Everything You Need to Know about Epigenetics
We've discussed epigenetics before -- for example, back in 2007 when we talked about how the dietary and environmental choices we make today affect our children…and their children. And now it seems, that almost every day, scientists are discovering how prominent a role epigenetics -- alterations in the way genetic traits express themselves without any changes in the DNA sequence itself -- play in almost every aspect of our health. A recent study, for example, has found that your place in society's pecking order causes epigenetic changes that make you more or less likely to die of a heart attack. Whereas a different study out of Stanford found that your lifestyle choices (what you eat and how much you eat) play a major role in determining the health and longevity of our offspring. Steadily, over the last decade, epigenetics has emerged from an obscure discovery of questionable importance to possibly the dominant player in our genetic make-up -- and thus, our health, longevity, and susceptibility to the major diseases of old age. Pretty important! With that in mind, we're going to take a look at genetics (the things you can't control) and epigenetics (the things you can) so as to understand the importance of the choices you make.
A chromosome is a threadlike molecular strand of DNA and its associated proteins in the nucleus of cells that carries the genes and functions that transmit our hereditary information. Each nucleus in each of the 60-90 trillion cells in your body contains 46 such chromosomes --23 from your mother paired up with 23 from your father. 22 of those pairs (44 chromosomes) are "developmental." And one pair (the XX or XY pair) determines sex. What makes chromosomes especially interesting is that they're not always present. They literally "gather together" out of DNA just before a cell divides, then dissipate once the division is complete. But even though they are transient, they are virtually identical every time they form. In other words, the chromosomes in your body are unique to you and are always identical to each other (give or take) across every cell in your body, whenever they take form before cell division.
Look inside the chromosomes and you'll see that each one is made of bundles of looping coils of DNA (deoxyribonucleic acid). DNA is an extremely long macromolecule that is the main component of chromosomes. It is the material that transfers genetic characteristics in all life forms. A DNA molecule consists of two nucleotide strands coiled around each other in a ladder-like arrangement linking the two nucleotides together. Nucleotides form the basic structural unit of DNA. There are four types of DNA nucleotides: Adenine, Cytosine, Guanine, and Thymine -- or A, C, G, and T, for short. Nucleotide strands fit together like two sides of a zipper, but in a very particular way. Adenine only pairs with thymine, and cytosine only pairs with guanine. So each rung in the DNA ladder is a pair of nucleotides, and each pair is either an A stuck to a T or a C stuck to a G. There are approximately six billion pairs of nucleotides (or 12 billion individual nucleotides) in each strand of DNA in each of the 60-90 trillion cells of your body. And amazingly, as infinitely varied as people seem to be, we are genetically all remarkably alike. Compare any two people and you'll find that 99.9% of their DNA is identical. All of the differences in all of the billions of people in the world are accounted for by that 0.1% difference.
A gene consists of a group of paired nucleotides in a specific sequence of DNA, located in a specific location on a chromosome. Genes are "the" hereditary units in an organism and determine the particular characteristics of that organism -- one gene to one characteristic. Genes vary in size, being anywhere from a few thousand pairs of nucleotides to over two million pairs. All in all, the six billion pairs of nucleotides comprise approximately 30,000 genes. Genes primarily perform their function by controlling the construction of proteins in your body through a process called transcription.
When talking about genetics, there are two words you will have to know: genotype and phenotype. Genotype refers to your actual genes for a given trait. In most cases, you've got two copies of a gene - one from your mother and one from your father. Phenotype, on the other hand, is what you actually turn out to be, the way these genes get expressed. When it comes to gene expression, there's a big picture and a little picture. A bit later, we'll explore the microcosmic view in more detail. For now though, let's talk about the big picture in phenotype gene expression.
Remember, we all get two genes for every trait: one from our mother and one from our father. If the two are the same -- let's say for short eye lashes -- no problem. You have short eyelashes. Both your genotype and phenotype are the same. But what if you got the long gene from your mother and the short gene from your father as your genotype? Well, as it turns out, you're going to have long eyelashes. That's going to be your phenotype. Why? Because long lashes are a dominant genetic trait, and in the case of a tie, the dominant trait wins out. The non-dominant trait is referred to as a recessive gene. It takes two recessive genes to manifest as a phenotype. For you to have short lashes, you have to inherit the short lash gene from both your father and mother. On the other hand, you'll have long lashes with just one copy of that trait. The bottom line is that for most genes, one trait is dominant, and the other recessive. Dominant genes win out in a tie. As we will see in a bit, this is very fortunate when it comes to most genetic diseases.
Incidentally, a small number of genes do not fall under the dominant/recessive model. On the contrary, they are what is known as codominant. The gene for blood type, for example, is codominant. If you get the type A blood gene from one parent and the type B gene from the other, neither one dominates. Instead, you end up with type AB blood.
Note: some traits are controlled by more than one gene. These are known as polygenic traits. Height, weight, and skin color are all polygenic traits. There is no single gene responsible for any of these traits. Instead, they are controlled by a combination of several genes all playing together. It is assumed that a number of inherited predispositions to certain diseases, such as heart disease, arteriosclerosis, and some cancers are polygenic.
At one time, RNA (ribonucleic acid) was thought to be much less important than DNA since it didn't carry any of the genetic characteristics of an organism. Big mistake! As we'll learn in a little bit, its role is key. Compositionally, RNA molecules are identical to an organism's DNA molecules -- except for the substitution of the sugar ribose molecule for deoxyribose and the substitution of a uracil molecule in the nucleotide base for thymine.
Mitochondria don't really play a role in the topic at hand, but they're so cool, I had to mention them. Mitochondria are separate little organelles located in every cell of your body. Their primary role is supplying energy to the cell in which they reside. In effect they are little ATP energy factories. In addition, they also play a role in other cellular processes such as signaling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth. So why am I mentioning them in a discussion of DNA and genetics, and what makes them so cool? As it turns out, the genomes inside your mitochondria are not the same as the DNA in the cell nucleus. In fact, mitochondrial DNA is vastly different, showing substantial similarity to bacterial genomes. The theory is that somewhere back in time, "a deal was struck." Animal cells agreed to "incorporate" bacteria into their cellular structure -- to provide a safe home for the bacteria -- in exchange for the bacteria working a number of important jobs necessary for the maintenance of those cells. Is that cool or what?
Replicating your genes
So far so good! We now know that every characteristic in your body -- from height to hair color, from any predisposition you have to high cholesterol to your ability to digest dairy -- is determined by your genes, which in turn regulate every single protein built in your body. Theoretically, whenever a cell divides, it's supposed to make an exact copy of itself -- a true clone. And part of that duplication involves making an exact duplicate of its chromosomes, DNA, and genes -- down to a perfect match of all six billion nucleotide pairs.
Not surprisingly, every now and then, an error creeps in during this duplication of the 12 billion nucleotides in a strand of DNA. In fact, DNA is constantly subject to mutations -- accidental changes in its code. Genes undergo mutation when their DNA sequence changes. And of course, once a change slips in, it is then duplicated and perpetuated every time that cell, or any of its daughter cells, replicate. In most cases, the mutations have no significant impact on the organism. Sometimes, on the other hand, the mutations may be notable -- if not immediately apparent -- such as causing a developmental change in the brains of an organism's children. And sometimes mutations can lead to missing or malformed proteins, and that can lead to diseases such as cancer. Then again, in some cases, the mutation is so notable that the cell cannot function at all and dies before it even has a chance to replicate -- thus eliminating that mutation from the "circle of life."
In fact, we all start out our lives with some mutations. These mutations inherited from your parents are called "germ-line" mutations. The use of the word germ here has nothing to do with "germs" as we normally think of them. Instead, it refers to those cells which are destined to become an egg or sperm -- i.e. germ cells. Think wheat germ. A germ-line mutation then is a mutation in a germ cell in a parent's body that is transmitted to a child. It is thus incorporated in every cell of their body. Germ-line mutations can play a key role in genetic diseases, not to mention certain types of cancer such as retinoblastoma. A germ-line mutation stands in contrast to what is known as a somatic mutation, which takes place in a single body cell during your lifetime. From there it may simply fade away, be transmitted on to daughter cells with no impact on the body as a whole. Or then again, it could spread to become metastatic cancer working its way through your entire body. Some somatic mutations occur during cell division, when DNA gets duplicated. Still other mutations are caused when DNA gets damaged by environmental factors, including UV radiation, chemicals, and viruses.
Note well. Few mutations are actually bad for you. In fact, some mutations can be beneficial. Over time, genetic mutations create genetic diversity, which keeps populations healthy. Most mutations have no effect at all. These are called silent mutations. Unfortunately, not all mutations are silent. Some cause inherited genetic disorders such as cystic fibrosis, sickle cell anemia, Tay-Sachs disease, phenylketonuria and color-blindness, among many others. All of these disorders are caused by the mutation of a single gene. Surprisingly, the fact that these mutations did not die out, but continued to spread over many generations, indicates that they may have actually served a function at one time. Sickle cell anemia, for example, may be malaria protective, which would have been a survival advantage for some populations living in Africa. Move to America where there is no malaria, and it's now just a disease.
Most inherited genetic diseases require a person to inherit copies of the mutated gene from both parents in order to manifest the disorder. This is one reason that marriage between close relatives is discouraged. Two genetically similar adults are more likely to give a child two copies of a defective gene. If you only inherit one gene, you get off free and clear but may pass the disease on to your children. That's why they are called recessive genes -- they recede into the background only to emerge unexpectedly in some future generation. It is estimated that most of us have between five and ten potentially deadly, recessive mutations in our genes. But since we only inherited the gene from one parent, not both, it's recessive so the disease doesn't manifest.
Diseases caused by just one copy of a defective gene, such as Huntington's disease, are rare. Thanks to natural selection, these dominant genetic diseases tend to get weeded out of populations over time, because afflicted carriers are more likely to die before reproducing.
Cancer, incidentally, rarely results from a single mutated gene. It usually requires a series of mutations within a single cell. Often, a faulty, damaged, or missing p53 gene is involved. The p53 gene makes a protein that stops mutated cells from dividing. Without this protein, cells divide unchecked and become tumors.
The bottom line is that genetics tends to move slowly -- usually taking thousands of years and multiple generations before a "genetic change" can take root across a notable section of the population. Exposure to a toxic chemical may cause cancer in the person exposed or a deformity in their first generation offspring. But a single exposure virtually never causes a DNA change that instantly manifests itself in a single individual or that passes itself along to an entire new generation of humanity.
In other words, the idea of being bitten by a radioactive spider causing you to become Spiderman pretty much only happens in comic books…or the movies made from them. And the idea that you can pass those superpowers on to the next generation, unless your spouse had a similar gene, is even more unlikely. And yet! We do see genetic like changes take place in individuals very quickly. And we do see broad "apparently" genetic changes passed on to future generations. So how does this apparent impossibility happen?
What Is Epigenetics?
As it turns out, the genes you have only tell part of the story. Identical twins with identical genes can still develop significant differences. This can happen because having a gene only gets you half way there. The gene has to be "turned on" (its normal state) in order to "express" itself. Thus, you can have two people with an identical gene, but if the gene is "turned on" in one individual and "turned off" in the other, the genetic trait will only manifest itself in the first individual. This process of turning genes "on" and "off" is epigenetics, which translates as "above" genetics. There's nothing sinister here. Epigenetics is a normal and necessary part of life. Think about this for a moment. Every cell in your body has the identical DNA. So what causes one cell to develop as a liver cell and another as a brain cell? The answer is epigenetics. Epigenetics suppresses all of the possibilities for cell development for any given cell -- but one. The one that is allowed to express itself determines what type of cell it is.
The primary vehicles for epigenetic changes are DNA methylation and histone modification. DNA methylation involves the addition of a methyl group (containing one carbon atom bonded to three hydrogen atoms) to select positions on the cytosine or adenine nucleotides. Histones are proteins found in cell nuclei. They are the chief protein components of chromatin, which serves as the spool around which DNA winds. Histone modification -- which is also the result of methylation -- causes the DNA to either stretch out or contract, which causes changes in protein production during transcription, which, as you will remember from the earlier video, is how specific proteins are spun out from DNA instructions.
Epigenetics changes the way genes express themselves with no changes in the underlying DNA sequence. These changes can pass through cell division after cell division for the remainder of the cell's life and may also be passed down through multiple generations if the changes take place in a sperm or egg cell. More importantly, unlike genetic changes, which can take thousands of years to be noticed, changes in gene expression can result from a single "stress" event and even be noticed in a matter of days -- with profound consequences.
Over time, epigenetic changes can profoundly alter our phenotypes. Experiments with identical twins have shown that everything from what we eat, drink, and smoke to the environmental factors we are exposed to -- even to stress itself -- can alter the way our genes express themselves up and down the line with a totality that is beyond imagining. And even the supplements you take can quickly change how your genes express themselves and, thus, your susceptibility to many diseases such as cancer.1
In the laboratory, scientists are learning how to regulate gene expression so that they can turn skin cells into heart cells for example. Already, they have transplanted these cells into mice with damaged hearts and seen those hearts repair themselves using the newly grown heart cells. There are a number of obstacles that need to be worked around before this becomes a usable therapy for people, but it's probably no more than a decade away.
How fast can epigenetic information change?
So far, other than one line stated a couple of paragraphs above, everything that we've talked about is beyond your control and pretty much of only theoretical value to you. It's now time to focus on the one line that matters to you. And that line is:
"Everything from what we eat, drink, and smoke to the environmental factors we are exposed to -- even to stress itself -- can alter the way our genes express themselves up and down the line with a totality that is beyond imagining."
According to Alan Cooper, a palaeobiologist at the University of Adelaide in South Australia, "Epigenetic modification strikes me as an ideal way for animals to respond to environmental change." This quotation was connected with a study published in PloS ONE that found that some 30,000 years ago, ice age bison used epigenetics to quickly adapt to rapid global temperature swings by growing and shedding wooly coats as necessary.2 Even more interesting, the study found that much of the epigenetic changes used to regulate the bison's DNA has been passed down unchanged to modern bison. In fact, most of the methylations they found in the 30,000 year old fossilized remains were in exactly the same spots as methylations in the same genes of modern cattle.
A recent study on chickens published in BMC Genomics provides another clue.3 For the last 8,000 years, humans have been raising and breeding chickens to the point that today's varieties -- coming from the original single pair of Red Junglefowl (Gallus gallus) -- is staggering. The traditional Darwinian explanation would be that over thousands of years, people have bred properties that have arisen through random, spontaneous mutations in the chickens' genes to produce these multitudinous varieties. But in evolutionary terms, the sudden emergence of such an enormous variety of domestic fowl of different colors, shapes, and sizes would have to have occurred in a staggeringly short time. How could it be? The researchers believe the answer lies in epigenetics.
They studied how individual patterns of gene activity in the brain were different for modern laying chickens than the original form of the species, the jungle reds. They discovered hundreds of genes in which the gene expression and activity were significantly different. The researchers also examined DNA to determine whether the epigenetic differences were hereditary, and they were. The chickens inherited both methylation and gene activity from their parents. After eight generations of cross breeding, the differences were still evident.
In summary, the results suggest that domestication has led to epigenetic changes. For more than 70% of the genes, domesticated chickens retained a higher degree of methylation. Since methylation is a much faster process than random mutations, and may occur as a result of stress and other experiences, this may explain how variation within a species can increase so dramatically in such a short time. In fact, as we're about to see, even a single exposure to a stress factor, such as a pesticide, may be enough to effect an epigenetic change.
Unto the third generation
A recent study published in the Proceedings of the National Academy of Sciences found that even a single exposure to a toxic chemical has the ability to negatively influence behavior of offspring for at least three generations after the initial exposure.4 That's just one exposure to one toxic chemical! As the study, says, "We find that a single exposure to a common-use fungicide (vinclozolin) three generations removed alters the physiology, behavior, metabolic activity, and transcriptome in discrete brain nuclei in descendant males."
Diet and epigenetics
Based on what we've seen so far, it should not be surprising that the nutrients in foods we eat have a profound impact on our epigenomes -- particularly those involved in making methyl groups, which are fundamental to epigenetics. As we've discussed in previous newsletters, this includes B6, folic acid, B12, TMG (trimethylglycine), and SAMe. As we now know, these nutrients are not only useful in preventing heart attacks, they also serve as methyl-donating nutrients that can rapidly alter gene expression, especially during early development when the epigenome is first being established. Remember, turning gene expression off is often as important to health as is letting a trait express itself.
And again, the effect does not have to be direct. It can be transgenerational. According to a 2007 Swedish study which tracked food availability between the ages of nine and twelve for paternal grandfathers, food shortages in the grandfathers' lives affected the lifespan of their grandchildren -- but in a surprising way. A shortage of food for the grandfather was associated with an extended lifespan in his grandchildren. Food abundance, on the other hand, was associated with a greatly shortened lifespan in the grandchildren as a result of increased diabetes and heart disease.5 It would seem that once again, the sins of the parents (in this case "worshipping" rich foods and overeating) are visited upon the children -- even unto the third generation.6 Very Biblical! Caloric restriction, on the other hand, not only prolongs the life of the restrictor but their progeny several generations on as well.
The relationship between epigenetics and cancer appears to be definite, but sometimes contradictory.7 For example, while it has been shown that cancer cells generally have low levels of DNA methylation, counterintuitively it has been shown that a diet low in folic acid (which you would think reduces methylation potential) has actually been linked to excessive methylation at certain genes, leading to a higher incidence in cancer. Excessive methylation, of the wrong kind in this case, might switch off vital genes and contribute to the development of cancer. And along the same lines, methylation of a gene involved in head and neck cancer is associated with low levels of folic acid in the diet.8 In fact, studies suggest a whole list of foods and nutrients, from alcohol to selenium9 that might influence methylation and cancer susceptibility.
So what's the evidence that certain compounds in the diet can influence epigenetic marks at certain genes? A quick scan of the scientific literature pulls up a few papers. For example, a study of patients with gastric (stomach) cancer inversely linked methylation of an important gene to a person's consumption of green tea and cruciferous vegetables.10 In other words, green tea and cruciferous vegetables suppressed unhealthy methylation. Then again, other researchers have linked folic acid and alcohol intake to methylation at certain key genes involved in both bowel cancer11 and breast cancer.12 So, low levels of folic acid can increase certain cancers and high levels can increase others. Sometimes it seems you can't win for losing.
So what is one to make of all of this? Are there any practical steps we can take to help us avoid disease in ourselves and our descendants?
- The simple answer is: yes!
- The middle of the road answer is: avoid toxins, pathogens, and the wrong sorts of foods and supplements that can lead to inappropriate epigenetic changes, while at the same time eating those foods and supplements that can promote positive changes.
- And the detailed answer is as follows.
Minimize exposure to toxins as much as possible, and detox regularly to remove toxins so as to reduce the time they have to negatively impact either your genotype or phenotype. As we discussed, actual DNA mutation is inevitable but in most cases has no immediate impact on your health. In fact, it is more likely that any DNA alterations, if they have any impact at all, will be on those who inherit your genetic code. And even in those cases where the genetic alteration turns a cell cancerous, most of the time your immune system will identify that cell as no longer part of "self" and will eliminate it before it can reproduce.
On the other hand, as we also discussed, toxins can have an immediate impact on how genes "express" themselves -- and thus, an immediate impact on your health. So again, but with an even stronger warning, you want to minimize your exposure to toxins as much as humanly possible and detox regularly.
Keep your immune system optimized
As just mentioned, one of the primary functions of your immune system is to identify and eliminate any cell that has become cancerous and is now working against your body's sense of "self." Keeping your immune system optimized, then, is essential if you want to maximize your resistance to cancer.
Make sure your diet contains all nutrients
You want to eat foods that provide the building blocks for methylation in the body -- and in the proper balance so that you don't over folate for example. And speaking of folic acid, beans of all kinds are great natural folate sources. Lentils, pintos, garbanzos, navy beans, and kidney beans top the list with asparagus and the leafy greens such as spinach and turnip greens close behind. Other methylation building blocks include:
The primary sources of choline are non-vegetarian. They include beef, eggs, chicken, turkey, scallops, and shrimp. Leading vegetable sources include collard greens, Swiss chard, and cauliflower -- but they have much less choline than the non-vegan options.
Eggs, fish, and meat are the top sources of methionine -- with sesame seeds, Brazil nuts, and cheese close behind.
As for the B vitamins, brewer's yeast, eggs, chicken, fish, liver, milk, cheese, carrots, spinach, grains, legumes, green leafy vegetables, and berries are all good food sources. Spirulina is a great source for all the B vitamins except B12. Note: for years, it was thought that edible seaweeds, fermented soya foods, and spirulina contained high levels of B12. They don't. What they contain are B12 analogues (chemical lookalikes) which your body cannot use. You'll need another source of B12.
Whole wheat, spinach, sugar beets and shellfish all contain high levels of natural TMG.
If you decide to supplement with the methyl building blocks, look for a mix that contains approximately 50 mg of B6, 500 mcg of B12, 800 mcg of folic acid, and 500 mg of TMG. It's good for your heart. It's good for your genes.
SAMe (S-adenosylmethionine) is a molecule produced constantly in every living cell. It's one of the most important methylating agents in the body. In fact, without SAMe, methylation would pretty much not work. Though various molecules can pass methyl groups to DNA, SAMe is the most active of all methyl donors. Our bodies make SAMe from methionine (one of the reasons we want to supplement it). Once a SAMe molecule passes its methyl group to DNA, it breaks down to form homocysteine. Homocysteine is a toxic molecule associated with systemic inflammation and heart disease. SAMe and homocysteine are essentially two sides of the same coin, or molecule in this case -- one beneficial and one inflammatory.
And that's where B6, B12, folic acid, and TMG come into play. With their help, your body converts homocysteine into glutathione -- an important antioxidant -- or recycles it back into beneficial methionine. Unfortunately, if any of these building blocks are in short supply, homocysteine levels rise continuously, thus leading to a chronic imbalance of homocysteine over SAMe. Supplementing with SAMe, in addition to obtaining adequate amounts of the other methylating agents, can correct this imbalance. For most people 200 mg of SAMe a day is enough. For special needs (SAMe works as an antidepressant), 400, 1,200, even 2,000 mg a day may be required.
The bottom line
Epigenetics and methylation are normal parts of life. They are neither good nor bad; they just are. Some controls on gene expression are required so that you can form different cells as needed. Other forms, such as those that promote cancer, not so much. There is nothing to panic or worry about. Simply try and minimize exposure to those things that are known to cause counterproductive methylations in your DNA -- even to the point of detoxing them out on a regular basis -- and provide your body with the nutrients you need to give your cells the best chance possible to replicate happy, identical clones.
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- 3. Daniel Nätt, Carl-Johan Rubin, Dominic Wright, Martin Johnsson, Johan Beltéky, Leif Andersson, Per Jensen BMC Genomics 2012, 13:59 (4 February 2012). <http://www.biomedcentral.com/1471-2164/13/59>
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- 5. Gunnar Kaati, Lars Olov Bygren, Marcus Pembrey, and Michael Sjöström. Transgenerational response to nutrition, early life circumstances and longevity." European Journal of Human Genetics (2007) 15, 784--790. <http://www.nature.com/ejhg/journal/v15/n7/full/5201832a.html>
- 6. Exodus 20:5
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- 8. Anna Eleftheriadou, Thomas Chalastras, Elisa Ferekidou,et al. "Association between Squamous Cell Carcinoma of the Head and Neck and Serum Folate and Homocysteine." Anticancer Research 26: 2345-2348 (2006). <http://ar.iiarjournals.org/content/26/3B/2345.full.pdf>
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- 10. Yasuhito Yuasa1, Hiromi Nagasaki1, Yoshimitsu Akiyama1, et al. "Relationship between CDX2 gene methylation and dietary factors in gastric cancer patients." Carcinogenesis vol.26 no.1 pp.193--200, 2005. <http://carcin.oxfordjournals.org/content/26/1/193.full.pdf>
- 11. Manon van Engeland, Matty P. Weijenberg, Guido M. J. M. Roemen, et al. Effects of Dietary Folate and Alcohol Intake on Promoter Methylation in Sporadic Colorectal Cancer: The Netherlands Cohort Study on Diet and Cancer." Cancer Res June 15, 2003 63; 3133. <http://cancerres.aacrjournals.org/content/63/12/3133>
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