The Epigenetics Revolution by Nessa Carey- Study Notes pt. 5 [Ch. 6]

Previous parts: 1, 2, 3, 4

 

So in this part we’ll be looking at epigenetic inheritance- more precisely, the question of whether epigenetic marks, be they DNA methylation or histone modifications, are passed on from generation to generation. The relevant experimental model here is, unsurprisingly, the mouse.

We need to bring back the agouti gene mouse talked about in the last part. In an experiment done by Emma Whitelaw, it was seen that a yellow mother only gives birth to yellow or lightly colored pups, never a dark one; while a dark mother may give birth to some dark pups. As was discussed in part 4- this particular phenotypic variation is epigenetic, not genetic. It was because of a retrotransposon being methylated that the agouti gene’s expression was silenced (lack of methylation would mean constitutive expression). So the fact that a phenotypic variation caused by epigenetic mechanisms is heritable goes some distance to prove that epigenetic patterns are in fact inherited.

Well, there are a few more complexities. For any such mother-offspring non-DNA inheritance, there are three possible explanations:

  1. It could be due to DNA methylation and/or histone modification marks being inherited transgenerationally, which is what we’re interested in.
  2. It could be due to the intrauterine environment that the offspring comes to have those peculiar features. In this case, perhaps the agouti gene affects other aspects of the organism, which may include the environment where the fetus is developed, or specific modes in which the fetus gets nutrition, etc. In that case, it’s not really epigenetic marks that are being inherited, but the fetus is affected by the way the mother’s intrauterine environment is set up (which in turn may have been due to the agouti gene, or some environmental effect or other).
  3. It could be that the cytoplasmic environment that the fetus receives from the egg is what’s responsible. The mother passes on quite a bit of cytoplasm in her egg, so maybe that was shaped in a particular way by genetics or environment, which contributed to the fetus’ development.

To rule out (2) above, scientists took fertilized eggs from a yellow mother and implanted it into a dark one and got the same results, showing intrauterine environments weren’t responsible. Complex breeding schemes also ruled out (3), establishing firmly that DNA methylation in the case of agouti gene repression can indeed be inherited transgenerationally. Also, male-to-offspring inheritance of epigenetic marks has also been demonstrated- and that effectively rules out (2) and (3). In addition to not contributing to the intrauterine environment whatsoever, males also contribute very little in terms of cytoplasmic content (the sperm is tiny compared to the egg).

This, of course, brings us to an intriguing possibility. We established in earlier posts that the effects of the environment is preserved in biological organisms via epigenetic marks. But if epigenetic marks are inherited, does it mean environmental changes that happen within an organism’s life are also inherited? Does it, then, give credence to Lamarck’s idea that acquired traits are sometimes inherited? The answer to both of these questions is yes.

Two papers published in Nature and Cell did the most to argue this point. One group worked with male inheritance (to rule out 2 and 3 above) involving a breed of rat. The males were given a high-fat diet and allowed to mate with ordinary females. The former were overweight and had many symptoms of type-2 diabetes. Their offspring, while normal weight, also had many of these symptoms, including irregular metabolism. Another group ran a similar experiment with an inbred mouse strain, where the males were given a very low-protein diet, allowed to mate with normal females, and ended up producing offspring with metabolic abnormalities. This latter group found peculiar epigenetic modifications in the liver of the offspring as well. A remarkable case of transgenerational inheritance was seen among rats, where if a drug is administered to a pregnant rat at the time when the testes are developing, not only do the male offspring show reduced fertility, but the effect is carried over the next three generations.

All of this taken together prove beyond doubt that Lamarckian inheritance is more than just a historical curiosity- it’s a real thing that occurs.

In the first part of this series, we talked about the Dutch Hunger Winter, and how effects due to diet seemed to be transferred across generations. If a mother was underfed in the first trimester, her granddaughter born of the child she was carrying had a higher chance of being overweight. This is weird on the everyday conception of inheritance, seeing the baby she was carrying never underwent malnutrition in her life. One could chalk that up as evidence for Lamarckism, but that couldn’t be said with certainty until these experiments were done. For one, there’s always the question of reliability of old records. In addition, the effects could be explained by the peculiarities of either the intrauterine or cytoplasmic environments. But now with the controlled experiments involving different mammalian models and a number of traits, we’re in a position to say with much more confidence that traits acquired from the environment (in molecular biology terms- DNA methylation of particular genes) are, under certain circumstances, transferred across generations.

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