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We're going to be releasing our COMT story soon. COMT is an important gene in the metabolism of neurotransmitters like dopamine and epinephrine. The GenEd COMT Story will tell you how your individual genotype at a specific location in COMT is important for dopamine metabolism and reward behaviors. As we work up to that release, we'll make blog posts about how GenEd builds a Story. Today's post is about the original description of the most famous SNP in COMT, rs4680. Rs4680 is a favorite SNP for companies that sell individualized genotyping reports. We've long suspected this is because of the great marketing tag that is almost always applied to COMT genotype at rs4680: "Warrior/Worrier". According to an excellent review article by Stein et al (1) David Goldman was their source for this wonderfully appealing dichotomy. Rather than repeat the excellent narrative found in the Stein et al paper, we're going to go back to the original peer-reviewed description of what would become the famous COMT SNP, rs4680 (2). Note that this paper, even after 20+ years in the literature, is still behind a paywall. Alas, this is not our problem to fix. Let's dissect what is freely available, the abstract. The authors assume we know enough about biochemistry to parse the acronym for COMT. COMT stands for Catechol O Methyl Transferase. "Catechol" is the chemistry word for molecules with a benzene ring and two hydroxyls. Benzene is a six carbon ring with alternating double bonds. Hydroxyls are the small molecule group -OH, an oxygen hooked to a hydrogen. The "O" is another chemistry term. In this context, it stands in for the Oxygen in one of the hydroxyls. "Methyl" is chemist-speak for a carbon with three hydrogens hooked to another molecule. "Transferase" is biochemist-speak for an enzyme-that-transfers or moves one part of a molecule to another. In the plainest English possible for this writer, COMT is the enzyme that transfers a methyl group to an oxygen on catechols. Why is transferring methyl groups to catechols important? Transferring a methyl group to a catecholamine like dopamine inactivates that catecholamine. As the authors point out, COMT doesn't just inactivate catecholamines like dopamine and epinephrine. COMT also inactivates drugs like L-DOPA. COMT's inactivating activity is variable between individual people. John Smith might have more active COMT than Joe Public. This is very important to people who might need L-DOPA. Depending on what studies you look at, it's probably also important for a host of other human diseases that involve catecholamine metabolism. This inter-individual variability in COMT was known before this paper. The authors major contribution was figuring out WHY there is variability between people in COMT activity. Note the date on reference 2. This study was done in the bad old days before gene sequencing was cheap and common. In the late 90s, biologists had to climb up snow-covered hills both ways to get to their PCR machines! Lachman et al developed an experiment that takes advantage of two common techniques in the pre-sequencing days of molecular biology: PCR and restriction enzymes. PCR is a technique for amplifying small amounts of a single chunk of DNA. Lachman et al PCRed "up" lots of COMT gene DNA from different people they already knew had different COMT enzyme activities. Restriction enzymes are tiny molecular machines built by bacteria to fight each other and viruses. Biologists in the dim recesses of time learned how to use these restriction enzymes to cut DNA in specific places. Restriction enzymes cleanly cut DNA in between exact sequences, making exactly two fragments of the PCRed gene. The restriction enzyme used by Lachman et al, Nla III, is one of these narrow specificity restriction enzymes. Think of Nla III as a pair of scissors that only cuts between two specific spellings of DNA letters, CATG and it's reciprocal GTAC: C A T G| |G T A C If you are lucky like the Lachman team in 1996, the location of your COMT mutation is between one of these two DNA words. Imagine Nla III sliding along the double helix, looking for its magical DNA letters. If the sequence is mutated, it doesn't cut! This effect is called a restriction fragment length polymorphism (RFLP) or "riflip". The Lachman group showed that one of these RFLPs is a misspelling of a part of the COMT gene. The more common G DNA base is misspelled as an A DNA base. This misspelling is propagated all the way to the COMT enzyme itself, resulting in a substitution of the more common amino acid valine (Val) for the amino acid methionine (Met) at position 158 in the COMT sequence. Swapping a bulky methionine for valine is roughly equivalent to asking your car to run on tires that are square instead of round. A car would move forward on square wheels, but it wouldn't be a very smooth ride. COMT enzymes with Val158 ("round tires") inactivate more catecholamines than COMT enzymes with Met158 ("square tires"). Before Lachman et al, no one knew exactly why there was so much variability in COMT activity. Their seminal work is the basis for everything we know about this particular mutation. We'll talk more about what catecholamine inactivation means for Warriors and Worriers in the next blog post. Be sure to follow along . . . 1. Stein DJ, Newman TK, Savitz J, Ramesar R (2006) Warriors versus worriers: The role of COMT gene variants. CNS Spectr 11(10):745–748. 2. Lachman HM, et al. (1996) Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6(3):243–50.
Before we load up a Story for our subscribers, the GenEd team reads a lot of literature. A LOT OF LITERATURE. We cull through the peer-reviewed article and reconstruct a historical narrative from the discovery of the variant to the latest interpretation of human phenotypes. At the very end we have two capsule synopses: one for scientists and one for beginners. Here's our "for scientists" summary for the rs16969968 SNP in CHRNA5: "CHRNA5, a well-studied gene in multiple human studies on the genetics of addiction, encodes the alpha 5 subunit of the nicotinic acetylcholine receptor. The rs16969968 SNP changes a phylogenetically conserved aspartate to an asparagine (D398N). The N398 protein has lower maximal responses to nAchR agonists and is strongly associated with increased risk of nicotine addiction. A mouse model of CHRNA5 knockout shows that the alpha5 subunit mediates transmission of aversive stimuli from the habenula to the VTA, decreasing dopamine release at the NAc. Carriers of the rs16969968 rare allele are predicted to have a blunted response to the aversive stimuli associated with drug intake, leading to increased consumption. Human fMRI studies show that the N398 allele is associated with reduced synchronization of a cortex-midbrain circuit involved in addiction behavior." Sounds a lot like most of the "reports" you've probably read for genetics results. Here's our "for beginners" summary for the same SNP in the same gene: "The scientific literature on the rare rs16969968 A allele is complex. In short, this genetic change seems to do two things. First, it lowers the response of the nicotine receptor to the brain’s own stimulating chemicals, lowering dopamine tone. And second, it seems to decrease a different function of the nicotine receptor, that of lowering dopamine when a noxious chemical is taken in. Together, the low basal tone that mediates for a person’s wanting to take something to feel better and the poor response to the noxious effect of certain chemicals creates a greater risk for addiction involving substances that others might find to be not a good drug (tobacco smoke)." Note that the "for beginners" summary has very few abbreviations and focuses closely on what a non-scientist human would care about. We'll make more posts in the future about the process of creating a GenEd Story. If you're interested in learning more, use the "Contact Us" link in the navbar above, or register and upload data to see your free MTHFR report.
Have you been digesting the news about Wuhan coronavirus? We've put together a great Story explaining a pretty cool part of coronavirus biology: ACE2. It turns out that SARS and 2019-nCoV both use the membrane protein ACE2 as their receptor for cell entry. In other words, ACE2 is the "hook" that these two coronaviruses use to latch onto their target cells in the lungs. Does ACE2 sound familiar? You're probably more familiar with its close homologue and homeostatic partner, ACE or ACE1. ACE is one of the master regulators of the renin-angiotensin system, a classic target of anti-hypertensive drugs. We're pretty excited about this Story. Join GenEd, upload your data, and expand your mind!
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