The Epigenetics Revolution (23 page)
Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
There is a clear biological basis to this, and perhaps unsurprisingly, it’s all down to genes and chromosomes. Humans have 23 pairs of chromosomes in their cells, and inherited one of each pair from each parent. Twenty-two of these pairs (imaginatively named chromosomes 1 to 22) are called autosomes and each member of a specific pair of autosomes looks very similar. By ‘looks’ we mean exactly that. At a certain stage in cell division the DNA in chromosomes becomes exceptionally tightly coiled up. If we use the right techniques we can actually see chromosomes down a microscope. These chromosomes can be photographed. In pre-digital days, clinical geneticists literally used to cut out the pictures of the individual chromosomes with a pair of scissors and rearrange them in pairs to create a nice orderly picture. These days the image processing can be carried out by a computer, but in either case the result is a picture of all the chromosomes in a cell. This picture is called a karyotype.
Figure 9.1
Karyotype of all the chromosomes in a male (top) and female (bottom) somatic cell. Note that the female cell contains two X chromosomes and no Y chromosome; the male cell contains one X chromosome and one Y chromosome. Note also the substantial difference in size between the X and Y chromosomes. Photos: Wessex Reg Genetics Centre/Wellcome Images.
Karyotype of all the chromosomes in a male (top) and female (bottom) somatic cell. Note that the female cell contains two X chromosomes and no Y chromosome; the male cell contains one X chromosome and one Y chromosome. Note also the substantial difference in size between the X and Y chromosomes. Photos: Wessex Reg Genetics Centre/Wellcome Images.
Karyotype analysis is how scientists originally discovered that there were three copies of chromosome 21 in the cells of people with Down’s syndrome. This is known as trisomy 21.
When we produce a human karyotype from a female, there are 23 pairs of identical chromosomes. But if we create a human karyotype from a male, the picture is different, as we can see in
Figure 9.1
. There are 22 obvious pairs – the autosomes – but there are two chromosomes left over that don’t look like each other at all. One is very large, one exceptionally small. These are called the sex chromosomes. The large one is called X, and the small one is called Y. The notation to describe the normal chromosome constitution of human males is 46, XY. Females are described as 46, XX because they don’t have a Y chromosome, and instead have two X chromosomes.
Figure 9.1
. There are 22 obvious pairs – the autosomes – but there are two chromosomes left over that don’t look like each other at all. One is very large, one exceptionally small. These are called the sex chromosomes. The large one is called X, and the small one is called Y. The notation to describe the normal chromosome constitution of human males is 46, XY. Females are described as 46, XX because they don’t have a Y chromosome, and instead have two X chromosomes.
The Y chromosome carries very few active genes. There are only between 40 and 50 protein-coding genes on the Y chromosome, of which about half are completely male-specific. The male-specific genes only occur on the Y chromosome, so females have no copies of these. Many of these genes are required for male-specific aspects of reproduction. The most important one in terms of sex determination is a gene called
SRY
. SRY proteins activate a testis-determining pathway in the embryo. This leads to production of testosterone, the archetypal ‘male’ hormone, which then masculinises the embryo.
SRY
. SRY proteins activate a testis-determining pathway in the embryo. This leads to production of testosterone, the archetypal ‘male’ hormone, which then masculinises the embryo.
Occasionally, individuals who phenotypically appear to be girls have the male 46, XY karyotype. In these cases the
SRY
gene is often inactive or deleted and consequently the foetus develops down the default female pathway
1
. Sometimes, the other scenario arises. Individuals who phenotypically appear to be boys can have the typically female karyotype of 46, XX. In these cases a tiny section of the Y chromosome containing the
SRY
gene has often transferred onto another chromosome during formation of sperm in the father. This is enough to drive masculinisation of the foetus
2
. The region of the Y chromosome that was transferred was too small to be detected by the karyotyping process.
SRY
gene is often inactive or deleted and consequently the foetus develops down the default female pathway
1
. Sometimes, the other scenario arises. Individuals who phenotypically appear to be boys can have the typically female karyotype of 46, XX. In these cases a tiny section of the Y chromosome containing the
SRY
gene has often transferred onto another chromosome during formation of sperm in the father. This is enough to drive masculinisation of the foetus
2
. The region of the Y chromosome that was transferred was too small to be detected by the karyotyping process.
The X chromosome is very different. The X chromosome is extremely large and carries about 1300 genes. A disproportionate number of these genes are involved in brain function. Many are also required for various stages in formation of the ovaries or the testes, and for other aspects of fertility in both males and females
3
.
3
.
Getting the dose right
So, about 1300 genes on the X chromosome. That creates an interesting problem. Females have two X chromosomes but males only have one. That means that for these 1300 genes on the X, females have two copies of each gene but males only have one. We might speculate from this that female cells would produce twice the amounts of proteins from these genes (referred to as X-linked genes) as males.
But our knowledge of disorders like Down’s syndrome makes this seem rather unlikely. Having three copies of chromosome 21 (instead of the normal two) results in Down’s syndrome, which is a major disorder in those individuals who are born with the condition. Trisomies of most other chromosomes are so severe that children are never born with these conditions, because the embryos cannot develop properly. For example, no child has ever been born who has three copies of chromosome 1 in all their cells. If the 50 per cent increase in gene expression from an autosome can cause such problems in trisomic conditions, how do we explain the X chromosome scenario? How is it possible for females to survive when they have twice as many X chromosome genes as males? Or, to put it the other way – why are males viable if they only have half as many X chromosome genes as females?
The answer is that expression of X-linked genes is actually pretty much the same in males and females, despite the different number of chromosomes, a phenomenon called dosage compensation. The XY system of sex determination doesn’t exist in other animal classes so X chromosome dosage compensation is limited to placental mammals.
In the early 1960s a British geneticist called Mary Lyon postulated how dosage compensation would occur at the X chromosome. These were her predictions:
1. Cells from the normal female would contain only one active X chromosome;
2. X inactivation would occur early in development;
3. The inactive X could be either maternally or paternally derived, and the inactivation would be random in any one cell;
4. X inactivation would be irreversible in a somatic cell and all its descendants.
These predictions have proven remarkably prescient
4
,
5
. So prescient, in fact, that many textbooks refer to X inactivation as Lyonisation. We’ll take the predictions one at a time:
4
,
5
. So prescient, in fact, that many textbooks refer to X inactivation as Lyonisation. We’ll take the predictions one at a time:
1. Individual cells from a normal female do indeed only express genes from one X chromosome copy – the other copy is, effectively, shut down;
2. X inactivation occurs early in development, at the stage when the pluripotent cells of the embryonic inner cell mass are beginning to differentiate into different lineages (near the top of Waddington’s epigenetic landscape);
3. On average, in 50 per cent of cells in a female the maternally derived X chromosome is shut down. In the other 50 per cent of cells it’s the chromosome inherited from Dad which gets inactivated;
4. Once a cell has switched off one of a pair of X chromosomes, that particular copy of the X stays switched off in all the daughter cells for the rest of that woman’s life, even if she lives to over 100 years of age.
The X chromosome isn’t inactivated by mutation; it keeps its DNA sequence entirely intact. X inactivation is the epigenetic phenomenon par excellence.
X inactivation has proven to be a remarkably fertile research field. Some of the mechanisms involved have turned out to have parallels in a number of other epigenetic and cellular processes. The consequences of X inactivation have important implications for a number of human disorders and for therapeutic cloning. Yet even now, 50 years on from Mary Lyon’s ground-breaking work, there remain a number of mysteries about how X inactivation actually takes place.
The more we ponder X inactivation, the more extraordinary it appears. For a start, the inactivation is only on the X chromosome, not on any of the autosomes, so the cell must have a way of distinguishing X chromosomes and autosomes from one another. Furthermore, the inactivation in the X doesn’t just affect one or a few genes, such as occurs in imprinting. No, in X inactivation, over 1,000 genes are turned off, for decades.
Think of a car manufacturer, with a factory in Japan and another in Germany. Imprinting is the equivalent of a few changes in specification for the different markets. The German factory may switch on the machine that installs the heater on the steering wheel and switch off the robot that inserts the automatic air freshener, whilst the Japanese factory does the opposite. X inactivation is the equivalent of shutting down and mothballing one factory, never to be re-opened unless the company is bought by a new manufacturer.
Random inactivation
The other major difference between X-inactivation and imprinting is that there is no parent-of-origin effect in X imprinting. In somatic cells, it doesn’t matter if an X chromosome was inherited from your mother or your father. Each has a 50 per cent chance of being inactivated. The reason why this is the case makes complete evolutionary sense.
Imprinting is about balancing out the competing demands of the maternal and paternal genomes, especially during development. The imprinting mechanisms that have evolved are specifically targeted at individual genes, or small clusters of genes, that particularly influence foetal growth. There are, after all, only 50–100 imprinted genes in the mammalian genome.
But X inactivation operates on a much greater scale. It’s a mechanism for switching off over 1,000 genes, en masse and permanently. A thousand genes is a lot, about 5 per cent of the total number of protein-coding genes, so there’s always a possibility that any given gene on an X chromosome may have a mutation.
Figure 9.2
compares the outcomes of imprinted X inactivation on the left, with random X inactivation on the right. For clarity, the diagram just exemplifies a mutation in a paternally inherited gene, with imprinted inactivation of the maternally derived X chromosome.
Figure 9.2
compares the outcomes of imprinted X inactivation on the left, with random X inactivation on the right. For clarity, the diagram just exemplifies a mutation in a paternally inherited gene, with imprinted inactivation of the maternally derived X chromosome.
By using
random
X inactivation, cells are able to minimise the effects of mutations in X-linked genes.
random
X inactivation, cells are able to minimise the effects of mutations in X-linked genes.
It’s important to bear in mind that the inactive X really is inactive. Almost all the genes are permanently shut off and this inactivation cannot normally be broken. When we refer to the active X chromosome, we are using slightly ambiguous shorthand. It doesn’t mean that every gene on that X is active all the time in every cell. Rather, the genes have the potential to be active. They are subject to all the normal epigenetic modifications and controls on gene expression, so that selected genes are switched on or off in a controlled manner, in response to developmental cues or environmental signals.
Figure 9.2
Each circle represents a female cell, containing two X chromosomes. The X chromosome inherited from the mother is indicated by the female symbol. The X chromosome inherited from the father is indicated by the male symbol, and contains a mutation, denoted by the white square notch. The left hand side of the diagram demonstrates that imprinted inactivation of the maternally derived X chromosome would result in all cells of the body expressing only the X chromosome carrying the mutation, which was inherited from the father. On the right hand side, the X chromosomes are randomly inactivated, independent of their parent-of-origin. As a result, on average, half of the somatic cells will express the normal version of the X chromosome. This makes random X inactivation a less risky evolutionary strategy than imprinted X inactivation.
Each circle represents a female cell, containing two X chromosomes. The X chromosome inherited from the mother is indicated by the female symbol. The X chromosome inherited from the father is indicated by the male symbol, and contains a mutation, denoted by the white square notch. The left hand side of the diagram demonstrates that imprinted inactivation of the maternally derived X chromosome would result in all cells of the body expressing only the X chromosome carrying the mutation, which was inherited from the father. On the right hand side, the X chromosomes are randomly inactivated, independent of their parent-of-origin. As a result, on average, half of the somatic cells will express the normal version of the X chromosome. This makes random X inactivation a less risky evolutionary strategy than imprinted X inactivation.
Women really are more complicated than men
One interesting consequence of X inactivation is that (epigenetically) females are more complicated than males. Males only have one X chromosome in their cells, so they don’t carry out X inactivation. But females randomly inactivate an X chromosome in all their cells. Consequently, at a very fundamental level, all cells in a female body can be split into two camps depending on which X chromosome they inactivated. The expression for this is that females are epigenetic mosaics.
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