Category: GenoType Diet
More 'damned data' (Charles Fort's words, not mine): studies from the scientific literature which could pass for some of the more outlandish statements in The GenoType Diet:
The phenotype of an individual is the result of complex interactions between genotype, epigenome and current, past and ancestral environment, leading to lifelong remodelling of our epigenomes. Various replication-dependent and -independent epigenetic mechanisms are involved in developmental programming, lifelong stochastic and environmental deteriorations, circadian deteriorations, and transgenerational effects. Several types of sequences can be targets of a host of environmental factors and can be associated with specific epigenetic signatures and patterns of gene expression. Depending on the nature and intensity of the insult, the critical spatiotemporal windows and developmental or lifelong processes involved, these epigenetic alterations can lead to permanent changes in tissue and organ structure and function, or to reversible changes using appropriate epigenetic tools. Given several encouraging trials, prevention and therapy of age- and lifestyle-related diseases by individualised tailoring of optimal epigenetic diets or drugs are conceivable. However, these interventions will require intense efforts to unravel the complexity of these epigenetic, genetic and environment interactions and to evaluate their potential reversibility with minimal side effects.
Nutri-epigenomics: lifelong remodelling of our epigenomes by nutritional and metabolic factors and beyond. Clin Chem Lab Med. 2007;45(3):321-7
Epigenomics or epigenetics refers to the modification of DNA that can influence the phenotype through changing gene expression without altering the nucleotide sequence of the DNA. Two examples are methylation of DNA and acetylation of the histone DNA-binding proteins. Dietary components - both nutrients and nonnutrients - can influence these epigenetic events, altering genetic expression and potentially modifying disease risk. Some of these epigenetic changes appear to be heritable. Understanding the role that diet and nutrition play in modifying genetic expression is complex given the range of food choices, the diversity of nutrient intakes, the individual differences in genetic backgrounds and intestinal physiological environments where food is metabolized, as well as the impact on and acceptance of new technologies by consumers.
Epigenomics and nutrition. Forum Nutr. 2007;60:31-41.
Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables, such as broccoli and broccoli sprouts. This anticarcinogen was first identified as a potent inducer of Phase 2 detoxification enzymes, but evidence is mounting that SFN also acts through epigenetic mechanisms. SFN has been shown to inhibit histone deacetylase (HDAC) activity in human colon and prostate cancer lines, with an increase in global and local histone acetylation status, such as on the promoter regions of P21 and bax genes. SFN also inhibited the growth of prostate cancer xenografts and spontaneous intestinal polyps in mouse models, with evidence for altered histone acetylation and HDAC activities in vivo. In human subjects, a single ingestion of 68 g broccoli sprouts inhibited HDAC activity in circulating peripheral blood mononuclear cells 3-6 h after consumption, with concomitant induction of histone H3 and H4 acetylation. These findings provide evidence that one mechanism of cancer chemoprevention by SFN is via epigenetic changes associated with inhibition of HDAC activity. Other dietary agents such as butyrate, biotin, lipoic acid, garlic organosulfur compounds, and metabolites of vitamin E have structural features compatible with HDAC inhibition. The ability of dietary compounds to de-repress epigenetically silenced genes in cancer cells, and to activate these genes in normal cells, has important implications for cancer prevention and therapy. In a broader context, there is growing interest in dietary HDAC inhibitors and their impact on epigenetic mechanisms affecting other chronic conditions, such as cardiovascular disease, neurodegeneration and aging.
Dietary histone deacetylase inhibitors: from cells to mice to man. Semin Cancer Biol. 2007 Oct;17(5):363-9. Epub 2007 May 5
The purpose of this paper was to selectively review the literature on the role of epigenetics in mental illnesses. Aberrant epigenetic regulation has been clearly implicated in the aetiology of some human illnesses. In recent years a growing body of evidence has highlighted the possibility that epigenetics may also play a key role in the origins and expression of mental disorders. Epigenetic phenomena may help explain some of the complexity of mental illnesses and provide a basis for discovering novel pharmacological targets to treat these disorders.
Role of epigenetics in mental disorders. Aust N Z J Psychiatry. 2008 Feb;42(2):97-107.
A complex combination of adult health-related disorders can originate from developmental events that occur in utero. The periconceptional period may also be programmable. We report on the effects of restricting the supply of specific B vitamins (i.e., B(12) and folate) and methionine, within normal physiological ranges, from the periconceptional diet of mature female sheep. We hypothesized this would lead to epigenetic modifications to DNA methylation in the preovulatory oocyte and/or preimplantation embryo, with long-term health implications for offspring. DNA methylation is a key epigenetic contributor to maintenance of gene silencing that relies on a dietary supply of methyl groups. We observed no effects on pregnancy establishment or birth weight, but this modest early dietary intervention led to adult offspring that were both heavier and fatter, elicited altered immune responses to antigenic challenge, were insulin-resistant, and had elevated blood pressure-effects that were most obvious in males. The altered methylation status of 4% of 1,400 CpG islands examined by restriction landmark genome scanning in the fetal liver revealed compelling evidence of a widespread epigenetic mechanism associated with this nutritionally programmed effect. Intriguingly, more than half of the affected loci were specific to males. The data provide the first evidence that clinically relevant reductions in specific dietary inputs to the methionine/folate cycles during the periconceptional period can lead to widespread epigenetic alterations to DNA methylation in offspring, and modify adult health-related phenotypes.
DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19351-6. Epub 2007 Nov
Major efforts have been directed towards the identification of genetic mutations, their use as biomarkers, and the understanding of their consequences on human health and well-being. There is an emerging interest, however, in the possibility that environmentally-induced changes at levels other than the genetic information could have long-lasting consequences as well. This review summarises our current knowledge of how the environment, nutrition, and ageing affect the way mammalian genes are organised and transcribed, without changes in the underlying DNA sequence. Admittedly, the link between environment and epigenetics remains largely to be explored. However, recent studies indicate that environmental factors and diet can perturb the way genes are controlled by DNA methylation and covalent histone modifications. Unexpectedly, and not unlike genetic mutations, aberrant epigenetic alterations and their phenotypic effects can sometimes be passed on to the next generation.
Environmental and nutritional effects on the epigenetic regulation of genes. Mutat Res. 2006 Aug 30;600(1-2):46-57. Epub 2006 Jul 18
The British biologist Conrad Hal Waddington conceived of genotype (your genetic plan) passing through environment into phenotype (the physical you) as a walk through an 'Epigenetic Landscape'. He conceived a mode of visualizing this process, in which phenotype development is seen as marbles rolling downhill. In the beginning development is plastic, and a cell can become many fates. However, as development proceeds, certain decisions cannot be reversed. This Landscape has hills, valleys, and basins and marbles compete for the grooves on the slope, and eventually coming to rest at the lowest points, which represent the eventual types of tissues they become.
The Epigenetic Landscape. (After Waddington, C. H., 1956, Principles of Embryology)
Waddington was a big thinker. Not only did he visualize development as passing through the peaks, slopes and valleys of the Epigenetic Landscape, he considered this process one of increasing constraint, or as being "canalizedâ€? as he referred to it: That the early choices influence the later options. If we think of the canals of Venice, the analogy works even better; our little gondola floats from one canal into another and then another. Each choice leaves it fewer options than before, and since gondolas need water, so we can't just pick it up and put plunk it into another canal.
Now just for a moment visualize a newly fertilized egg. It already contains all the wisdom and information needed to eventually go on to produce a completely formed human being in its DNA, but over time it must develop various cell lines (called germ layers) that can then go off and further distinguish themselves as arteries, nerves and organs. Its unfolding is stochastic (a process that is non-deterministic in the sense that the current state state does not fully determine its next state.).
"Stochastic" is one of those great words that is more often misunderstood than understood. It is often quoted as being synonymous with random, but the actual Greek seems to imply something closer to "unknowable." It's often used in the arts (very often in music composition.)
In short: We know it's going to happen; we just don't know what is going to happen.
Your journey from genetic imprinting (the genes that were determined at conception) to full phenotype (the physical you) is to a great degree a stochastic process. which is why Waddington's metaphor is so great. Any architect will tell you that a house almost never winds up like that original plans. Environmental variables (cost of materials, availability) alter reality as the construction project moves from one stage to the other. We cannot always predict the eventual outcome, but we can describe and learn about the landscape in which it takes place and that, to a degree allows us to understand things.
Hindsight is always 20/20, because the outcome almost always describes the process.
That journey started long before your conception, since epigenetic gene control is hereditable.
You are in essence, not what you eat, but rather what your parents, grand parents and even great grandparents ate. Unlike defective genes, which are damaged for life, epigenetically controlled genes can be repaired. And, activation and silencing tags that are knocked off can be regained via nutrients, drugs, and enriching experiences. (1)
Conceivably the cancer you may get today may have been caused by your grandmother's exposure to an industrial poison 50 years ago, even though your grandmother's genes were not changed by the exposureâ€¦ or the mercury you're eating today in fish may not harm you directly, but may harm your grandchildren (2)
These inherited traits can continue to influence the onset of diseases like diabetes, obesity, mental illness and heart disease, from generation to generation.
All in all, the next few years should prove most interesting...
The post-genomic era, which is fueled by automation and other technologies, provokes a change in our grossly naive view of genetic determinism (that single genes govern complex traits) to the obvious reality that most human diseases are complex entities. Gene(s), although necessary, contribute only partially to disease, while environmental factors, lifestyles, epigenetics and epistasis significantly influence pathophysiology and, eventually, the expression of transient biomarkers that can be utilized for diagnosis and prognosis. Human osteoarthritis and rheumatoid arthritis are multifactorial, complex diseases. The genetic inheritance of these diseases remains elusive, although they tend to run in families wherein some siblings have a two- to tenfold increased risk of developing the diseases.
From: Future of genomics in diagnosis of human arthritis: the hype, hope and metamorphosis for tomorrow
Ashok R Amin?, Seth D Thompson? & Shailey A Amin
August 2007, Vol. 2, No. 4, Pages 385-389
Epigenetic alterations have been known to be of importance in cancer for ~2 decades. This has made it possible to decipher epigenetic codes and machinery and has led to the development of a new generation of drugs now in clinical trials. Although less conspicuous, epigenetic alterations have also been progressively shown to be relevant to common diseases such as atherosclerosis and type 2 diabetes. Imprinted genes, with their key roles in controlling feto-placental nutrient supply and demand and their epigenetic lability in response to nutrients, may play an important role in adaptation/evolution. The combination of these various lines of research on epigenetic programming processes has highlighted new possibilities for the prevention and treatment of metabolic syndrome.
From: Nutritional Epigenomics of Metabolic Syndrome
Catherine Gallou-Kabani, and Claudine Junien
Diabetes 54:1899-1906, 2005
1. Asim K. Duttaroy Evolution, Epigenetics, and Maternal Nutrition 2006 Darwin Day Celebration.
2. Montague T. A New Way to Inherit Environmental Harm. Synthesis/Regeneration 39 (Winter 2006)
From Percept Mot Skills. 2008 Dec;107(3):737-46.
Twin and family study findings indicate a substantial heritability of digit ratio (2D:4D), a putative marker for the masculinizing effects of prenatal androgen exposure. Functional polymorphisms of the X-linked androgen receptor gene, i.e., androgen sensitivity, contribute somewhat to the expression of 2D:4D in men, but otherwise the genetics of 2D:4D is unknown. This study investigated differences in 2D:4D by self-reported ABO blood type and Rhesus factor, two easily collectible genetic traits, in two samples (combined N=1273). Effects of blood groups on 2D:4D were small and not significant in all tests in both samples; however, two consistent patterns emerged across samples. Of the ABO types, AB had the lowest right-hand 2D:4D, the highest left-hand 2D:4D, and the lowest right-minus-left difference in 2D:4D, and Rhesus factor Rh- had higher left-hand 2D:4D and lower right-minus-left difference in 2D:4D than Rh+. If replicable, this may suggest genes contributing to the expression of 2D:4D reside in the vicinity of the gene loci (chromosomal locations: 9q34.2 and 1p36.11) of these blood groups or pleiotropic effects of the blood-group genes.
As if I needed further convinced that epigenetics (the control of gene expression through nutrition) is the great wave of the future, a pre-publication results of a study released to members of The Epigenetic Society should satisfy for quite a while.
In a study soon to be published in the Journal Biological Psychiatry, researchers looked at the epigenetic effects of childhood maltreatment and early trauma. Using laboratory rats (whose epigenetic mechanisms are very similar to humans) the researchers exposed infant rats to stressed caretakers who predominately displayed abusive behaviors.
They found that early maltreatment produced persistent changes in the methylation of a gene called BDNF (brain derived neurotrophic factor) that is responsible for the developmental health of the cerebral cortex.
In addition, they observed disturbed BDNF methylation in the offspring of females that had previously experienced the maltreatment regimen, indicating that the epigenetic effects of abuse, trauma and neglect were carried from one generation to the next.
The GenoType Diet carries the promise of a genetic redemption of sorts, since as in the words of one researcher “Unlike defective genes, which are damaged for life, methylated genes can be demethylated. And, methyl tags that are knocked off can be regained via nutrients, drugs, and enriching experiences.” (2)
- Tania L. Roth TL, Farah D. Lubin FD, Adam J. Funk and J. David Sweatt. Lasting Epigenetic Influence of Early-life Adversity on the BDNF Gene. Biological Psychiatry, In Press
- Asim K. Duttaroy Evolution, Epigenetics, and Maternal Nutrition 2006 Darwin Day Celebration.
The New York Times had an extensive discussion of epigenetics in their February 24 issue:
The ideal of regenerative medicine is to convert a patient’s normal body cells first back into the embryonic state, and then into the specific cells lost to disease. But to prepare such cells safely and effectively, researchers will probably need to learn how to control and manipulate the chromatin of the epigenome as well as the transcription factors that shape cell identity.