The Epigenetics Revolution полностью

^{Figure 5.4 Variations in DNA methylation (represented by black circles) influence expression of a retrotransposon. The variation in expression of the retrotransposon in turn affects expression of the agouti gene, leading to coat colour variability between genetically identical animals.}

Here, DNA methylation is effectively working like a dimmer switch. When the retrotransposon is unmethylated, it shines to its fullest extent, producing lots of the abnormal RNA. The more the retrotranposon is methylated, the more its expression gets turned down.

The agouti mouse has provided a quite clear-cut example of how epigenetic modification, in this case DNA methylation, can make genetically identical individuals look phenotypically different. However, there is always the fear that agouti is a special case, and maybe this is a very uncommon mechanism. This is particularly of concern because it’s proved very difficult to find an agouti gene in humans – it seems to be in that 1 per cent of genes we don’t share with our mouse neighbours.

There is another interesting condition found in mice, in which the tail is kinked. This is called Axin-fused and it also demonstrates extreme variability between genetically identical individuals. This has been shown to be another example where the variability is caused by differing levels of DNA methylation in a retrotransposon in different animals, just like the agouti mouse.

This is encouraging as it suggests this mechanism isn’t a one off, but kinked tails still don’t really represent a phenotype that is of much concern to the average human. But there’s something we can all get on board with: body weight. Genetically identical mice don’t all have the same body weight.

No matter how tightly scientists control the environment for the mice, and especially their access to food, identical mice from inbred mouse strains don’t all have exactly the same body weight. Experiments carried out over many years have shown that only about 20–30 per cent of the variation in body weights can be attributed to the post-natal environment. This leaves the question of what causes the other 70–80 per cent of variation in body weight[35]. Since it isn’t being caused by genetics (all the mice are identical) or by the environment, there has to be another source for the variation.

In 2010, Professor Emma Whitelaw, the terrifically enthusiastic and intensely rigorous mouse geneticist working at the Queensland Institute of Medical Research, published a fascinating paper. She used an inbred strain of mice and then used genetic engineering to create subsets of animals which were genetically identical to the starting stock, except that they only expressed half of the normal levels of a particular epigenetic protein. She performed the genetic engineering independently in a number of mice, so that she could create separate groups of animals, each of which was mutated in a different gene coding for epigenetic proteins.

When Professor Whitelaw analysed the body weights of large numbers of the normal or mutated mice, an interesting effect appeared. In a group of normal inbred mice, most of the animals had relatively similar body weights, within the ranges found in many other studies. In the mice with low levels of a certain epigenetic protein, there was a lot more variability in the body weights within the group. Further experiments published in the same paper assessed the effects of the decreased expression of these epigenetic proteins. Their decreased expression was linked to changes in expression levels of selected genes involved in metabolism[36], and increased variability in that expression. In other words, the epigenetic proteins were exerting some control over the expression of other genes, just as we might expect.

Emma Whitelaw tested a number of epigenetic proteins in her system, and found that only a few of them caused the increased variation in body weight. One of the proteins that had this effect was Dnmt3a. This is one of the enzymes that transfers methyl groups to DNA, to switch genes off. The other epigenetic protein that caused increased variability in body weight was called Trim28. Trim28 forms a complex with a number of other epigenetic proteins which together add specific modifications to histones. These modifications down-regulate expression of genes near the modified histones and are known as repressive histone modifications or marks. Regions of the genome that have lots of repressive marks on their histones tend to become methylated on their DNA, so the Trim28 may be important for creating the right environment for DNA methylation.