The Epigenetics Revolution

One of the first aspects to be studied was the effect of the famine on the birthweights of children who had been in the womb during the famine. If a mother was well-fed around the time of conception and malnourished only for the last few months of the pregnancy, her baby was likely to be born small. If, on the other hand, the mother suffered malnutrition for the first three months of the pregnancy only (because the baby was conceived towards the end of this terrible episode), but then was well-fed, she was likely to have a baby with normal body weight. The foetus ‘caught up’ in body weight, because foetuses do most of their growing in the last few months of pregnancy.

But here’s the thing – epidemiologists were able to study these groups of babies for decades and what they found was really surprising. The babies who were born small stayed small all their lives, with lower obesity rates than the general population. Even more unexpectedly, the adults whose mothers had been malnourished only early in their pregnancy had higher obesity rates than normal. Recent reports have shown a greater incidence of other health problems as well, including certain aspects of mental health. If mothers suffered severe malnutrition during the early stages of pregnancy, their children were more likely than usual to develop schizophrenia. This has been found not just in the Dutch Hunger Winter cohort but also in the survivors of the monstrous Great Chinese Famine of 1958 to 1961, in which millions starved to death as a result of Mao Tse Tung’s policies.

Even though these individuals had seemed perfectly healthy at birth, something that had happened during their development in the womb affected them for decades afterwards. And it wasn’t just the fact that something had happened that mattered, it was when it happened. Events that take place in the first three months of development, a stage when the foetus is really very small, can affect an individual for the rest of their life.

This is completely consistent with the model of developmental programming, and the epigenetic basis to this. In the early stages of pregnancy, where different cell types are developing, epigenetic proteins are probably vital for stabilising gene expression patterns. But remember that our cells contain thousands of genes, spread over billions of base-pairs, and we have hundreds of epigenetic proteins. Even in normal development there are likely to be slight variations in the expression of some of these proteins, and the precise effects that they have at specific chromosomal regions. A little bit more DNA methylation here, a little bit less there.

The epigenetic machinery reinforces and then maintains particular patterns of modifications, thus creating the levels of gene expression. Consequently, these initial small fluctuations in histone and DNA modifications may eventually become ‘set’ and get transmitted to daughter cells, or be maintained in long-lived cells such as neurons, that can last for decades. Because the epigenome gets ‘stuck’, so too may the patterns of gene expression in certain chromosomal regions. In the short term the consequences of this may be relatively minor. But over decades all these mild abnormalities in gene expression, resulting from a slightly inappropriate set of chromatin modifications, may lead to a gradually increasing functional impairment. Clinically, we don’t recognise this until it passes some invisible threshold and the patient begins to show symptoms.

The epigenetic variation that occurs in developmental programming is at heart a predominantly random process, normally referred to as ‘stochastic’. This stochastic process may account for a significant amount of the variability that develops between the MZ twins who opened this chapter. Random fluctuations in epigenetic modifications during early development lead to non-identical patterns of gene expression. These become epigenetically set and exaggerated over the years, until eventually the genetically identical twins become phenotypically different, sometimes in the most dramatic of ways. Such a random process, caused by individually minor fluctuations in the expression of epigenetic genes during early development also provides a very good model for understanding how genetically identical Avy/a mice can end up with different coat colours. This can be caused by randomly varying levels of DNA methylation of the Avy retrotransposon.

Such stochastic changes in the epigenome are the likely reason why even in a totally inbred mouse strain, kept under completely standardised conditions, there is variation in body weight. But once a big environmental stimulus is introduced in addition to this stochastic variation, the variability can become even more pronounced.