I’ve been busy — I’m teaching genetics this term, and usually the first two thirds of the course is trivial to prepare for — we’re covering Mendelian genetics, and the early stuff is material the students have seen before and are at least generally familiar with the concepts, and all I have to do is cover them a little deeper and with a stronger quantitative component. That’s relatively easy.
The last part of the course, though, is where we start moving into uncharted waters for them, and every year I have to rethink how I’m going to cover the non-Mendelian concepts, and sometimes my ideas work well, and sometimes they don’t. If I teach it for another 20 years, I’ll eventually reach the point where every lecture has been honed into a comprehensible ideal. At least that’s my dream.
Anyway, one of the subjects we’re covering in the next lecture or two is imprinting, and I know from past experience that this can cause mental meltdowns in my students. This makes no sense if you’re used to thinking in Punnett squares! So I’ve been reworking this little corner of the class, and as long as I’m putting together a ground-up tutorial on the subject, I thought I might as well put it on the web. So here you are, a basic introduction to imprinting.
Here’s a somewhat hypothetical situation. You have two genes, A and B, which have different roles in the two sexes. In females, A is inactivated by modification of the DNA — methyl groups are added to the DNA strand to prevent transcription. I’ve drawn it below with a little pink box to indicate the female pattern of methylation. The female still has two active copies of the B gene.
The male has the complementary pattern. He uses the A gene, but turns off the B gene with methyl groups. In my cartoon, I’ve drawn a little blue box to show the male pattern of methylation.
Now the happy couple produces gametes, eggs and sperm. The female produces egg cells that still have the female pattern of methylation—gene A is turned off. The male produces sperm that have gene B turned off. And then they get together at fertilization to produce a zygote or embryo which has a mixed pattern of methylation: on one chromosome, A is inactivated, and on the other chromosome, B is inactivated. This means that the zygote still has one functioning A and B gene…it has both working.
What’s described above is the normal state of affairs. Now it may be that the zygote needs both A and B genes functional — there could be functions at the sexually indifferent stage of early development that demand that both genes be operational. Later, when the sexes differentiate, then the embryo may change the pattern of methylation to that seen in one sex or the other. So, for instance, if the zygote happened to be male, it would remove the little pink methylation block to turn on both A genes, and put a blue methylation block on the B gene.
So far, so good, I hope. Now let’s look at an unusual situation.
This diagram is just like the one above, with one change. The male has a deletion on one chromosome, marked in red, that destroys both the A and B genes on that chromosome. He’s fine, though: he still has a working copy of the A gene on the other chromosome, and because he’s male, he had the B gene shut off anyway. It’s all good, until he starts producing sperm…and half of his sperm will carry the deletion, and therefore will not contribute either an A or B gene to his progeny.
With some genes, this is OK, because he can count on his female partner to provide good copies of the A and B genes, making up for his shortcoming. In this case, though, there’s a problem: yes, the mother provides an A and B gene, but the A gene is methylated or imprinted, and doesn’t do anything in the embryo! This can be big trouble if the A gene provides something essential for early development.
There’s another way this problem can come up that doesn’t involve a deletion—it’s called uniparental disomy.
In this case, the mother has a nondisjunction, an error in meiosis that produces an egg with two instead of one copy of the chromosome. This is bad news, because when fertilized by a normal sperm, the zygote will be trisomic for that chromosome. Trisomies are deleterious; the only viable autosomal trisomy in humans is trisomy 21, also known as Down syndrome, so this accident is most likely to result in a spontaneous abortion and loss of the embryo. However, sometimes in the cases of trisomies, cells will ‘kick out’ the extra chromosome and develop normally. That’s a useful mechanism for rescuing the embryo from a meiotic error, but in this case it has an additional problem.
What if the extra chromosome that is booted out is the one from the male?
Now the zygote is left with the right number of chromosomes (it is disomic), but they both come from one parent (uniparental), and have the pattern of imprinting of that parent. In this example, both A genes are maternally imprinted and blocked from expression, so the embryo is effectively lacking A.
Does this ever happen in the real world? Yes. In humans we’ve got one clear example, called Prader-Willi syndrome. There is a series of genes on chromosome 15 that have different patterns of methylation in males and females, and as diagrammed above, in normal cases the zygote receives both the male and female pattern of methylation, and all is well. If a zygote receives only the female pattern, either because of a deletion on the father’s chromosome or because of uniparental disomy, it will develop abnormally, exhibiting a range of common effects that include early hyperphagia (they can’t stop eating), obesity, and learning disabilities.
There is also a complementary syndrome. What if the deletion is on the maternal chromosome, so only the paternal pattern of gene expression is found in the zygote? It’s exactly the same genetics, but the sole difference is in whether the trait is passed on from the mother, or from the father. In this case, the child would have Angelman syndrome, cause by an absence of necessary maternal gene products. Angelman syndrome is much more severe, causing large developmental delays, seizures, and ataxia, or jerky movements (also, curiously, Angelman kids are often also cheerful, happy people).
The important point here is that you don’t just inherit genes: you also inherit a history of modification of those genes. Your chromosomes are modified by passage through your mother and your father, and normally, that pattern isn’t visible because the modifications complement each other to produce progeny with a functional mixture of active and inactive genes. In some cases, though, heritable or developmental changes to the chromosomes allow us to peek through and see the effect of imprinting.