The Epigenetics Revolution

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.

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’[119]. 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.

Name of syndrome

Karyotype i.e. set of chromosomes

Gender

Frequency of live births (known cases, probably under-estimated)

Common symptoms

Turner

45,X

Female

1 in 2,500

Short stature

Infertility

Webbed neck

Kidney abnormalities

Trisomy X

47,XXX

Female

1 in 1,000

Tall stature

Infertility

Unusual facial features

Poor muscle tone

Klinefelter’s

47,XXY

Male

1 in 1,000

Lanky build or rounded body type

Infertility

Language deficits

Table 9.1 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.