MTHFR is the name given to several genes which code for the enzyme of the same name. Because it’s a genetic matter, we’re concerned with how the mutated versions of the genes are handed down. MTHFR is not a disease, though, so “dominant” and “recessive” are non-issues. Rather, the degree of dysfunction is dependent on which and how many mutations an individual receives. (See the previous post for more information.) It can be a little confusing for parents to sort out the likelihood of their children’s receiving certain combinations of mutations, so let’s take a closer look, with some illustrations.
Some of you may remember Punnett squares from your high school biology days. One of the most common illustrations used is blue vs. brown eyes, and a Punnett square for working that out looks something like this:
Designations for one parent’s gene pair is written across the top (we’ll call that Dad), and designations for the other parent’s gene pair is written down the left side (we’ll call that Mom). In this case, the capital B is for brown (capital because brown is dominant) and the lowercase b is for blue (because blue is recessive). Each of the blocks of the grid indicates the intersection of a potential marker handed down from Dad and one handed down from Mom, so when the chart is full, each block shows a possible combination their offspring could receive.
In this example, Mom and Dad each have one brown-eye gene and one blue-eye gene. Looking at the completed chart, we can see that for each child they produce, there’s a 50% chance (2 in 4) the child will also receive one of each, a 25% chance (1 in 4) he’ll receive two brown-eye genes, and a 25% chance (1 in 4) he’ll receive two blue-eye genes. (Not directly relevant to our discussion, but in case you were wondering about the dominance, this equates to a 75% chance of brown eyes, since a recessive trait requires two matching copies.)
Are you with me so far?
Let’s apply this same principle to MTHFR. Since we’re not looking at a dominant or recessive trait but, rather, a reduction in enzyme for each mutation, we won’t use letters; we’ll use these smiley/sad faces. (For now, we’re only looking at a single MTHFR gene.)
In this instance, the sad face is a “bad” or mutated copy, and a smiley face is a “good,” normal, or “wild-type” copy. In our example, both Mom and Dad are heterozygous for this gene. (See the previous post for more detail. In short, that means each parent has one “bad” copy and one “good” copy — which you can see in the image.)
The offspring in this instance has a 25% chance of having no mutation (on this gene), a 50% chance of being heterozygous, and a 25% chance of being homozygous.
Let’s try a slightly different example. What if dad is heterozygous but Mom is homozygous?
In this instance, the child has a 50% chance of being heterozygous for this gene, a 50% chance of being homozygous, and no chance of not inheriting any mutation.
Looking at Multiple Genes
Unfortunately, MTHFR is a little more complicated than that, because there are two major genes that impact the enzyme. So you may want to know what the chances are of your children inheriting various combinations of these two genes. The chart gets a little more complex here, but it can be done. It can be a little confusing at first; look carefully at the diagram, and draw it out yourself on paper if you need to, and you’ll get it. (It isn’t hard, just a little hard to keep track of all the “moving parts”!)
So what we want to do here is make a graph where all the different combinations a parent could possibly pass down are across the top and down the left, rather than individual genes. Depending on the starting point, this may result in graphs of different sizes. For our example, we’re going to use one parent who is compound heterozygous (has one “bad” copy of each of the two major MTHFR genes) — this is “Dad,” across the top of the chart — and one parent who is homozygous (two “bad” copies) for one of the major genes but has no mutations on the other — this is “Mom,” down the left.
Take a moment to look carefully at the chart and make sure you understand why we have what we do across the top and down the left. I’ve added colored rings to indicate the two different genes. Let’s say blue is C677T and red is A1298C, for the sake of this illustration.
Mom has only “good” copies of C677T, so that’s all she can hand down, and only “bad” copies of A1298C. So on the left we have only one option — Mom must pass down a “good” C677T and a “bad” A1298C. There are no other choices.
Dad, however, has one “bad” copy of each, so there are several possibilities. He could pass down his “good” copy of both, or his “bad” copy of both (see the first and last columns). Or he could pass down one “good” C677T and one “bad” A1298C. Or the other way around. (See the center two columns.)
Make sure you’re straight on this, and then we can move on to the blocks in the grid. Each block in the grid is once again an intersection of an option handed down from Dad and one from Mom. So, for instance, in our first square we have the scenario where the child received both of Dad’s “good” copies, and the necessary one of each from Mom. And so on across the chart.
Now, you might be wondering why we can get away with only one row representing Mom, even though there’s one possible combination. (If this wasn’t a curiosity for you, just skip this paragraph so it doesn’t unnecessarily confuse you!) Mathematically, don’t we need to consider that even though the combinations are the same, there are two copies, so it’s doubled? No, this isn’t necessary. If you want to test it, you can draw a second row using the same combination again. What you’ll find is that although the numbers change, the percentages don’t. The chance of having no C677T mutation and only one A1298C mutation, for instance, becomes 2/8 rather than 1/4 — but that’s still a 25% chance.
Getting back on track…
Here’s what that looks like when we add the terminology to it:
(The parenthetical ones just mean “for one gene.”)
Now, your genetic combination and your spouse’s might be different than this. That’s all right; you can still draw it out in the same manner. You just need as many columns and rows as it takes to account for all the combinations a given parent could possibly pass down. Once you have those drawn out, go back into the blocks and put Dad’s and Mom’s together.