How Genetic Imprinting Works: Mechanisms and Diseases
Genetic imprinting is the phenomenon by which one parent’s copy of a gene is expressed, while the other parent’s copy is inhibited. During parental gametogenesis, the genetic material is "wiped clean" of epigenetic alterations (such as methylation) to provide a clean slate for any necessary epigenetic modifications for the offspring. One such modification that is added following this erasure is methylation, which dictates which parent’s gene to express.
One important case of imprinting occurs on chromosome 11 in mice. The genes of interest on this chromosome, Igf2 and H19, dictate mouse growth. The maternal chromosome 11 will be demethylated during oogenesis, and it is never re-methylated. Thus, the differentially methylated region (DMR) of chromosome 11 is not methylated in the maternal copy of chromosome 11 passed on to the offspring. The situation is reversed in spermatogenesis: following initial demethylation, de novo methylation re-methylates the DMR. Thus, the offspring's paternal copy of chromosome 11 has a methylated DMR.
The mechanism of the effect of DMR methylation status on the expression of Igf2/H19 is as follows:
The inhibitors for Igf2 and H19 are circulating. If the DMR is not methylated, then the Igf2 inhibitor binds because H19 inhibitor cannot. This is maternal. H19 is transcribed since the inhibitor hasn’t bound.
The inhibitors for Igf2 and H19 are circulating. If the DMR is methylated, then the H19 inhibitor binds because Igf2 inhibitor cannot. This is paternal. Igf2 is transcribed since the inhibitor hasn’t bound.
To summarize, methylation status on the DMR dictates which gene, Igf2 or H19, is expressed, in a given chromosome. Ideally, the offspring will receive one maternal and one paternal chromosome, so the offspring will have a balance of Igf2 (growth-promoting) and H19 (growth-inhibiting) associated factors.
Here's a short way to remember this:
Good Igf2 = larger = good for dad = paternal
Good H19 = smaller = good for mom = maternal
Human genes can also be transmitted with imprinting patterns. Normally, the PWS and AS genes on chromosome 15 are transmitted via imprinting. However, in the cases of Prader-Willi Syndrome (PWS) and Angelman Syndrome (AS), the offspring's chromosomes lack an active PWS or AS gene, respectively, due to a deletion of both sites in one parent.* PWS results from paternal deletion of this region of chromosome 15. The maternal copy expresses AS, so the offspring lacks an active copy of the PWS gene to balance this out. Conversely, when the maternal region of chromosome 15 is deleted, only the paternal active PWS is expressed in the offspring, causing AS syndrome due to a lack of the active AS gene. PWS patients are often obese and have reduced motor function. AS patients are often thin, hyperactive, and frequently suffer from seizures.
*EDIT: I wrote this back when I was young and ignorant, two or so weeks ago. Here’s the truth: there is only one site involved in PWS and AS; if the chromosome with the deletion is inherited from the mother, AS will result. If inherited from the father, PWS will result. The rest of this is correct, though.
Here's a short way to remember this:
PWS syndrome = no PWS gene = low activity = paternal deletion
AS syndrome = no AS gene = high activity = maternal deletion
And this, my friends, is my understanding of imprinting!
Extra:
I used Brooker's Genetics 6ed and my notes from deep within Google Drive. Further reading: Brooker's Genetics 6ed Chapter 5. All images (except cover) from Brooker’s.
ANOTHER UPDATE: (3/9)
So I’m looking over this article again and it seems to not explain this concept very well. I’ve missed a lot of context (tbh, at the time of writing the article, I didn’t really get it). So here’s some videos I found that contextualize this article:
