The Epigenetics Revolution

The most useful mouse model for exploring how epigenetic changes can lead to phenotypic differences between genetically identical individuals is called the agouti mouse. Normal mice have hair which is banded in colour. The hair is black at the tip, yellow in the middle and black again at the base. A gene called agouti is essential for creating the yellow bit in the middle, and is switched on as part of a normal cyclical mechanism in mice.

There is a mutated version of the agouti gene (called a) which never switches on. Mice that only have the a, mutant version of agouti have hair which is completely black. There is also a particular mutant mouse strain called Avy, which stands for agouti viable yellow. In Avy mice, the agouti gene is switched on permanently and the hair is yellow through its entire length. Mice have two copies of the agouti gene, one inherited from the mother and one from the father. The Avy version of the gene is dominant to the a version, which means that if one copy of the gene is Avy and one is a, the Avy will ‘overrule’ a and the hairs will be yellow throughout their length. This is all summarised in Figure 5.2.

^{Figure 5.2 Hair colour in mice is affected by the expression of the agouti gene. In normal mice, the agouti protein is expressed cyclically, leading to the characteristic brindled pattern of mouse fur. Disruption of this cyclical pattern of expression can lead to hairs which are either yellow or black throughout their length.}

Scientists created a strain of mice that contained one copy of Avy and one copy of a in every cell. The nomenclature for this is Avy/a. Since Avy is dominant to a, you would predict that the mice would have completely yellow hair. Since all the mice in the strain are genetically identical, you would expect that they would all look the same. But they don’t. Some have the very yellow fur, some the classic mouse appearance caused by the banded fur, and some are all shades in-between, as shown in Figure 5.3.

^{Figure 5.3 Genetically identical mice showing the extent to which fur colour can vary, depending on expression of the agouti protein. Photo reproduced with the kind permission of Professor Emma Whitelaw.}

This is really odd, since the mice are all genetically exactly the same. All the mice have the same DNA code. We could argue that perhaps the differences in coat colour are due to environment, but laboratory conditions are so standardised that this seems unlikely. It’s also unlikely because these differences can be seen in mice from the same litter. We would expect mice from a single litter to have very similar environments indeed.

Of course, the beauty of working with mice, and especially with highly inbred strains, is that it’s relatively easy to perform detailed genetic and epigenetic studies, especially when we already have a reasonable idea of where to look. In this case, the region to examine was the agouti gene.

Mouse geneticists knew how the yellow phenotype was caused in Avy yellow mice. A piece of DNA had been inserted in the mouse chromosome just before the agouti gene. This piece of DNA is called a retrotransposon, and it’s one of those DNA sequences that doesn’t code for a protein. Instead, it codes for an abnormal piece of RNA. Expression of this RNA messes up the usual control of the downstream agouti gene and keeps the gene switched on continuously. This is why the hairs on the Avy mice are yellow rather than banded.

That still doesn’t answer the question of why genetically identical Avy/a mice had variable coat colour. The answer to this has been shown to be due to epigenetics. In some Avy/a mice the CpG sequences in the retrotransposon DNA have become very heavily methylated. As we saw in the previous chapter, DNA methylation of this kind switches off gene expression. The retrotransposon no longer expressed the abnormal RNA that messed up transcription from the agouti gene. These mice were the ones with fairly normal banded mouse coat colour. On other genetically identical Avy mice, the retrotransposon was unmethylated. It produced its troublesome RNA which messed up the transcription from the agouti gene so that it was switched on continuously and the mice were yellow. Mice with in-between levels of retrotransposon methylation had in-between levels of yellow fur. This model is shown in Figure 5.4.