The Epigenetics Revolution (13 page)
Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
The match may not be perfect, but we can unravel a surprising amount of fundamental biology this way. Various comparative studies have shown that many systems have stayed broadly the same in different organisms over almost inconceivably long periods. The epigenetic machinery of yeast and humans, for example, share more similarities than differences and yet the common ancestor for the two species lies about one billion years in the past
3
. So, epigenetic processes are clearly fairly fundamental things, and using model systems can at least point us in a helpful direction for understanding the human condition.
3
. So, epigenetic processes are clearly fairly fundamental things, and using model systems can at least point us in a helpful direction for understanding the human condition.
In terms of the specific question we’ve been looking at in this chapter – why genetically identical twins often don’t seem to be identical – the animal that has been most useful is our close mammalian relative, the mouse. The mouse and human lineages separated a mere 75 million or so years ago
4
. 99 per cent of the genes found in mice can also be detected in humans, although they aren’t generally absolutely identical between the two species.
4
. 99 per cent of the genes found in mice can also be detected in humans, although they aren’t generally absolutely identical between the two species.
Scientists have been able to create strains of mice in which all the individuals are genetically identical to each other. These have been incredibly useful for investigating the roles of non-genetic factors in creating variation between individuals. Instead of just two genetically identical individuals, it’s possible to create hundreds, or thousands. The way this is done would have made even the Ptolemy dynasty of ancient Egypt blush. Scientists mate a pair of mice who are brother and sister. Then they mate a brother and sister from the resulting litter. They then mate a brother and sister from their litter and so on. When this is repeated for over twenty generations of brother-sister matings, all the genetic variation gets bred out, throughout the genome. All mice of the same sex from the strain are genetically identical. In a refinement of this, scientists can take these genetically identical mice and introduce just one change into their DNA. They may use such genetic engineering to create mice which are identical except for just one region of DNA that the experimenters are most interested in.
A mouse of a different colour
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.
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
A
vy
, which stands for
a
gouti
v
iable
y
ellow
. In
A
vy
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
A
vy
version of the gene is dominant to the
a
version, which means that if one copy of the gene is
A
vy
and one is
a
, the
A
vy
will ‘overrule’
a
and the hairs will be yellow throughout their length. This is all summarised in
Figure 5.2
.
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
A
vy
, which stands for
a
gouti
v
iable
y
ellow
. In
A
vy
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
A
vy
version of the gene is dominant to the
a
version, which means that if one copy of the gene is
A
vy
and one is
a
, the
A
vy
will ‘overrule’
a
and the hairs will be yellow throughout their length. This is all summarised in
Figure 5.2
.
Scientists created a strain of mice that contained one copy of
A
vy
and one copy of
a
in every cell. The nomenclature for this is
A
vy
/a
. Since
A
vy
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.
A
vy
and one copy of
a
in every cell. The nomenclature for this is
A
vy
/a
. Since
A
vy
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 5.2
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.
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.
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.
agouti
gene.
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.
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.
Mouse geneticists knew how the yellow phenotype was caused in
A
vy
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
A
vy
mice are yellow rather than banded.
A
vy
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
A
vy
mice are yellow rather than banded.
That still doesn’t answer the question of why genetically identical
A
vy
/a
mice had variable coat colour. The answer to this has been shown to be due to epigenetics. In some
A
vy
/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
A
vy
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
.
A
vy
/a
mice had variable coat colour. The answer to this has been shown to be due to epigenetics. In some
A
vy
/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
A
vy
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
.
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.
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.
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.
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.
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.
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
5
. 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.
5
. 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
6
, 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.
6
, 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.
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