The Epigenetics Revolution (26 page)
Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
Duchenne muscular dystrophy is a severe muscle wasting disease caused by mutations in the X-linked
DYSTROPHIN
gene. This is a large gene that encodes a big protein which acts as an essential shock absorber in muscle fibres. Boys carrying certain mutations in
DYSTROPHIN
suffer major muscle loss that usually results in death in the teenage years. Females with the same mutation are usually symptom-free. The reason for this is that muscle has a very unusual structure. It is called a syncytial tissue, which means that lots of individual cells fuse and operate almost like one giant cell, but with lots of discrete nuclei. This is why most females with a
DYSTROPHIN
mutation are symptom-free. There is enough normal DYSTROPHIN protein encoded by the nuclei that switched off the mutated
DYSTROPHIN
gene to keep this syncytial tissue functioning healthily
24
.
DYSTROPHIN
gene. This is a large gene that encodes a big protein which acts as an essential shock absorber in muscle fibres. Boys carrying certain mutations in
DYSTROPHIN
suffer major muscle loss that usually results in death in the teenage years. Females with the same mutation are usually symptom-free. The reason for this is that muscle has a very unusual structure. It is called a syncytial tissue, which means that lots of individual cells fuse and operate almost like one giant cell, but with lots of discrete nuclei. This is why most females with a
DYSTROPHIN
mutation are symptom-free. There is enough normal DYSTROPHIN protein encoded by the nuclei that switched off the mutated
DYSTROPHIN
gene to keep this syncytial tissue functioning healthily
24
.
There are occasional cases where this system breaks down. There was a case of female monozygotic twins where one twin was severely affected by Duchenne muscular dystrophy and the other was healthy
25
. In the affected twin, the X inactivation had become skewed. Early in tissue differentiation the majority of her cells that would give rise to muscle happened, by ill chance, to switch off the X chromosome carrying the normal copy of the
DYSTROPHIN
gene. Thus, most of the muscle tissue in this woman only expressed the mutated version of DYSTROPHIN, and she developed severe muscle wasting. This could be considered the ultimate demonstration of the power of a random epigenetic event. Two identical individuals, each with two apparently identical X chromosomes, had a completely discordant phenotype, because of a shift in the epigenetic balance of power.
25
. In the affected twin, the X inactivation had become skewed. Early in tissue differentiation the majority of her cells that would give rise to muscle happened, by ill chance, to switch off the X chromosome carrying the normal copy of the
DYSTROPHIN
gene. Thus, most of the muscle tissue in this woman only expressed the mutated version of DYSTROPHIN, and she developed severe muscle wasting. This could be considered the ultimate demonstration of the power of a random epigenetic event. Two identical individuals, each with two apparently identical X chromosomes, had a completely discordant phenotype, because of a shift in the epigenetic balance of power.
Sometimes, however, it is essential that
individual cells
express the correct amount of a protein. You may have noticed in
Chapter 4
that Rett syndrome only affected girls. One might hypothesise that boys are somehow very resistant to the effects of the
MeCP2
mutation, but actually the opposite is true.
MeCP2
is carried on the X chromosome so a male foetus that inherits a Rett syndrome mutation in this gene has no means of expressing normal MeCP2 protein. A complete lack of normal MeCP2 expression is generally lethal in early development, and that’s why very few boys are born with Rett syndrome. Girls have two copies of the
MeCP2
gene, one on each X chromosome. In any given cell, there is a 50 per cent chance that the cell will inactivate the X that carries the unmutated
MeCP2
gene and that the cell will not express normal MeCP2 protein. Although a female foetus can develop, there are ultimately major effects on normal post-natal brain development and function when a substantial number of neurons lack MeCP2 protein.
individual cells
express the correct amount of a protein. You may have noticed in
Chapter 4
that Rett syndrome only affected girls. One might hypothesise that boys are somehow very resistant to the effects of the
MeCP2
mutation, but actually the opposite is true.
MeCP2
is carried on the X chromosome so a male foetus that inherits a Rett syndrome mutation in this gene has no means of expressing normal MeCP2 protein. A complete lack of normal MeCP2 expression is generally lethal in early development, and that’s why very few boys are born with Rett syndrome. Girls have two copies of the
MeCP2
gene, one on each X chromosome. In any given cell, there is a 50 per cent chance that the cell will inactivate the X that carries the unmutated
MeCP2
gene and that the cell will not express normal MeCP2 protein. Although a female foetus can develop, there are ultimately major effects on normal post-natal brain development and function when a substantial number of neurons lack MeCP2 protein.
One, two, many
There are other issues that can develop around the X chromosome. One of the questions we need to answer about X inactivation, is how good mammalian cells are at counting. In 2004 Peter Gordon of Columbia University in New York reported on his studies on the Piraha tribe in an isolated region of Brazil. This tribe had numbers for one and two. Everything beyond two was described by a word roughly equating to ‘many’
26
. Are our cells the same, or can they count above two? If a nucleus contains more than two X chromosomes, can the X inactivation machinery recognise this, and deal with the consequences? Various studies have shown that it can. Essentially, no matter how many X chromosomes (or more strictly speaking X Inactivation Centres) are present in a nucleus, the cell can count them and then inactivate multiple X chromosomes until there is only one remaining active.
26
. Are our cells the same, or can they count above two? If a nucleus contains more than two X chromosomes, can the X inactivation machinery recognise this, and deal with the consequences? Various studies have shown that it can. Essentially, no matter how many X chromosomes (or more strictly speaking X Inactivation Centres) are present in a nucleus, the cell can count them and then inactivate multiple X chromosomes until there is only one remaining active.
This is the reason why abnormal numbers of X chromosomes are relatively frequent in humans, in contrast to abnormalities in the number of autosomes. The commonest examples are shown in
Table 9.1
.
Table 9.1
.
Table 9.1
Summary of the major characteristics of the commonest abnormalities in sex chromosome number in humans.
Summary of the major characteristics of the commonest abnormalities in sex chromosome number in humans.
The infertility that is a feature of all these disorders is in part due to problems when creating eggs or sperm, where it’s important that chromosomes line up in their pairs. If there is an uneven total number of sex chromosomes this stage goes wrong and formation of gametes is severely compromised.
Leaving aside the infertility, there are two obvious conclusions we can draw from this table. The first is that the phenotypes are all relatively mild compared with, for example, trisomy of chromosome 21 (Down’s syndrome). This suggests that cells can tolerate having too many or too few copies of the X chromosome much better than having extra copies of an autosome. But the other obvious conclusion is that an abnormal number of X chromosomes does indeed have some effects on phenotype.
Why should this be? After all, X inactivation ensures that no matter how many X chromosomes are present, all bar one get inactivated early in development. But if this was the end of the story there would be no difference in phenotype between 45, X females compared with 47, XXX females or with the normal 46, XX female constitution. Similarly, males with the normal 46, XY karyotype should be phenotypically identical to males with the 47, XXY karyotype. In all of these cases there should be only one active X chromosome in the cells.
One thought as to why people with these karyotypes were clinically different was that maybe X inactivation is a bit inefficient in some cells, but this doesn’t seem to be the case. X inactivation is established very early in development and is the most stable of all epigenetic processes. An alternative explanation was required.
The answer has its origin about 150 million years ago, when the XY system of sex determination in placental mammals first developed. The X and Y chromosomes are probably descendants of autosomes. The Y chromosome has changed dramatically, the X chromosome much less so
27
. However, both retain shadows of their autosomal past. There are regions on both the X and the Y called pseudoautosomal regions. The genes in these regions are found on both the X and the Y chromosome, just in the same way as pairs of autosomes have the same genes in the same positions, one inherited from each parent.
27
. However, both retain shadows of their autosomal past. There are regions on both the X and the Y called pseudoautosomal regions. The genes in these regions are found on both the X and the Y chromosome, just in the same way as pairs of autosomes have the same genes in the same positions, one inherited from each parent.
When an X chromosome inactivates, these pseudoautosomal regions are spared. This means that, unlike most X-linked genes, those in the pseudoautosomal regions don’t get switched off. Consequently, normal cells potentially express two copies of these genes in all cells. The two copies are expressed either from the two X chromosomes in a normal female or from the X and the Y in a normal male.
But in Turner’s syndrome, the affected female only has one X chromosome, so she expresses only one copy of the genes in the pseudoautosomal region, half as much as normal. In Trisomy X, on the other hand, there are three copies of the genes in the pseudoautosomal regions. As a result, the cells in an affected region will produce proteins from these genes at 50 per cent above the normal level.
One of the genes in the X chromosome pseudoautosomal regions is called
SHOX
. Patients with mutations in this gene have short stature. It is likely that this is also why patients with Turner’s syndrome tend to be short – they don’t produce enough SHOX protein in their cells. By contrast, patients with Trisomy X are likely to produce 50 per cent more SHOX protein than normal, which is probably why they tend to be tall
28
.
SHOX
. Patients with mutations in this gene have short stature. It is likely that this is also why patients with Turner’s syndrome tend to be short – they don’t produce enough SHOX protein in their cells. By contrast, patients with Trisomy X are likely to produce 50 per cent more SHOX protein than normal, which is probably why they tend to be tall
28
.
It’s not just humans who have trisomies of the sex chromosomes. One day you may be happily amazing your friends with your confident statement that their tortoiseshell cat is female when they deflate you by telling you that their pet has been sexed by the vet and is actually a Tom. At this point, smile smugly and then say ‘Oh, in that case he’s karyotypically abnormal. He has an XXY karyotype, rather than XY’. And if you’re feeling particularly mean, you can tell them that Tom is infertile. That should shut them up.
Science commits suicide when it adopts a creed.
Thomas Henry Huxley
One of the most influential books on the philosophy of science is Thomas Kuhn’s
The Structure of Scientific Revolutions
, published in 1962. One of the claims in Kuhn’s book is that science does not proceed in an orderly, linear and polite fashion, with all new findings viewed in a completely unbiased way. Instead, there is a prevailing theory which dominates a field. When new conflicting data are generated, the theory doesn’t immediately topple. It may get tweaked slightly, but scientists can and often do continue to believe in a theory long after there is sufficient evidence to discount it.
The Structure of Scientific Revolutions
, published in 1962. One of the claims in Kuhn’s book is that science does not proceed in an orderly, linear and polite fashion, with all new findings viewed in a completely unbiased way. Instead, there is a prevailing theory which dominates a field. When new conflicting data are generated, the theory doesn’t immediately topple. It may get tweaked slightly, but scientists can and often do continue to believe in a theory long after there is sufficient evidence to discount it.
We can visualise the theory as a shed, and the new conflicting piece of data as an oddly shaped bit of builder’s rubble that has been cemented onto the roof. Now, we can probably continue cementing bits of rubble onto the roof for quite some time, but eventually there will come a point when the shed collapses under the sheer weight of odd bits of masonry. In science, this is when a new theory develops, and all those bits of masonry are used to build the foundations of a new shed.
Kuhn described this collapse-and-rebuild as the paradigm shift, introducing the phrase that has now become such a cliché in the high-end media world. The paradigm shift isn’t just based on pure rationality. It involves emotional and sociological changes in the psyches of the upholders of the prevailing theory. Many years before Thomas Kuhn’s book, the great German scientist Max Planck, winner of the 1918 Nobel Prize for Physics, put this rather more succinctly when he wrote that, ‘Scientific theories don’t change because old scientists change their minds; they change because old scientists die
1
.’
1
.’
We are in the middle of just such a paradigm shift in biology.
In 1965, the Nobel Prize in Physiology or Medicine was awarded to François Jacob, André Lwoff and Jacques Monod ‘for their discoveries concerning genetic control of enzyme and virus synthesis’. Included in this work was the discovery of messenger RNA (mRNA), which we first met in
Chapter 3
. mRNA is the relatively short-lived molecule that transfers the information from our chromosomal DNA and acts as the intermediate template for the production of proteins.
Chapter 3
. mRNA is the relatively short-lived molecule that transfers the information from our chromosomal DNA and acts as the intermediate template for the production of proteins.
We’ve known for many years that there are some other classes of RNA in our cells, specifically molecules called transfer RNA (tRNA) and ribosomal RNA (rRNA). tRNAs are small RNA molecules that can hold a specific amino acid at one end. When an mRNA molecule is read to form a protein, a tRNA carries its amino acid to the correct place on the growing protein chain. This takes place at large structures in the cytoplasm of a cell called ribosomes. The ribosomal RNA is a major component of ribosomes, where it acts like a giant scaffold to hold various other RNA and protein molecules in position. The world of RNA therefore seemed quite straightforward. There were structural RNAs (the tRNA and rRNA) and there was messenger RNA.
For decades, the stars of the molecular biology catwalk were DNA (the underlying code) and proteins (the functional, can-do molecules of the cell). RNA was relegated to being a relatively uninteresting intermediate molecule, carrying information from a blueprint to the workers on the factory floor.
Everyone working in molecular biology accepts that proteins are immensely important. They carry out a huge range of functions that enable life to happen. Therefore, the genes that encode proteins are also incredibly important. Even small changes to these protein-coding genes can result in devastating effects, such as the mutations that cause haemophilia or cystic fibrosis.
But this world view has potentially left the scientific community a bit blinkered. The fact that proteins, and therefore by extension protein-coding genes, are vitally important should not imply that everything else in the genome is unimportant. Yet this is the theoretical construct that has applied for decades now. That’s actually quite odd, because we’ve had access for many years to data that show that proteins can’t be the whole story.
Why we don’t throw away our junk
Scientists have recognised for some time that the blueprint is edited by cells before it is delivered to the workers. This is because of introns, which we met in
Chapter 3
. They are the sequences that are copied from DNA into mRNA, but then spliced out before the message is translated into a protein sequence by the ribosomes. Introns were first identified in 1975
2
and the Nobel Prize for their discovery was awarded to Richard Roberts and Phillip Sharp in 1993.
Chapter 3
. They are the sequences that are copied from DNA into mRNA, but then spliced out before the message is translated into a protein sequence by the ribosomes. Introns were first identified in 1975
2
and the Nobel Prize for their discovery was awarded to Richard Roberts and Phillip Sharp in 1993.
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