This post (and chapter) has to do with a question we discussed in the opening post of this series: why are identical twins not identical in every way? Consider schizophrenia. Since it’s been proven to have a genetic basis, if one of the twin were schizophrenic- we’d expect the other to be so too. But that happens only half the time. That probability is still tragic, but given that this disease has a genetic basis, and identical twins have identical genomes, shouldn’t we expect both pairs to have the condition if either has it?
Scientists have designed interesting experiments to answer this question. Let’s consider our model first: genetically identical mus musculus. We’re looking at three genetic varieties based on the color of their hair.
Normal mouse- Has banded hair, which means their hair is black at the top and bottom (root), but yellow in the middle. This particular phenotype is due to the agouti gene. In normal mice, the agouti gene is switched on and off cyclically, resulting in this banded pattern.
Mouse with a genotype- The agouti gene for them is wholly inactive, and their hair is black all the way as a result.
Mouse with Avy genotype- For this interesting variety, there’s a retrotransposon insertion just upstream of the agouti gene. This element codes for a piece of RNA that messes with agouti regulation, keeping it switched on permanently. As a result, Avy mice have yellow hair all the way through.
Scientists crossed pure Avy breed with the a variety, resulting in a strain with an Avy/a genotype. Avy happens to be dominant over a, so scientists expected all the mice to have yellow hair. That, however, didn’t happen- the mice, although genetically identical, had their hair color varying across the board:
Why would this extent of variation be noticed in genetically identical mice, who were all supposed to be yellow?
The answer is given by epigenetics. It was discovered that the aforementioned retrotransposon which controlled the transcription of the agouti gene could be methylated. In some of the mice, this was heavily methylated, reducing the activity of the agouti gene and expression of yellow hair. In others, the amount of methylation was low which let the retrotransposon keep the gene almost permanently active.
This sort of epigenetic-level control has been noticed not only in the case of hair color, but also for kinked tails, body weight, and other phenotypic properties. This mechanism seems representative of how epigenetic modifications can tinker with expression of particular genes even among genetically identical individuals. There are some additional observations to be made here.
First, this and other experiments showed epigenetic proteins to have a clear purpose. Naked DNA- without any epigenetic interference- would be subject to random transcription. Genes would be switched on all over the place without any rhyme or reason. This sort of spurious transcription is often called transcriptional noise. The key function of epigenetic proteins is to reduce this noise. Reduce, mind you, not eliminate- they function as something of a dimmer switch. In the agouti gene experiment above, the level of transcription was reduced by methylation to different degrees in different mice.
From the perspective of the cell, this sort of transcription dimming is something of a balancing act- on one hand, this gives the cell some flexibility to switch certain genes on and off. The cells have a degree of transcriptional autonomy which wouldn’t have been afforded to it were epigenetics to turn off transcription altogether. This sort of autonomy would be required if the cell faces adverse environmental conditions, say, where it would need to express proteins which it had no need of otherwise. On the other hand, the epigenetic control of genes also keep the cells committed enough to their respective lineage, to make sure rods don’t start expressing hemoglobin all of a sudden, say.
Second, there’s a degree of stochasticity or randomness to this process. There’s no easily graspable reason that can be offered within the realm of biology as to why certain mice get more or less methylation than its siblings. To ask that question is just to ask why particular mutations happen in the DNA (some of it may be directed based on cell function and chromosome context- I’m not talking about that). That simply has to do with the randomness inherent in really small things interacting with each other. Similarly, in the case of agouti methylation, levels of methylation that are more or less stochastically fixed during early development stays with the organism throughout their lives. Which brings us to the next point.
Third, running with our earlier analogy (see last post) of seeing an organism’s development as a Rube Goldberg machine- in such a machine, earlier events determine its course in the longer run. Same goes for development. Epigenetics is incredibly significant during early development, because what the cells acquire in terms of epigenetic marks during this period tend to stay with them in the long run. These effects are also amplified as development wears on. As mentioned above, the setting down of these epigenetic marks can certainly be random within some extents, but it can also be affected by environment. Certain environmental nudges during early development are picked up by the cell’s epigenetic writers, and they remain with the organism.
This also helps to explain the other phenomenon we brought up in part 1 of this series- the Dutch Hunger Winter. Malnutrition during certain parts of early development endowed the developing baby with certain epigenetic marks, and that stayed with them for all time to come.