Figure 6.1 The effects of malnutrition across two generations of children and grandchildren of women who were pregnant during the Dutch Hunger Winter. The timing of the malnutrition in pregnancy was critical for the subsequent effects on body weight.
The effects on the birth weight of baby Camilla shown at the bottom left are really odd. When Camilla was developing, her mother Basje was presumably healthy. The only period of malnutrition that Basje had suffered was twenty or more years earlier, when she was going through her own first stages of development in the womb. Yet it seems that this has an effect on her own child, even though Camilla was never exposed to a period of malnutrition during early development.
This seems like a good example of transgenerational (Lamarckian) inheritance, but has it has been caused by an epigenetic mechanism? Did an epigenetic change (altered DNA methylation and/or variations in histone modifications) that had occurred in Basje as a result of malnutrition during her first twelve weeks of development in the womb get passed on via the nucleus of her egg to her own child? Maybe, but we shouldn’t ignore that there are other potential explanations.
For example, there could be an unidentified effect of the early malnutrition which means that when pregnant, Basje will pass more nutrients than normal across the placenta to her foetus. This would still create a transgenerational effect – Camilla’s increased size – but it wouldn’t be caused by Basje passing on an epigenetic modification to Camilla. It would be caused by the conditions in the womb when Camilla was developing and growing (the intra-uterine environment).
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.
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.
Is there an alternative way of investigating transgenerational inheritance? If this phenomenon also occurs in other species, it would give us a lot more confidence that these effects are real. This is because experiments in model systems can be designed to test specific hypotheses, rather than just using the datasets that nature (or history) provides.
This is where we come back to the agouti mouse. Emma Whitelaw’s work showed that the variable coat colour in the agouti mouse was due to an epigenetic mechanism, specifically DNA methylation of a retrotransposon in the agouti gene. Mice of different colour all had the same DNA sequence, but a different degree of epigenetic modification at the retrotransposon.
Professor Whitelaw decided to investigate if the coat colour could be inherited. If it could, it would show that it’s not only DNA that gets transmitted from parent to offspring, but also epigenetic modifications to the genome. This would provide a potential mechanism for the transgenerational inheritance of acquired characteristics.
When Emma Whitelaw allowed female agouti mice to breed, she found the effect that is shown in Figure 6.2. For convenience, the picture only shows the offspring who inherited the Avy retrotransposon from their mother, as this is the effect we are interested in.
If the mother had an unmethylated Avy gene, and hence had yellow fur, all her offspring also had either yellow fur, or slightly mottled fur. She never had offspring who developed the very dark fur associated with the methylation of the retrotransposon.