Wednesday, June 22, 2011

Ancestral Allele ApoE4: Super Brain Power, Fertility, Lipophilic Immunity

Ancestral Nutrition: The Imperfect Diet Cleaves Adaptive Genetic Polymorphisms

Hat tip to B. Pottenger for the latest science daily (HERE) on the importance of ancestral, customized nutrition for our health. Chilton et al found desaturase/FADS variants in African Americans which take medium chain n-6 PUFAs (polyunsaturated fatty acids) and convert them into long chain n-6 PUFAs, like arachidonic acid which may increase systemic inflammation. They purport this may explain the inordinate increase in Western diseases observed in African Americans who display a certain FADS genotype variant for fatty acid disposal when they eat the high n-6 PUFA Western diet, including prostate cancer, diabetes, diabetic complication, heart attacks, obesity and dementia/Alzheimers. [I edited the last post -- continental Africans also have a high rate of apoE4 in addition to current hunter-gatherer groups in Africa.]

ApoE4, The Ancestral Allele = Carnivorous and Fatty Acid-Adaptive Allele

It is clear that our ancient hominid predecessors had something special that allowed them to leave Africa ~2 mya and navigate the terrain and uncertain food, energy and climate allotments. Like others I subscribe to the marine hypothesis (Cunnane SC) that certain brain nutrients are essential for IQ and brain function. Both Cunnane and Jonathon CK Wells writes about the 'fattiness' of the human brain and how this factored into our brain evolution and global domination of every potential ecological niche... not withstanding the moon and interplanetary travel as well. Wells' book 'The Evolutionary Biology of Human Body Fatness: Thrift and Control' details the fats that built our history and brains.

A couple evolutionary biologists also assert that the APOE4 allele is our 'meat-adaptive' gene. Well. This makes sense to a finite degree however no research that I could find illustrates apoE increasing proteins into the brain or digestion... On the other hand, the research is highly demonstrative of apoE4 increasing FATTY ACIDS into our brains, mitochondrial metabolism and enhancement of neural efficiency.

My view:
apoE4 -- Infiniti of cars (same Nissan engine), running on super premium fuel (ancestral allele)
apoE3 -- Nissan Maxima (wild type allele), runs both regular and premium fuels
apoE2 -- Nissan Sentra, on regular unleaded (agarian allele??)
apoE combos -- Prius hybrids (phenotype varying by degrees)

One change of the protein structure of apoE at the 61 spot from T to R/arginine may have set the stage for evolution of other nervous system and housekeeping genes that not only grew a superior engine in the brain but also the chassis/architecture of our hard drives. The ancestral apoE4 allels may be one among several genetic variations that sets us vastly apart from our not so distant primate past.

Super Brain Power + Super Brain Fuel

Though in the medical literature is rife with negative associations between apoE4 and a variety of conditions, my observations are that in those who exhibit high LDLs appear to display the most supreme levels of super-healing and extraordinary intelligence. See Hyperlipid (Peter D. for studies where high LDL associated with positive improvements and longevity, HERE J-LITT. Please also review the neurobio series on Alzheimer's by the wonderful Emily D. at Ev Psych and how low cholesterol is associated with lower cognition HERE.

As you can see from Mahley and Rall's 2000 publication, LDL sharply corresponds to apoE status. E4, the highest; E2, the lowest LDL. Do most cardiologists know this as they prescribe cookie-cutter NCEP/ATPIII-aligned statins? Please.

The density of the LDL determines its function. Small dense is damaging. For E4, dietary carbohydrates and dietary deficiencies of saturated fat dramatically shape and create small, dense, harmful LDL particles. The only rare cases of coronary calcification improvement on EBCT at a coronary heart website were the uncommon participant on a lower carb, HIGH SATURATED FAT intake. E4 appear exquisitely more sensitive to diet, exercise, fats/carbs and environmental toxicants.

Mondadori et al used new technology fMRIs to brain scan young chess-playing individuals and compared their the apoE status. The apoE4 showed increased memory, retrieval, neuropsychology and apparently neural efficiency. E4 indeed appear to run their brains on better fuel, e.g. fatty acids, the currency of nervous system cells.

Why is this not observed in E4 carriers in older age in the industrial populations? In the prior post, researchers discussed how the cysteine amino acid is lacking in E4, at the 112 site. E2 has 2 cysteine's per allele; E3, 1 cysteine; E4, N-O-N-E. This protein conformation apparently stupendously reduces the capacity for apoE to shuttle trace metals out of nervous system tissues. Many enzymes regulate and control metals in the brain however having the E4 allele is like a neuronal death sentence in a world that is contaminated by metals, not excluding one's own oral cavity. Sources of neolethal metal: dental amalgams (50% are mercury which gas off), stents, ortho/dental implants, well water, water purification at municipal plants (alum/Al), lead from leaded fuel/diesel, copper piping, fish intake (the EPA advises pregnant women limit fish, shouldn't we non-pregnant as well?), vaccines (Hep B, flu, whooping cough, Td, etc) and broken Hg thermometers.

Super Fertility = (Pre-Industrial) ApoE4 Populate the World

The literature abounds with cases of higher infertility in apoE4 women. FYI All literature needs to be viewed from an evolutionary perspective and in this context the great majority of these studies for me only demonstrate that the Western diet/lifestyle are particularly adverse to the hunter-gatherer types who carry the E4 allele. If a person carries the E4, then consuming an anti-HG diet (e.g. refined, non-ancestral), then the preponderance of small dense, oxidizable LDL and a hyperactive immune system which searches and scars, yes of course, will result in higher rates of infertility, fibroids, ovarian cysts, PCOS and less pregnancies, as countless PubMed articles report.

One study looked at HG super fertility... In African-Ecuadorians and a HG group, Capaya Indians, indeed the # of gestations and pregnancies were astoundingly higher in E4 carrier women. See citation below Corbo et al. They hypothesize that higher rates of sex hormone steroidogenesis can potentially occur with the E4 genotype.

My own family may also be a prime example. On low carb, mod-high sat fat, my LDLs are greater than 130s which is 'high' for the medical establishment, EVEN THOUGH THE HDL-CHOLESTEROL ECLIPSES THE S.A.D. HDL for women at 105 mg/dl. Both my father and stepmother's side each have 12 children (with 1-2 nonsurviving siblings). How is this humanly possible, as a mom, I used to WONDER OUT LOUD IN HORROR. I think Catholic families might relate... I could have a litter kids if I didn't have a brakestop. My parents and step mother are from an ancient nomadic group (Hakka, part of Han) and in all likelihood harbor the E4 allele somewhere, as my LDLs my appear to indicate. Each of my siblings and I (4 total) have had an autoimmune disorder and are somewhat sensitive to modern pollution and toxicants (gluten, dairy/casein, medications, and sulfa-, nickel-, metal-allergies).

Super Immunity

In a seminal article in PNAS, Caleb Finch's 'Evolution of the human lifespan and diseases of aging: Roles of infection, inflammation, and nutrition' talks about how humans evade infections and the role of apoE4. As a carnivorous creature, hominids had access to ingestion of better protein, trace minerals and fats. The apoE system shuttles cholesterol and the contents of LDL and HDL particles into nervous system tissues (iodine, zinc, tocopherols, ubiquinone, vit K2, etc).

By absorbing fats from the intestines quickly, this sequesters fat from parasites, bacteria and other pathogens. It is believed this might be one mechanism of super immunity which is observed in E4 carriers. Finch and Stanford (QJB, 2004) report 'In chronic infections by hepatitis C virus (HCV), apoE4 carriers had milder liver disease (Wozniak et al. 2002). The protection against HCV by apoE4 is consistent with the role of lipoproteins in transmission of HCV and other viruses (Wozniak et al. 2002), and fulfills hypotheses that apoE4 is a resistance factor for lipophilic parasites (Martin 1999) and that apoE4 confers advantages in early life (Charlesworth 1996). ApoE may also influence infections by other viruses and by prions, but the evidence is less clear (Table 3, Note 1d and Appendix).'

Human Migration: Evolution of Machinery to Convert Saturated Fat into Omega-3 PUFAs

How did humans go so far north, such high altitudes where seemingly harsh climate and terrains existed? Many SNP variants have apparently evolved which helped our ancestors thrive and live very full lives in certain microecological niches on earth. One thing that has baffled me to know end is the apparent n-3 pufa sources in northern Europe, Africa or northern China as hominids moved there 200,000 years ago. The FADS gene clusters of polymorphisms definitely explains a lot as to how the delta 5 and 6 desaturases control elongation of fatty acids to the ever important essential brain nutrient n-3 pufa.

Terrestrial Brain nutrient allocation and Adaptation from Sahara marine-sources (hypothesis):
EPA DHA n-3 pufa: ???! from where, ?megafauna and small animal predation
ALA n-3 pufa: wild greens
Iodine: ApoE4, possible iodine-oral cavity cellular conservative adaptations, polymorphs of MT1,2,3
Zinc: ApoE4
Magnesium: ApoE4
Taurine: Raw megafauna hunt successes, small animals, fish/seafood from local rivers/tributaries
UVB induced vitamin D: grubs, lighter eyes, lighter skin, melanin reduction, megafauna livers
Red wine: j/k

In a prospective human intervention trial, Dabadie et al gave myristic acid, a 14 carbon SATURATED FATTY ACID, to humans and showed an increase and significant enrichment of DHA, omega-3 pufa, in tissues. The authors later performed another study, increasing the myristic and giving ALA and found a J- or U-shaped curve where less DHA changes were seen at higher saturated fat intakes.

I think this is the first and only study that I could find where saturated fat can be under the influences of our desaturases to produce and synthesize a necessary and essential brain long-chain omega-3. Lard is 1% myristic, the head oil of sperm whale 15% and dairy fat 10%.


1. The impact of FADS genetic variants on ω6 polyunsaturated fatty acid metabolism in African Americans. Mathias RA, Sergeant S, Ruczinski I, Torgerson DG, Hugenschmidt CE, Kubala M, Vaidya D, Suktitipat B, Ziegler JT, Ivester P, Case D, Yanek LR, Freedman BI, Rudock ME, Barnes KC, Langefeld CD, Becker LC, Bowden DW, Becker DM, Chilton FH.
BMC Genet. 2011 May 20;12:50.

Simopoulos AP.
Exp Biol Med (Maywood). 2010 Jul;235(7):785-95.

3. A 'desaturase hypothesis' for atherosclerosis: Janus-faced enzymes in omega-6 and omega-3 polyunsaturated fatty acid metabolism.
Martinelli N, Consoli L, Olivieri O.
J Nutrigenet Nutrigenomics. 2009;2(3):129-39.

4. Apolipoprotein E polymorphism and fertility: a study in pre-industrial populations.
Corbo RM, Ulizzi L, Scacchi R, Martínez-Labarga C, De Stefano GF. Free PDF.
Mol Hum Reprod. 2004 Aug;10(8):617-20.

5. n-3 Fatty acid erythrocyte membrane content, APOE varepsilon4, and cognitive variation: an observational follow-up study in late adulthood. Free PDF. [This will be discussed later (someday). N-3 is a surrogate for mercury toxicity via fish/seafood consumption esp in apoE4 who hoard/harbor trace metals.]
Whalley LJ, Deary IJ, Starr JM, Wahle KW, Rance KA, Bourne VJ, Fox HC.
Am J Clin Nutr. 2008 Feb;87(2):449-54.

6. Moderate intake of myristic acid [MEDIUM CHAIN SATURATED FAT] in sn-2 position has beneficial lipidic effects and enhances DHA [OMEGA-3 PUFA] of cholesteryl esters in an interventional study [HUMAN].
Dabadie H, Peuchant E, Bernard M, LeRuyet P, Mendy F.
J Nutr Biochem. 2005 Jun;16(6):375-82.

7. Omega-3 fatty acid docosahexaenoic acid increases SorLA/LR11, a sorting protein with reduced expression in sporadic Alzheimer's disease (AD): relevance to AD prevention. Free PDF.
J Neurosci. 2007 Dec 26;27(52):14299-307.

8. Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers. Free PDF.
Mondadori CR, de Quervain DJ, Buchmann A, Mustovic H, Wollmer MA, Schmidt CF, Boesiger P, Hock C, Nitsch RM, Papassotiropoulos A, Henke K.
Cereb Cortex. 2007 Aug;17(8):1934-47.

9. Superior performance [CHESS PLAYING/STRATEGIZING] and neural efficiency: the impact of intelligence and expertise.
Grabner RH, Neubauer AC, Stern E.
Brain Res Bull. 2006 Apr 28;69(4):422-39.

10. Evolution in health and medicine Sackler colloquium: Evolution of the human lifespan and diseases of aging: roles of infection, inflammation, and nutrition. Free PDF.
Finch CE.
Proc Natl Acad Sci U S A. 2010 Jan 26;107 Suppl 1:1718-24.

11. Accelerated evolution of nervous system genes in the origin of Homo sapiens. Free PDF.
Cell. 2004 Dec 29;119(7):1027-40.

12. Apolipoprotein E: far more than a lipid transport protein. Free PDF.
Mahley RW, Rall SC Jr.
Annu Rev Genomics Hum Genet. 2000;1:507-37.

13. Meat-adaptive [URRG fat adaptive] genes and the evolution of slower aging in humans. Free PDF.
Finch CE, Stanford CB.
Q Rev Biol. 2004 Mar;79(1):3-50. Review.

Wednesday, June 15, 2011

Human DNA Migration and How to Extract DNA From a Banana

Nelly Furtado Mash-Up

DNA Mash-Ups

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.

Cetus Corp

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)
--Aboriginal/hunter-gatherer subpopulations

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 cysteine
amino-acids in its structure, ε3 has one cysteine and
one arginine, and ε 4 has two arginine amino-acids and
no cysteine [6]. 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].
Conceivably, 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.

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.