The Epigenetics Revolution

It’s also important to remember that a human egg is large. It contains a nucleus which is relatively small in volume compared to the surrounding cytoplasm. Imagine a grape inside a satsuma to gain some idea of relative sizes. The cytoplasm carries out a lot of functions when an egg gets fertilised. Perhaps something occurred during early developmental programming in Basje that ultimately resulted in the cytoplasm of her eggs containing something unusual. That might sound unlikely but egg production in female mammals is actually initiated early in their own embryonic development. The earliest stages of zygote development rely to a large extent on the cytoplasm from the egg. An abnormality in the cytoplasm could stimulate an unusual growth pattern in the foetus. This again would result in transgenerational inheritance but not through the direct transmission of an epigenetic modification.

So we can see that there are various mechanisms that could explain the inheritance patterns seen through the maternal line in the Dutch Hunger Winter survivors. It would help us to understand if epigenetics plays a role in acquired inheritance if we could study a less complicated human situation. Ideally, this would be a scenario where we don’t have to worry about the effects of the intra-uterine environment, or the cytoplasm of the egg.

Let’s hear it for fathers. Because men don’t get pregnant, they can’t contribute to the developmental environment of the foetus. Males also don’t contribute much cytoplasm to the zygote. Sperm are very small and are almost all nucleus – they look like little bullets with tails attached. So if we see transgenerational inheritance from father to child, it isn’t likely to be caused by intra-uterine or cytoplasmic effects. Under these circumstances, an epigenetic mechanism would be an attractive candidate for explaining transgenerational inheritance of an acquired characteristic.

Greedy fellows in Sweden

Some data suggesting that male transgenerational inheritance can occur in humans comes from another historical study. There is a geographically isolated region in Northern Sweden called Överkalix. In the late 19th and early 20th centuries there were periods of terrible food shortages (caused by failed harvests, military actions and transport inadequacies), interspersed with periods of great plenty. Scientists have studied the mortality patterns for descendants of people who were alive during these periods. In particular, they analysed food intake during a stage in childhood known as the slow growth period (SGP). All other factors being equal, children grow slowest in the years leading up to puberty. This is a completely normal phenomenon, seen in most populations.

Using historical records, the researchers deduced that if food was scarce during a father’s SGP, his son was at decreased risk of dying through cardiovascular disease (such as stroke, high blood pressure or coronary artery disease). If, on the other hand, a man had access to a surfeit of food during the SGP, his grandsons were at increased risk of dying as a consequence of diabetic illnesses[42]. Just like Camilla in the Dutch Hunger Winter example, the sons and grandsons had an altered phenotype (a change in the risk of death through cardiovascular disease or diabetes) in response to an environmental challenge they themselves had never experienced.

These data can’t be a result of the intra-uterine environment nor of cytoplasmic effects, for the reasons outlined earlier. Therefore, it seems reasonable to hypothesise that the transgenerational consequences of food availability in the grandparental generation were mediated via epigenetics. These data are particularly striking when you consider that the original nutritional effect happened when the boys were pre-pubescent and so had not even begun to produce sperm. Even so, they were able to pass an effect on to their sons and grandsons.

However, there are some caveats around this work on transgenerational inheritance through the male line. In particular, there are risks involved in relying on old death records, and extrapolating backwards through historical data. Additionally, some of the effects that were observed were not terribly large. This is frequently a problem when working with human populations, along with all the other issues we have already discussed, such as our genetic variability and the impossibility of controlling environment in any major way. There is always the risk that we draw inappropriate conclusions from our data, rather as we believe Lamarck did with his studies on the families of blacksmiths.

The heretical mouse