Darn, My Genes Don't Fit

Many people have written to me asking about the genetic theories of Amy Yasko, a medical researcher. She is interested in the chemistry behind the Methylation Cycle of human metabolism. One branch of this chemical pathway leads to the formation of sulfite from animal protein. Hence the concern of those with a sulfite intolerance. Following is my take on the issue. Although an interesting subject, if this is your first visit to the No Sulfites website, I suggest you skip this page for the time being.

The methylation cycle is shown in the diagram above. At first glance, it seems a bit overwhelming but the more you look, the more sense it makes. Of interest is the circle to the right with the word Methionine at the top. Methionine is an amino acid derived from animal protein. The diagram shows that methionine is first converted to SAMe, then SAH, homocycteine and back to methionine as you rotate clockwise around the circle. This is a schematic representation of the chemical reactions that transform methionine into chemicals that your body needs. If everything is working properly, methionine travels around this circle many times before it is used up and has to be replaced ( by eating more meat or fish. ) The primary function of this cycle is the addition of a methyl group ( CH3 ) to the workhorse chemical s-adenosyl methionine ( SAMe ). SAMe then transports methyl groups all over the body to aid in a myriad of necessary chemical reactions. After SAMe donates a methyl group, it transforms into homocysteine where it can continue to loop back to methionine or drop out to form taurine, glutathione or sulfite. All of these reactions are controlled by enzymes referenced by initials in blue boxes. The enzymes themselves are created by genes referenced by the same blue initials. In particular, the CBS gene is responsible for the enzyme cystathionine beta synthase which converts homocycteine into cystathionine on its way toward sulfite. If any gene in this diagram contains a mutation, the associated enzyme may not function properly, leading to health issues.

DNA StructureThere are at least 20,000 human genes packed into 23 chromosome pairs, half contributed by your mother and half by your father. This is what we call DNA, deoxyribonucleic acid. All of these genes and chromosomes are built as strings of just four different chemicals, called nucleotides. These nucleotides have names but are usually noted as letters: C,G,A,T for cytosine, guanine, adenine, thymine. Each chromosome is built as a double spiral formed from long strings of the four nucleotides. For stability, each half of the spiral is a mirror image of the other half with C bonded to G and A bonded to T all the way down the helix. One side of the helix is identified as the "Plus Orientation" while the other is termed "Minus". This is an important distinction since a gene segment described as ...CCGATT... on the plus side would become ...GGCTAA... on the minus side. The most common mutation of a gene is called a SNP, pronounced "snip" and standing for Single Nucleotide Polymorphism. It just means that one of the nucleotides in the gene was replaced by a different one. To identify simple SNP mutations, the gene initials are followed by numbers and letters that may indicate the location and codes of the altered nucleotide in the string. For instance, a common mutation of the CBS gene is given the name CBS C699T. While all mutations modify the gene, some have little or no effect while some dramatically change your body chemistry. All of this information appears to be confusing because of the many strange new words. Good grief, methylation, homocysteine and polymorphism! But the concepts are quite simple. The genetic code is just a fancy Morse Code with C,G,A,T instead of dots and dashes. If you are keying Morse Code and you screw up a dot-dash, your SOS call may turn into SIS. As a result, your sister gets called instead of the coast guard. Same is true of your genes. If a C nucleotide is replaced by a T, your gene may build an enzyme that doesn't work as well as intended.

To find out more about my own genetics, I ordered the "23andME" home gene kit and was sent a sample collection tube. I spit into the tube and several weeks later my results were online. The current price of the gene kit is $199. Now, "23andME" doesn't sequence your entire genome for this price. They just look for the most common mutations, scanning about 600 thousand of 10 million estimated SNPs. They then generate charts detailing your genetic history and possilble health concerns. For instance, my ancestors were Scottish, Welsh and German with a little Neanderthal thrown in. It's all very entertaining and well worth the price. But the prize is a complete list of your personal SNP mutations. It can be viewed in "Plus Orientation" format using the Browse Raw Data function. Also, the data file can be downloaded and further evaluated by doctors and various internet engines. One of my favorites is a service at www.promethease.com costing only $5 which will configure your SNP file into a format that is easy to read and investigate. Promethease makes use of the information at www.SNPedia.com which catalogs SNP mutations and matches them to relevant research reports. It's a great way to start your own genetic research. To find out more about the mutations of most concern to Amy Yasko, you may search either Promethease or SNPedia using the term "Yasko" to return a list of her targeted mutations. Another useful site is MTHFR Support at www.mthfrsupport.com which generates a very nice multi-color report called Sterling's App for $30.

Methyl GroupThe mutations studied by Amy Yasko affect many of our most basic bio-chemical pathways. The Methylation Cycle is all about making methyl groups available to the cells and organs of your body. A methyl group is the simplest organic compound, one carbon bonded to three hydrogen, CH3. Being so basic, it is used over and over in the chemical dance of life. Methyl groups turn genes on/off, build neurotransmitters, process hormones, create immune cells, synthesize DNA, produce energy, protect nerves and maintain cell membranes to name a few. Mutated genes can compromise enzymes which interfere with normal metabolism. Yasko's work has identified many of the chemicals impacted by methyl mutations and she suggests supplements which may bypass the difficulties. For instance, some of the mutations associated with chronic fatigue syndrome appear on the MTHFR gene which produces an enzyme to convert folic acid to its bio-active cousin, methyl folate. Those cursed with such mutations can't create methyl folate no matter how much folic acid they consume and this brings things to a dead stop. So, the Yasko solution is to supplement with methyl folate, not the more common folic acid. Again, a very simple idea in a confusing forest. The theory is appealing because it not only explains health issues but suggests steps that can actually help. And it doesn't involve potentially dangerous or expensive medical procedures, just economical supplements.

The sulfite part of the Yasko theory looks at the three branches of the methyl cycle emerging from homocycsteine. Refering to the diagram above, homocysteine can revert to methionine via the enzymes MS/MSR or BHMT. It can also exit toward sulfite via CBS. According to Yasko, if you have mutations to MS/MSR or BHMT that decrease their effectiveness or mutations to CBS that enhance effectiveness, more sulfite will be produced resulting in a sulfite intolerance. Wow, I cannot ignore a statement like that, especially since I am lucky enough to have the required mutations. Here are my pertinent mutations:

CBS C699T Homozygous (+/+) Up regulation as much as 15 times normal
BHMT-2 Homozygous (+/+) Down regulation
BHMT-4 Homozygous (+/+) Down regulation
BHMT-8 Heterozygous (+/-) Down regulation

The gene names are followed by (+/+) meaning a homozygous common mutation from both parents or (+/-) meaning a heterzygous mixed mutation from just one parent. Up regulation means the mutated gene is more active than the normal wild gene. Down regulation means less active. This set of SNPs fits Yasko's theory to the tee. But, as you know, some of the best theories don't hold water. For instance, the theory that the universe rotates about the Earth was popular for thousands of years. Although it seems reasonable when you watch the sky, it just isn't true. So, I looked a little deeper into things. Yasko suggests that my set of mutations should decrease the resting level of homocysteine and produce excess ammonia as a by-product of cysteine creation. My blood test results for both homocysteine and ammonia were normal, contradicting the theory. What else doesn't fit? The SNPedia website has information on the percentages of people with any given mutation. At least one copy of the CBS C699T mutation is present in 66% of those of Northern European descent. It's more common than the wild gene, suggesting that it is a beneficial rather than detrimental mutation. And sulfite sensitivity affects no where near 2/3 of the population, so the percentages don't fit. Finally, as part of my previous food tests, I actually swallowed methionine supplements. I react as if methionine releases 70 ppm of sulfite upon metabolism. Now, 70 ppm certainly places methionine on my watch list of sulfited ingredients. But, since a normal diet contains only 2 grams of methionine as part of meat, fish and eggs, 70 ppm would release only 140 ug of sulfite. According to the FDA, normal people can handle nearly 60 mg ( 60,000 ug ) of sulfite. So, the little bit from methionine would not affect normal people and would not create a sulfite sensitivity. I watch the size of my meat dishes because I am sensitive to just a few hundred micrograms of sulfite. But my tolerance is low whether I eat meat or not.

Website Resources for Genetic Information

23 and ME Gene Testing for $199: www.23andme.com
Promethease Gene Analysis for $5: www.promethease.com
MTHFR Group Sterling's App for $30: www.mthfrsupport.com
The SNPedia Data Bank of SNP Mutations: www.snpedia.com
Yasko Protocol ( Resources Menu Pick ): www.dramyyasko.com
Heart Health Fixer ( Methyl Cycle Menu Pick ): www.heartfixer.com

All in all, I think the Yasko approach to supplementation as a work around for genetic defects has great merit. Her arguments are compelling and her solutions are safe and economical. Many people seem to have been helped by her methods. However, when it comes to sulfites, I do not believe methyl gene defects are a direct cause of intolerance. For more information, I suggest the websites in the table above.

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