The Epigenetics Revolution

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 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.}

By using 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.

Women really are more complicated than men