The Epigenetics Revolution

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[94]. 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[95]. 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[96].

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:

Cells from the normal female would contain only one active X chromosome;

X inactivation would occur early in development;

The inactive X could be either maternally or paternally derived, and the inactivation would be random in any one cell;

X inactivation would be irreversible in a somatic cell and all its descendants.

These predictions have proven remarkably prescient[97][98]. So prescient, in fact, that many textbooks refer to X inactivation as Lyonisation. We’ll take the predictions one at a time:

Individual cells from a normal female do indeed only express genes from one X chromosome copy – the other copy is, effectively, shut down;

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);

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;

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.