The Epigenetics Revolution

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.

By contrast, if the mother’s Avy gene was heavily methylated, resulting in her having dark fur, some of her offspring also had dark fur. If both grandmother and mother had dark fur, then the effect was even more pronounced. About a third of the final offspring had dark fur, compared with the one in five shown in Figure 6.2.

^{Figure 6.2 The coat colour of genetically identical female mice influences the coat colour of their offspring. Yellow female mice, in whom the agouti gene is expressed continuously, due to low levels of DNA methylation of the regulatory retrotransposon, never give birth to dark pups. The epigenetically – rather than genetically – determined characteristics of the mother influence her offspring.}

Because Emma Whitelaw was working on inbred mice, she was able to perform this experiment multiple times and generate hundreds of genetically identical offspring. This was important, as the more data points we have in an experiment, the more we can rely on the findings. Statistical tests showed that the phenotypic differences between the genetically identical groups were highly significant. In other words, it was very unlikely that the effects occurred by chance[43].

The results from these experiments showed that an epigenetically-mediated effect (the DNA methylation-dependent coat pattern) in an animal was transmitted to its offspring. But did the mice actually inherit directly an epigenetic modification from their mother?

There was a possibility that the effects seen were not directly caused by inheritance of the epigenetic modification at the Avy retrotransposon, but through some other mechanism. When the agouti gene is switched on too much, it doesn’t just cause yellow fur. Agouti also mis-regulates the expression of other genes, which ultimately results in the yellow mice being fat and diabetic. So it’s likely that the intra-uterine environment would be different between yellow and dark pregnant females, with different nutrient availability for their embryos. The nutrient availability could itself change how particular epigenetic marks get deposited at the Avy retrotransposon in the offspring. This would look like epigenetic inheritance, but actually the pups wouldn’t have directly inherited the DNA methylation pattern from their mother. Instead, they’d just have gone through a similar developmental programming process in response to nutrient availability in the uterus.