Possible New Support of "
Androgens in Human Evolution:" DHEA, Mitochondrial Gene ATP6, and Leigh's Syndrome (Disease)Copyright 2004, James Michael Howard, Fayetteville, Arkansas, U.S.A.
It is my hypothesis that human evolution was directly affected by testosterone and dehydroepiandrosterone (DHEA). Of importance to this treatise is that I think DHEA was directly involved in survival of hominids / humans because of the ability of DHEA to enhance thermogenesis. Therefore, DHEA would become more important for survival in individuals living in cold environments. Increased selection pressure for DHEA in surviving individuals may have affected the mitochondrial mutation rate and changed their mitochondrial DNA appropriately. This is the point of possible support.
Mishmar, et al., report "…ATP6 gene [in human mitochondria] had the highest amino acid sequence variation of any human mtDNA gene, even though ATP6 is one of the more conserved mtDNA proteins." (Proceedings of the National Academy of Sciences U S A. 2003 Jan 7;100(1):171-6. Abstract at bottom of this treatise.) Berdanier, et al., demonstrated a connection of DHEA with mitochondrial ATP6: "Work with primary cultures of hepatocytes showed that not only does retinoic acid increase mitochondrial ATPase 6 [same as ATP6] gene expression but so too does the steroid hormone intermediate, dehydroepiandrosterone (DHEA)." (Diabetes Research and Clinical Practice 2001 Dec;54 Suppl 2:S11-27). I suggest these two citations add support to my thesis that DHEA was / is involved in human evolution.
Now, I was doing some literature search concerning "ATP6" and happened onto "Leigh's Syndrome or Disease," an entity which I had considered in the past may be due to low DHEA. Well, as it turns out, Leigh's Disease is characterized by a mutation in the mitochondrial gene, ATP6, the gene that increased by DHEA (foregoing paragraph).
"The mutation in the mitochondrial ATP synthase subunit 6 gene (ATP6 T8993G) was identified in a male infant who died at age 15 months of Leigh syndrome. He had 94% mutated mitochondrial DNA (mtDNA) in muscle and 92% in lymphocytes." (Hum Genet. 1995 Sep;96(3):290-4).
"Leigh syndrome is a heterogeneous neurologic disease characterized by seizures, developmental delay, muscle weakness, respiratory abnormalities, optic abnormalities, including atrophy and ophthalmoplegia, and progressive cranial nerve degeneration with early onset in infants and children. Diagnosis can be confirmed by characteristic pathologic findings of necrosis in the basal ganglia, thalamus, and brainstem. Severe dysfunction of mitochondrial energy metabolism is generally present and involved in the etiology of this degenerative central nervous system disease. At the molecular level, a number of point mutations have been located in mitochondrial DNA genes, including ATPase6 and tRNA(Lys) genes, and in nuclear genes encoding subunits of oxidative enzymes, such as pyruvate dehydrogenase. Biochemically these mutations are responsible for enzymatic defects in either respiratory complexes (I, IV, or V) or pyruvate dehydrogenase. We describe here the first case of Leigh syndrome with marked depletion of mitochondrial DNA levels in skeletal muscle and abnormal activities in skeletal muscle of mitochondrial respiratory complexes I, III, IV, and V." (Pediatr Neurol. 2002 Mar;26(3):239-42).
A source on the internet (http://www.diseasedir.org.uk/genetic/mt01.htm ) states that the pathology of Leigh Syndrome is "Leigh Syndrome generally results in Brain damage, through the degredation of brain neurones. Liver and Heart are sometimes affected. Neurones are often demyelinated (myelin is a sheath covering nerves which allow the nerve impulse to travel faster)." It is part of my work that DHEA positively affects all tissues, especially nervous tissues, especially the brain. Therefore, I suggest the lack of interaction of DHEA with ATPase6 of mitochondria may produce the brain damage of Leigh's. The following citation shows that treatment with DHEA "DHEA-treated nerves had significantly more myelinated axons, larger average fiber diameter, and greater axonal cross-sectional areas in the proximal, middle, and distal sections. Myelin thickness did not differ between groups, except at 6 weeks between the DHEA and vehicle-treated groups. We conclude that subepineurial dehydroepiandrosterone treatment reduced the extent of denervation atrophy and induced an earlier onset of axonal regeneration." (Microsurgery 2003; 23: 49-55, abstract just below.) Another source of regarding pathogenesis of Leigh's states that Leigh's might begin in late adolescence or early adulthood. This is the same time and pattern that often occurs in the onset of schizophrenia, another disease that I suggest results from low DHEA (look for "schizophrenia" at www.anthropogeny.com/physiology.html ). Also, Leigh's symptoms "usually begin between the ages of 3 months and 2 years," a time when DHEA levels are unusually low. Pyruvate hydrogenase deficiency has also been linked to Leigh's disease and some treatments (soybean oil) designed around PDH deficiency have demonstrated some amelioration (E. J. Neurology 1999; 6: 613). Soy stimulates DHEA. Well, a study was done which found "…marked enhancement of T-lymphocyte pyruvate dehydrogenase activities in both groups of study subjects following DHEA." (J Soc Gynecol Investig 1994; 1: 74-8) It appears that substances that stimulate DHEA (soy) and DHEA, alone, may be beneficial in Leigh's Disease. I suggest this may be worth considering. Anyway, these children have no real treatment and face a short life span characterized by a devastating course. I suggest DHEA should be tried as a treatment for these children.
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Microsurgery. 2003; 23(1): 49-55. |
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Proceedings of the National Academy of Sciences U S A. 2003 Jan 7; 100(1): 171-6.
Natural selection shaped regional mtDNA variation in humans.
Mishmar D, Ruiz-Pesini E, Golik P, Macaulay V, Clark AG, Hosseini S, Brandon M, Easley K, Chen E, Brown MD, Sukernik RI, Olckers A, Wallace DC.
Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, 92697-3940, USA.
Human mtDNA shows striking regional variation, traditionally attributed to genetic drift. However, it is not easy to account for the fact that only two mtDNA lineages (M and N) left Africa to colonize Eurasia and that lineages A, C, D, and G show a 5-fold enrichment from central Asia to Siberia. As an alternative to drift, natural selection might have enriched for certain mtDNA lineages as people migrated north into colder climates. To test this hypothesis we analyzed 104 complete mtDNA sequences from all global regions and lineages. African mtDNA variation did not significantly deviate from the standard neutral model, but European, Asian, and Siberian plus Native American variations did. Analysis of amino acid substitution mutations (nonsynonymous, Ka) versus neutral mutations (synonymous, Ks) (kaks) for all 13 mtDNA protein-coding genes revealed that the ATP6 gene had the highest amino acid sequence variation of any human mtDNA gene, even though ATP6 is one of the more conserved mtDNA proteins. Comparison of the kaks ratios for each mtDNA gene from the tropical, temperate, and arctic zones revealed that ATP6 was highly variable in the mtDNAs from the arctic zone, cytochrome b was particularly variable in the temperate zone, and cytochrome oxidase I was notably more variable in the tropics. Moreover, multiple amino acid changes found in ATP6, cytochrome b, and cytochrome oxidase I appeared to be functionally significant. From these analyses we conclude that selection may have played a role in shaping human regional mtDNA variation and that one of the selective influences was climate.