Gene expression tends to have what’s known as a stochastic component, by which we simply mean there’s a bit of random variability in the levels. If one of the chromosomes is expressing a slightly higher amount of one or more key factors, this may be sufficient to build a self-amplifying network of proteins and RNA molecules. Because the inequality in expression is essentially stochastic (due to random ‘noise’) the inactivation will also be essentially random across the hundred or so cells.
Here’s a possible way of visualising this. Imagine you get home late one evening and you have a hankering for melted cheese on two slices of toast. Just as you start to make this delicious supper, you realise you don’t have much cheese in the fridge. What do you do? Make two rounds where neither really contains enough cheese to be satisfying? Or concentrate all of it on one slice, so that you get the dairy hit you are craving? Most people probably choose the latter, and in a way this is what the pair of X chromosomes do during the phase when random inactivation is taking place in the embryo. Evolution has favoured a process whereby, rather than each have a sub-critical amount of a key factor, the factor migrates to the chromosome that has slightly more to begin with. The more you have, the more you get.
X inactivation is entirely dependent on ‘junk’ DNA, and really gives the lie to that terminology. The process is absolutely essential in female mammals for normal cell function and a healthy life. It also has consequences in various disease states. Full-blown Fragile X syndrome of mental retardation, which we encountered in Chapter 1, only affects boys. This is because the gene is carried on the X chromosome. Women have two X chromosomes. Even if one of their chromosomes carries the mutation, enough protein is produced from the other (normal) one to avoid the worst of the symptoms. But males only possess one X chromosome and one Y chromosome, which is very small and doesn’t carry many genes apart from the sex determining ones. Consequently, there is no compensatory normal Fragile X gene in males who carry a mutation on their X chromosome. If their sole X chromosome carries the Fragile X expansion, they can’t produce the protein and so they develop symptoms.
This is also true of a whole range of genetic disorders where the mutated gene is carried on the X chromosome. Boys are more likely to have symptoms of an X-linked genetic disorder than girls, because the boys can’t compensate for a faulty gene on their single X chromosome. Relevant medical conditions range from relatively mild issues such as red — green colour blindness to much more severe diseases. These include haemophilia B, the blood clotting disorder. Queen Victoria was a carrier of this condition and one of her sons (Leopold) was a sufferer and died at the age of 31 from a brain haemorrhage. Because at least two of Victoria’s daughters were also carriers, and the royal families of Europe tended to inter-marry, this mutation was passed on to various other dynasties, most famously the Romanov line in Russia.{126}
Although women carrying the mutation that causes haemophilia only produce 50 per cent of the normal amounts of the clotting factor, this is enough to protect them from symptoms. This is partly because this clotting factor is released from cells and circulates in the bloodstream, where it reaches high enough levels for protection against bleeds, no matter where they happen.
There are, however, circumstances wherein the presence of two X chromosomes in a woman doesn’t guarantee protection from an X-linked disorder. Rett Syndrome is a devastating neurological disease which presents in some ways as a really extreme form of autism. Baby girls appear to be perfectly healthy when born and they reach all the normal developmental milestones for the first six to eighteen months of life. But after that, they begin to regress. They lose any spoken language skills they have developed. They also develop repetitive hand actions, and lose purposeful ones such as pointing. The girls suffer serious learning disability for the rest of their lives.{127}
Rett Sydrome is caused by mutations in a protein-coding gene on the X chromosome.[16],{128} Affected females have one normal copy of this gene, and one version which is mutated and can’t produce functional protein. Assuming random X inactivation, we expect that on average half of the cells in the brain will express normal amounts of the protein, and there will be no expression from the other ones. It is obvious from the clinical presentation that there are severe problems if half the brain cells can’t express this protein.
Rett Syndome pretty much only affects girls. This is unusual for an X-linked disorder, where girls are usually carriers and boys are affected. This might make us wonder how boys are protected from the effects of a Rett mutation. But the reality is that they are not. The reason we almost never find boys who are affected by Rett Syndrome is because affected male embryos don’t develop properly and the foetuses don’t survive to term.
Scientists are trained to think about many things during our education and careers. But something we are rarely asked to ponder is the role played by luck. Even when we do, we usually dress it up with terms like ‘random fluctuations’ or ‘stochastic variation’. And that’s a shame, because sometimes ‘luck’ is probably a better description.
Duchenne muscular dystrophy is a severe muscle wasting disease, which we first met in Chapter 3. Boys with this disorder are fine initially but during childhood their muscles begin to degenerate, in a characteristic pattern. For example, in the legs the thigh muscles begin to waste first. The boys develop very large calves as their bodies try to compensate, but after a while these muscles also wither. The children are usually wheelchair users by their teens and the average life expectancy is only 27 years of age. The early mortality is caused to a large extent by the eventual destruction of the muscles involved in breathing.{129}
Duchenne muscular dystrophy is caused by a mutation in a gene on the X chromosome that encodes a large protein called dystrophin.{130} This protein seems to act as a sort of shock absorber in muscle cells. Because of the mutation, males can’t produce functional protein and this ultimately leads to destruction of the muscle. Carrier females will usually produce 50 per cent of the normal amounts of functional dystrophin protein. This is generally sufficient, because of an odd anatomical feature. As we develop, individual muscle cells fuse to create a large super-cell with lots of individual nuclei in it. This means each super-cell has access to multiple copies of the necessary genes, in all the different nuclei. So the muscles of carrier females overall contain enough dystrophin protein for normal activity, instead of one cell with enough, and one cell with none.
There was an unusual case of a woman with all the classic symptoms of Duchenne muscular dystrophy. This is very rare but there are ways we could predict this would happen. One possibility would be if her mother was a carrier and her dad was a Duchenne sufferer who survived long enough to father a child. If that was the case she would definitely have inherited a mutated gene from her father (because he would only possess one — affected — X chromosome). There would be a one in two chance that any egg produced by her carrier mother also contained a mutated dystrophin gene. If that scenario had occurred, neither of her X chromosomes would have a normal copy of the gene, and she wouldn’t be able to produce the necessary protein.
16
The gene is called MeCP2 and its role is to bind to epigenetically modified (methylated) DNA, where it interacts with other proteins and represses gene expression at the sites where it binds.