If you've hung around health forums on the interwebs before, chances are you've heard people talking about SNPs. This topic can be pretty confusing even to relatively well-informed folks, so this blog post is designed to be very simple introduction to what a SNP is, and what it isn't.
Before we dive into SNPs, I'm going to lay some groundwork with basic genetics. But, if you don't want to read all the way through, here's a summary of what a SNP is:
SNP stands for single nucleotide polymorphism. These are variations in the sequence of our DNA that contribute to your individual traits and metabolism. There over 10 million SNPs in human DNA. They are not technically mutations (although many people refer to them incorrectly as mutations) because they occur with enough frequency in the human population. A true mutation occurs in less than 1% of the population, while a SNP occurs in more than 1%.
Think of SNPs as naturally occurring genetic variations that everyone have. They are a huge component of what makes us who we are. They can be used to better understand our internal metabolism, predispositions to certain conditions, and why we respond the way we do to things like food, drugs, toxins, and other environmental exposures. The functional result depends on what allele or genetic variant you have in a particular SNP. I'll explain more how this happens below.
OK! On to the article:
According to the almighty wikipedia, DNA carries the genetic instructions used in the growth, development, functioning and reproduction of all known living organisms.
Got it. Great. How the hell does it do that?
DNA is composed of 4 nucleotides that repeat in various patterns. The 4 nucleotides are:
- A (adenine)
- T (thymine)
- C (cytosine)
- G (guanine)
If you notice in the diagram below, adenine is paired with thymine and cytosine is paired with guanine. This always happens this way, and allows scientists to look at only one strand of DNA to know how the other strand reads. This is literally the programming language with which life is built. We'll talk about how this code and utilized in the section on RNA.
There are roughly 3 Billion Base Pairs in each copy of your DNA, and there's a copy of of your DNA in the nucleus in each cell in your body. 99% is the same as every other humans' DNA, and the 1% variance accounts for the unique human that you are. Think of the sequence of nucleotides in your body as the basic recipe for you.
Chromatin and Histones
Everyone knows the classic double helix shape of DNA in the image above, and most people imagine it that way. However, this is what DNA looks like when it's uncoiled. If it were stretched out, like the image above, the amount of DNA in each cell in your body would total about 6 feet in length. So, it has to be tightly wound up in order to fit. And, as you'll see later on, the specific way DNA gets wound up has a major impact on how it functions.
Notice in the image below how DNA coils itself. First it wraps itself around proteins called histones, and then forms a denser mass called chromatin, which then forms itself into the shape of a chromosome. While this isn't relevant for defining what a SNP is, it does help you visualize DNA a bit better, and its very important in the discussion of how epigenetics works.
RNA is another chain of nucleotides responsible for reading or transcribing the DNA. It essentially copies the code and transfers it to ribosomes where the instructions are read and translated into chains of amino acids or proteins. It is single stranded and chemically similar to DNA except it uses uracil (U) in place of thymine (T). In the first diagram, you can see how RNA unzips a section of DNA and stores the code for transport.
The Central Dogma of Biology
What I've just described is known as the central dogma of biology. DNA is transcribed by RNA and then translated into proteins (polypeptides in the diagram below) via the ribosome (basically a little protein factory in your cells). Due to the specific code of your DNA, you produce specific proteins that cause your eyes to be blue, hair to be brown, and create the sum total of the biochemical processes.
Coding vs. Non-Coding Regions
Not all your DNA is meant to be used like this, however. A region of DNA that gets transcribed and translated into proteins is called a coding region or an "exon". A significant portion of your DNA is actually non-coding, but serves a specific function in how it regulates the how the coding regions are read.
Non-coding regions within a gene are called introns, and non-coding regions outside a gene are called regulatory sequences. Regulatory sequences either promote or suppress the expression of a gene, which we'll talk about in the next section.
Non-coding regions are relevant to SNPs because a SNP can either fall in a coding region or a non coding region. However, just because a SNP is in a non-coding region does not make it less relevant. Some of the most impactful SNPs we know are in non-coding regions.
Telomeres are another example of non-coding DNA. They sit at the end of your chromosomes and help protect them from copy errors and degradation as they are duplicated millions upon millions of times. Telomeres are one of the hottest area of longevity research today because of the association with telomere integrity and healthy aging vs disease states.
Epigenetics: Control Over Genes
While this seems like a neatly packaged explanation of how biology works, it's not nearly the whole picture. Since this article is focused on what a SNP is, I won't go too far into it, but know that the products of genes (the proteins we just talked about) can be modified by a number of factors. There are places directly the DNA (called CpG sites) that molecules can bind to that can either turn up or down the expression of that gene.
- Methyl groups turn down the expression of genes. This means that the RNA either doesn't read that section of DNA.
- Acetyl groups turn up the expression of genes. This means that the RNA is encouraged to read that section DNA and translate it.
Remember the histones from above? Special epigenetic factors can either loosen or tighten the way DNA is wrapped around histones, making it easier or more difficult for RNA to read it. When a histone is wrapped extremely tightly, RNA polymerase simply can't access it. And, conversely, when DNA is wrapped loosely around a histone, it gives RNA access to it.
There are many different types of epigenetic modifications, and many still to discover. The important thing to know is that unlike your base DNA code which does not change, epigenetic markers are dynamic and change over time in response to the environment. One gene can produce thousands of variations upon the same protein based on what type of epigenetic marks are present. I mention this, because it is important to understand that while the base code of your DNA and SNPs does not change over time, it is to epigenetically possible to modify the expression of those SNPs.
Single Nucleotide Polymorphisms
Remember the nucleotides from above? When you're conceived, you get half your nuclear DNA from your mother and the other half from your father. The recombination of nucleotides gives rise to what are known as alleles. Because humans have diploid chromosomes (or two sets of matching chromosomes, one from each parent) an allele has two nucleotides associated with it. Chromosomes are made up of genes, which are made up by sequences of nucleotides.
An example of an allele of a SNP might be GG, AA, or AG. This describes that at a particular position in a gene, you either have a guanine on each chromosome (GG), adenine on each chromosome (AA), or an adenine on one and a guanine on the other (AG). In the image below, you can see that instead of a C on the top strand of example 1, there is a T in the same position in example 2.
So, if this SNP is in a coding region of a gene, it will change the protein that gets translated from that gene. Proteins are long chains of amino acids strung together, and their function is determined by the order of amino acids present. Other factors like shape and folding structure influence the function of the protein too, but for now just focus on the composition of that protein.
Let's take a look at an example of a SNP:
MTHFR 677T: How to Name it
MTHFR is one of the best known SNPs, so we'll use it as an example. First of all, let's break down the nomenclature a little bit. Gene names and identifying numbers can be really confusing, especially when looking at older studies where there was less consistency with how things were named.
677 is the name that scientists gave this particular place in the gene where this SNP occurs when they first discovered it. T is the less common allele and defines the "risk" allele for the SNP. Sometimes it is also refered to as 677C>T (denoting the two possible alleles, and showing that C is the major allele and T is the minor allele). But, the best and most consistent identifier for any SNP is the RS number.
MTHFR 677t is identified as rs1801133. This number can be used to look up your variant in 23andMe, SNPedia, or any other database. RS numbers are now the standard for identifying SNPs. They make it very simple, but sometimes determining an RS can confounded by older studies that had not adopted the standard.
MTHFR 677T: What it do?
MTHFR is a gene that codes for an enzyme called methylene tetrahydrofolate reductase. Its a mouthful, but its a very important enzyme that helps process folate, an essential B-vitamin. It is usually the rate limiting step in the folate cycle, meaning that if you don't have enough of the enzyme, it clogs up the whole process and prevents adequate amounts of methyl groups from being made. Methyl groups are used to convert homocysteine into methionine, which then becomes the main methyl donor in the body and is used in thousands of reactions throughout the body including the epigenetic methyl markers on DNA that I described above. In the simplified diagram below you'll see how these pieces fit. If there's not enough MTHFR available, there's not enough methyl groups available to covert homocysteine into methionine.
The CC allele type has a fully MTHFR functioning enzyme; however, the T allele creates a less functional protein. The CT variant's enzyme is about 40% less functional, and the TT variant is about 70% less functional.
So not suprisingly, the T allele is associated with higher levels of homocysteine, an important marker of cardiac risk. And, it is associated with a litany of other conditions:
- Strokes [R, R1, R2, R3]
- Heart disease [R]
- High Blood Pressure [R]
- Male infertility especially in Asian populations [R, R1,R2, R3]
- Depression [R] [R].
- Autism spectrum disorders [R, R1, R2, R3]
- Alzheimers[R, R1]
- Parkinsons [R, R1]
- Rheumatoid Arthritis [R]
- Migraines [R, R1, R2]v
- Diabetes kidney problems [R, R1, R2, R3].
- Schizofrenia [R, R1]
- Bipolar Disorder [R, R1]
- Cancer – [R, R1].
- Hearing impairment [R]
- Lower Bone Mineral Density in the spine and neck [R]
- Cluster Headache [R]
- Epilepsy [R]
- Peripheral Arterial Disease [R]
- Recurrent pregnancy loss [R, R1]
- Pre-eclampsia, a serious complication of pregnancy [R].
- Having a Down syndrome child if the mother has a mutation [R].
- Neuronal tube defects (NTD) such as anencephaly and spina bifida in newborns [R].
- Cleft lip and palate [R]
- Cataracts [R]
Pretty crazy list right? BUT, the important thing to know is that most of these effects ONLY show up when there is insufficient folate in the diet. For someone with a T variant, this is a perfect example of how to use nutrigenetics to reduce the genetic predisposition to disease. By keeping dietary levels of folate high, these risks either go away or are significantly reduced.
An important thing to keep in mind as well, is that even the the 677T variant is associated with these conditions, there are a number of other genes in the folate and methylation cycle that can help offset a poorly functioning 677T. When looking at SNPs, it is important to view them form a systems approach. Understanding what MTFHR does and why it creates these risks is WAY more important than just knowing whether you have a single risk variant or not.
Major vs Minor Alleles
Almost all alleles occur at varying frequencies throughout the population. For example, the C allele of a SNP might occur in 70% of humans, and the T allele at 30%. The CC variant might occur in 50% of the population, CT in 35%, and TT in 15%.
The more frequently occurring allele is known as the wild type, ancestral, dominant or major allele and the less frequently occurring allele is known as the minor, recessive, or mutant allele. I'm not a big fan of the word "mutant" to describe this because of all the connotations associated with it, but it does get used occasionally.
One big takeaway here is that simply because an allele is less frequent in the population does not mean it confers a risk of any kind. This is sometimes the case, but the major allele that occurs more frequently can sometimes have health predispositions associated with it while the minor allele can have protective benefits.
A SNP is a single nucleotide polymorphism, or a change in the genetic code that influences the production of proteins either directly or as a promoter. While there are over 10 million SNPs in the human genome, some are more relevant than others. Some have no known effect all while others like MTHFR are very high impact. Knowing which ones to look for and how they interact is key to using them to successfully improving your health and learning more about your self. As more and more studies come out, our collective knowledge of how and why humans respond as individuals (and not an average) will to continue to grow and lead to a better understanding of health.
Learning about SNPs may seem daunting, but it is truly part of the the next frontier in health. Effecting everything from memory to sleep quality to carbohydrate metabolism to how dry your earwax is (seriously), understand your SNPs can you give you more control over your health, and truly shed light on "why." If you've ever stood at a supplement aisle wondering "which one of this is actually going to help me?" then learning about your SNPs is the next logical step.
Want to start learning about what SNPs you have? Go grab an ancestry kit from 23andMe and get started. You only need to buy the ancestry package, not the health and wellness package, as they provide you with the same raw data either way.
Caveat: When I work with clients I look at hundreds of SNPs to get the big picture. Its easy to get hyperfocused on a single gene or SNP, and while sometimes focusing on one can be helpful, to really shift health it is important to approach it from a holistic systems perspective. Want me to take a look at your genetics from this perspective? Contact me for a free 30 minute consultation and let me help you optimize your health, no matter where you are on your path.