It’s no accident that this system has only arisen in mammals. Female mammals make an extraordinarily large investment in the development of their offspring. They keep them inside their body, sharing nutrients with them via the placenta. Now, there are plenty of examples in other classes where a female invests in her young. Think of birds incubating their eggs, or crocodiles building elaborate nest piles and carefully regulating the temperature. But in no other class does the female actually nourish the developing embryos so dramatically.
But for good evolutionary reasons, there is a limit to this degree of maternal commitment. In terms of passing on her genes successfully, the female mammal would prefer to have more than one shot on goal. It’s possible that there may be other potential mates who are fitter (in evolutionary terms) than the one whose offspring she is carrying. So although she invests a lot in each pregnancy, it makes sense for the female to be able to breed more than once. There is a definite benefit to ensuring that the developing embryo or embryos gain enough nutrition from her that they have an excellent chance of surviving and reproducing themselves. But it doesn’t make sense to divert such a large amount of nutrition to the embryo that the mother ends up losing so much condition that she doesn’t survive or is subsequently infertile.
But the same isn’t really true for the male. It doesn’t really matter to him if his offspring draw so much nutrient from their mother that she never reproduces again. In evolutionary terms, all he wants is for his offspring to be as well-nourished and strong as possible, so that they have the greatest chance of reaching sexual maturity and passing on his genes. He is likely to breed with other females, as relatively few mammals mate for life.
Female mammals can’t make decisions about the proportion of nourishment they pass on to the embryos in the uterus. They aren’t like birds who can abandon a nest. So evolution has reached an epigenetic stand-off in a nutritional arms race. Imprinting has evolved to balance out the competing demands of the male and female contributions to the genome. At a small number of genes, epigenetic modifications on the DNA inherited from the father set up patterns of gene expression that promote embryo growth. At the same genes, a different pattern of epigenetic modifications on the DNA inherited from the mother has the opposite effect.
During development, the relevant paternal genes often drive expression of a large, efficient placenta, as this is the organ that nourishes the embryos. That’s why in the hydatidiform moles, where all the genetic material is from the father, there is an abnormal and very large placenta.
The number of imprinted protein-coding genes is fairly small, about 140 in mice.{184} They occur in clusters of between two and twelve genes and many of these clusters are quite similar to those in the human genome.{185} Perhaps unsurprisingly, the number of imprinted genes is much lower in marsupials where the young are only nourished in utero for a rather short period.{186}
The most critical component in each cluster is a region of junk DNA that controls the expression of the protein-coding genes. This critical component is called the imprinting control element, or ICE. It’s a little like lighting a room with twelve light bulbs. If you want to adjust the level of light in the room, you could use a range of bulbs with different luminosities, and you could have a separate switch for each. But that’s a fairly labour-intensive way of controlling the overall light level. Much better to have all twelve bulbs on one circuit and control them simultaneously with either an on/off switch or a dimmer switch if you want a bit more flexibility.
The ICE acts as the central dimmer switch, but there’s a slight complication compared with our electrical analogy. The reason why the ICE is important is because it is responsible for driving the expression of a large non-coding RNA molecule. This long non-coding RNA can switch off the expression of the genes in the surrounding cluster. So, essentially, imprinting is critically dependent on two types of junk DNA — ICE regions on the genome, and the long non-coding RNAs the ICEs control. If the long non-coding RNA at a specific cluster is switched on, it switches off expression of the protein-coding genes in that cluster. On the other hand, if the long non-coding RNA driven by the ICE is repressed, the protein-coding genes in the cluster can be activated.
Imprinting critically depends on the junk DNA and its crosstalk with the epigenetic system. The ICE can be epigenetically modified. Expression of the long non-coding RNA is dependent on whether or not the DNA at its ICE is methylated. If the ICE DNA is methylated, this prevents expression of the long non-coding RNA. If the ICE has escaped methylation, the long non-coding RNA will be expressed. Essentially there is a reciprocal arrangement. If the long non-coding RNA is expressed, the genes in the cluster on the same chromosome will be switched off. If the long non-coding RNA is not expressed, the genes in the cluster on the same chromosome will be switched on. The long non-coding RNAs in the imprinted regions are sometimes extraordinarily long, the biggest being a staggering 1 million bases in length.{187}
Unfortunately, we are still a bit sketchy in our understanding of the exact mechanisms that the long non-coding RNAs use to repress the expression of the nearby gene cluster. It certainly seems to involve the epigenetic system again, resulting in the deposition of repressive epigenetic modifications on the protein-coding genes. If key epigenetic genes such as the major repressor that we met in Chapter 9 are knocked out in developing embryos, some of the imprinted genes that would normally be switched off are expressed.{188} It’s not just restricted to the major repressor either, as knockout of other epigenetic genes that establish repressive histone modifications has similar effects.{189},{190} This demonstrates the importance of the epigenetic system in carrying out the instructions of the long non-coding RNA. It’s likely this is because the long non-coding RNA attracts these enzymes to the imprinted cluster, thereby targeting the histone modifications to the protein-coding genes.
Epigenetic modifications are also present at the ICE itself. As we would expect, if the ICE DNA is methylated, the histone modifications are ones which are associated with switching genes off. If the ICE is unmethylated, the histone modifications are those which are associated with switching genes on. The pattern of epigenetic modifications on the ICE is completely consistent across the DNA and histone proteins.{191}
In the imprinting process, the critical determinant is whether or not the junk DNA forming the ICE is methylated or not. There have been suggestions that the methylation of the ICEs evolved when silencing of nearby parasitic elements such as those we met in Chapter 4 spread into neighbouring regions. This may have conferred a fitness advantage, and been selected for in subsequent generations.{192} It’s intriguing that in the most primitive mammals, the egg-laying monotremes such as the duck-billed platypus and the echidna, there are uncharacteristically few parasitic elements near the regions where we would expect to find the ICEs in higher mammals.{193}
But how does the methylation pattern become established at the ICE in modern mammals and passed on, given that it is not dependent on differences in DNA sequences between the maternally and paternally derived genomes? How does it get set properly? A woman will inherit imprinted regions from her father in which the ICE is methylated/non-methylated to signify she received this region from her dad. But if she passes this same imprinted region on to her child, this paternal imprint must be removed and replaced with one showing it came from mother.