Putting my gametes where my mouth is

I promised to tell you why I am not freaking out about the possibility that JD's one mutation can cause our sons to lack the sperm delivery vehicle. So here comes.

I teach biology and study how to teach it well. Which means that I demand one thing above all from my students-- that they think. Sad but true-- precious few show up these days to the institutions of higher learning with a good set of skills in this area. Much of what I do professionally is aimed at helping those who did not develop this skill set before surrendering themselves to my tender mercies. So I teach scientific process and reasoning, and I demand that my students apply both. Along with the body of knowledge available to them. So it only seems fair that I should demand no less from myself when the subject at hand is our very own reproductive decisions.

Let's take it step by step then. But before we do, we have to have a little vocabulary lesson. Partially because I am used to using the terminology, and partially because this stuff is complicated enough that using the terminology correctly actually helps to keep things straight (at least in my opinion). Ok, so our genetic information is encoded in a molecule called DNA. The shape of it is two strands that each have a direction running in opposite directions twisting together to form the famous double helix. The backbone on those strands is uniform along the entire length, and the information is encoded in the pieces that are located on the inside of the double helix and are called bases. There are four bases-- A, T, G, and C. These bases pair with each other to stabilize the molecule of DNA, A with T and C with G. This is how it is possible to reconstruct the sequence of each of the strands in the double helix by looking at the other-- just reverse the direction and write down the partner base. DNA in our cells is kept in chromosomes, of which we have 46, 23 from mom and 23 from dad. 22 of 23 are autosomes, meaning they exist in both males and females, and one is the sex chromosome-- females have XX (one X from each) and males have XY (X from mom and Y from dad).

Genes are units of genetic information. They encode which proteins are made, when, and in what quantities. Genes do not occupy the whole length of the chromosomes-- there are also stretches of DNA that have no function we understand today. Each chromosome contains hundreds to thousands of genes, in addition to that space we don't know much about. If one or more of the bases in a part of a chromosome that corresponds to a gene gets changed in some way-- deleted, repeated, substituted with a different base, whether, when, how much, and what protein is made may change. These different changed versions of the same gene are called alleles. In genetics problems alleles are usually labeled to indicate that they are versions of the same gene, such as D and d, for example. In real life, alleles are often named for how they differ from the "normal" allele which is called wild type. To the first approximation, we have two alleles for each of our genes-- one from mom and one from dad (except, of course, for the genes found exclusively on the Y chromosome).

Some alleles are responsible for differential traits, such as eye color, or a disease. Some traits are dominant, such that it is enough to have one allele associated with the trait to exhibit the trait, so an individual with alleles Dd would exhibit the trait. Other traits are recessive, such that in order to exhibit the trait an individual needs to have a copy of the allele from both mom and dad, i.e. only dd individuals will exhibit the trait. But real life is messy, and sometimes these dominant traits do not exhibit full penetrance, which means that some Dd individuals will exhibit the trait, and some won't.

And this appears to be the situation with JD'd mutation. He is a carrier (i.e. an individual with the Dd genetic background, who is unaffected by the disease but is carrying the d allele and can pass it on to his offspring) of a particular allele of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the gene defects in which are responsible for cystic fibrosis (CF), but only when both copies are defective. Well, it turns out that this particular gene gets around, and in some cases of the congenital bilateral absence of vas deferens (CBAVD) the patients are of the Dd persuasion for the CFTR gene. Like JD, although he himself doesn't have that trait. And since he only has a D or a d to offer to our offspring, while I apparently got it made with a D and another D (i.e. I am DD on this as per the test at the time of my pregnancy with Monkey-- we may have to examine my alleles more closely to make sure one of the rarer alleles wasn't missed to make the final decision), our kids have a 50% chance of being carriers for this allele themselves. And if a kid in question is a boy, he might, with some probability, have CBAVD.

So why am I not running through the streets screaming my head off? Well, because it is entirely unclear to me how big the risk actually is. I couldn't find any statistics on what percentage of men who are Dd for CFTR actually have CBAVD. It makes sense that these statistics are lacking because men who can procreate successfully won't even know their genetic make up with respect to this. It also makes sense that the percentage has to be rather low, or the spread of CF would've come to a screeching halt some time ago since (1) to have CF you need to have two defective alleles; (2) one of these has to have come from your father; (3) if most men with Dd had CBAVD, they would not be able to procreate. So there would be no new CF cases. Which would be nice, but clearly isn't what actually is hapening.

Moreover, did you know that there is a lot of different alleles of the CFTR gene? And some combinations of d1d2 lead to CF. Some combinations lead to more severe CF, and some to less severe. I also found this interesting paper that showed that in many cases of CBAVD the patient is also d1d2 for CFTR (i.e it is possible that CBAVD is also a recessive trait for which not all culprit alleles have been identified, rather than a dominant trait with incomplete penetrance as I suggested above).

So what we have is unknown odds of passing along a genetic condition which may amount to infertility for a boy offspring of ours. The way to avoid these unknown odds is to go with PGD, preimplantation genetic diagnosis, and to discard the embryos found to have the Dd variety. PGD, of course, comes with its own set of issues, such that not all embryos survive the test. And if we have to go with ICSI, we may already be looking at a smaller number of viable embryos.

If I assigned a problem like that to my students, I would want them to say that deciding on a course of action should depend on what the unknown odds are and on how much is the risk of having a baby with CBAVD personally important to us. To which I would have to say, right now, not important enough to discard an otherwise good-looking embryo.

And so we are back to weighing the probabilities-- the probability of a boy baby having CBAVD given the Dd genetics vs the probability that a good-looking embryo will be thwarted because of trying to prevent CBAVD. And I am not sweating it because I figure I will go and see what the genetics counselors have to say about these odds. Maybe there are actual numbers out there that will help us make a decision. I hope so. I will also suggest that my alleles of CFTR get reexamined to determine whether I am really only able to contribute Ds to our offspring. But in the meantime, the problem has no solution due to incomplete information, and we wait.