band' with 'low fat diet']
Dreon DM, Fernstrom HA, Miller B, Krauss RM.
Arterioscler Thromb Vasc Biol. 1995 Jan;15(1):105-11.
5. Carbohydrate intake, serum lipids and apolipoprotein E phenotype show association in children.
Ruottinen S, Rönnemaa T, Niinikoski H, Lagström H, Saarinen M, Pahkala K, Kaitosaari T, Viikari J, Simell O.
Acta Paediatr. 2009 Oct;98(10):1667-73.
6. Apolipoprotein E genotyping as a potential biomarker for mercury neurotoxicity. Free PDF.
Godfrey ME, Wojcik DP, Krone CA.
J Alzheimers Dis. 2003 Jun;5(3):189-95.
7. Function and Comorbidities of Apolipoprotein E in Alzheimer's Disease. Free PDF
Valérie Leduc, Dorothée Domenger, Louis De Beaumont, Daphnée Lalonde, Stéphanie Bélanger-Jasmin, and Judes Poirier
Int J Alzheimers Dis. 2011; 2011: 974361.
8. Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history. (Email me for PDF)
Eisenberg DT, Kuzawa CW, Hayes MG.
Am J Phys Anthropol. 2010 Sep;143(1):100-11.